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Papers: 18 Jul 2020 - 24 Jul 2020

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The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises.

The current International Association for the Study of Pain (IASP) definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a reevaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain, to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year.

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Maturational Changes in Mouse Cutaneous Touch and Piezo2-Mediated Mechanotransduction.

The age of studied animals has a profound impact on experimental outcomes in animal-based research. In mice, age influences molecular, morphological, physiological, and behavioral parameters, particularly during rapid postnatal growth and maturation until adulthood (at 12 weeks of age). Despite this knowledge, most biomedical studies use a wide-spanning age range from 4 to 12 weeks, raising concerns about reproducibility and potential masking of relevant age differences. Here, using mouse behavior and electrophysiology in cultured dorsal root ganglia (DRG), we reveal a decline in behavioral cutaneous touch sensitivity and Piezo2-mediated mechanotransduction in vitro during mouse maturation but not thereafter. In addition, we identify distinct transcript changes in individual Piezo2-expressing mechanosensitive DRG neurons by combining electrophysiology with single-cell RNA sequencing (patch-seq). Taken together, our study emphasizes the need for accurate age matching and uncovers hitherto unknown maturational plasticity in cutaneous touch at the level of behavior, mechanotransduction, and transcripts.

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Human Labor Pain Is Influenced by the Voltage-Gated Potassium Channel K6.4 Subunit.

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant K6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (K6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing K6.4-Met419, the voltage dependence of inactivation for K2.1 is more depolarized compared with neurons overexpressing K6.4. Finally, K6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K6.4 can influence human labor pain by modulating the excitability of uterine nociceptors.

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Orchestrating Opiate-Associated Memories in Thalamic Circuits.

Disrupting memories that associate environmental cues with drug experiences holds promise for treating addiction, yet accessing the distributed neural network that stores such memories is challenging. Here, we show that the paraventricular nucleus of the thalamus (PVT) orchestrates the acquisition and maintenance of opiate-associated memories via projections to the central nucleus of the amygdala (CeA) and nucleus accumbens (NAc). PVT→CeA activity associates morphine reward to the environment, whereas transient inhibition of the PVT→NAc pathway during retrieval causes enduring protection against opiate-primed relapse. Using brain-wide activity mapping, we revealed distributed network activities that are altered in non-relapsing mice, which enabled us to find that activating the downstream NAc→lateral hypothalamus (LH) pathway also prevents relapse. These findings establish the PVT as a key node in the opiate-associated memory network and demonstrate the potential of targeting the PVT→NAc→LH pathway for treating opioid addiction.

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The Parabrachial Nucleus Directly Channels Spinal Nociceptive Signals to the Intralaminar Thalamic Nuclei, but Not the Amygdala.

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.

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Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice.

Despite their ubiquitous presence, placebos and placebo effects retain an ambiguous and unsettling presence in biomedicine. Specifically focused on chronic pain, this review examines the effect of placebo treatment under three distinct frameworks: double blind, deception, and open label honestly prescribed. These specific conditions do not necessarily differentially modify placebo outcomes. Psychological, clinical, and neurological theories of placebo effects are scrutinized. In chronic pain, conscious expectation does not reliably predict placebo effects. A supportive patient-physician relationship may enhance placebo effects. This review highlights "predictive coding" and "bayesian brain" as emerging models derived from computational neurobiology that offer a unified framework to explain the heterogeneous evidence on placebos. These models invert the dogma of the brain as a stimulus driven organ to one in which perception relies heavily on learnt, top down, cortical predictions to infer the source of incoming sensory data. In predictive coding/bayesian brain, both chronic pain (significantly modulated by central sensitization) and its alleviation with placebo treatment are explicated as centrally encoded, mostly non-conscious, bayesian biases. The review then evaluates seven ways in which placebos are used in clinical practice and research and their bioethical implications. In this way, it shows that placebo effects are evidence based, clinically relevant, and potentially ethical tools for relieving chronic pain.

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The social threats of COVID-19 for people with chronic pain.

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Nonsteroidal Anti-inflammatory Drugs vs Cognitive Behavioral Therapy for Arthritis Pain: A Randomized Withdrawal Trial.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for knee osteoarthritis. However, they are associated with uncertain long-term clinical benefit and significant toxic effects.

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Molecular, circuit, and anatomical changes in the prefrontal cortex in chronic pain.

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Considering the potential for an increase in chronic pain after the COVID-19 pandemic.

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The mindful migraine: does mindfulness-based stress reduction relieve episodic migraine?

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BCI training to move a virtual hand reduces phantom limb pain: A randomized crossover trial.

To determine whether training with a brain-computer interface (BCI) to control an image of a phantom hand, which moves based on cortical currents estimated from magnetoencephalographic signals, reduces phantom limb pain.

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Transcribed ultraconserved noncoding RNA uc.153 is a new player in neuropathic pain.

Transcribed ultraconserved regions are a novel class of long noncoding RNAs and are completely conserved in humans, rats, and mice. Transcribed ultraconserved regions have been implicated in diverse biological processes; however, very little is currently known about their role in pain modulation. Here, we found that the level of the spinal transcribed ultraconserved region uc.153 was significantly increased in a mouse model of sciatic nerve chronic constriction injury (CCI)-induced chronic neuropathic pain. The knockdown of spinal uc.153 prevented and reversed chronic constriction injury-induced pain behaviours and spinal neuronal sensitization. By contrast, the overexpression of spinal uc.153 produced pain behaviours and neuronal sensitization in naive mice. Moreover, we found that uc.153 participates in the regulation of neuropathic pain by negatively modulating the processing of pre-miR-182-5p. Collectively, our findings reveal an important role for uc.153 in pain modulation and provide a novel drug target for neuropathic pain therapy.

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Regulatory T cells counteract neuropathic pain through inhibition of the Th1 response at the site of peripheral nerve injury.

The inflammatory/immune response at the site of peripheral nerve injury participates in the pathophysiology of neuropathic pain. Nevertheless, little is known about the local regulatory mechanisms underlying peripheral nerve injury that counteracts the development of pain. Here, we investigated the contribution of regulatory T (Treg) cells to the development of neuropathic pain by using a partial sciatic nerve ligation model in mice. We showed that Treg cells infiltrate and proliferate in the site of peripheral nerve injury. Local Treg cells suppressed the development of neuropathic pain mainly through the inhibition of the CD4 Th1 response. Treg cells also indirectly reduced neuronal damage and neuroinflammation at the level of the sensory ganglia. Finally, we identified IL-10 signaling as an intrinsic mechanism by which Treg cells counteract neuropathic pain development. These results revealed Treg cells as important inhibitory modulators of the immune response at the site of peripheral nerve injury that restrains the development of neuropathic pain. In conclusion, the boosting of Treg cell function/activity might be explored as a possible interventional approach to reduce neuropathic pain development after peripheral nerve damage.

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Psychological and psychosocial predictors of chronic post-surgical pain: a systematic review and meta-analysis.

Knowledge about psychological and psychosocial predictors of chronic post-surgical pain is important to identify patients at risk for poor outcomes. The objective of this systematic review with meta-analysis was to assess the effect of such predictors. A comprehensive search of the available literature on this topic was performed using the electronic databases PubMed, Scopus, Embase and PsycInfo. Estimates of the effect of each predictor were extracted and both a narrative and a quantitative synthesis of these estimates was performed. Multiple imputation was employed to take into account the effect of non-significant estimates in case they were not reported by original studies. From a sample of 8322 records, 83 articles were included in the narrative synthesis and 41 studies were employed to perform the meta-analyses. The narrative synthesis showed that evidence about the effect of psychological predictors is heterogeneous, with few expected predictors, such as optimism, mental health and surgical fear, consistently associated with chronic post-surgical pain. In contrast, the meta-analyses showed that state anxiety, trait anxiety, mental health, depression, catastrophizing and, to a lesser extent, kinesiophobia and self-efficacy, have a weak but significant association with chronic post-surgical pain. In conclusion, this study showed that psychological predictors have a significant association with chronic post-surgical pain and that state anxiety is the most explicative one.

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Machine learning suggests sleep as a core factor in chronic pain.

Patients with chronic pain have complex pain profiles and associated problems. Subgroup analysis can help identify key problems. We used a data-based approach to define pain phenotypes and their most relevant associated problems in 320 patients undergoing tertiary pain management. Unsupervised machine learning analysis of parameters "pain intensity", "number of pain areas", "pain duration", "activity pain interference" and "affective pain interference", implemented as emergent self-organizing maps, identified three patient phenotype clusters. Supervised analyses, implemented as different types of decision rules, identified "affective pain interference" and the "number of pain areas" as most relevant for cluster assignment. These appeared 698 and 637 times, respectively, in 1000 cross-validation runs among the most relevant characteristics in an item categorization approach in a computed ABC analysis. Cluster assignment was achieved with a median balanced accuracy of 79.9%, a sensitivity of 74.1%, and a specificity of 87.7%. In addition, among 59 demographic, pain etiology, comorbidity, lifestyle, psychological, and treatment-related variables, sleep problems appeared 638 and 439 times among the most important characteristics in 1000 cross-validation runs where patients were assigned to the two extreme pain phenotype clusters. Also important were the parameters "fear of pain", "self-rated poor health", and "systolic blood pressure". Decision trees trained with this information assigned patients to the extreme pain-phenotype with an accuracy of 67%. Machine learning suggested sleep problems as key factors in the most difficult pain presentations, therefore deserving priority in the treatment of chronic pain.

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Identifying oxidized lipid mediators as prognostic biomarkers of chronic post-traumatic headache.

Chronic Post Traumatic Headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic non-traumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use. Pain reduction was associated with alterations in oxylipins derived from n-3 and n-6 fatty acids, suggesting that oxylipins could potentially mediate clinical pain reduction. The objective of the present study was to investigate whether circulating oxylipins measured in the acute setting following TBI, could serve as prognostic biomarkers for developing chronic PTH. Participants enrolled in the Traumatic Head Injury Neuroimaging Classification Protocol provided serum within 3 days of TBI and were followed up at 90 days post-injury with a neurobehavioral symptom inventory (NSI) and satisfaction with-life-survey (SWLS). Liquid chromatography tandem mass spectrometry methods profiled 39 oxylipins derived from n-3 docosaheaxaenoic acid (DHA), and n-6 arachidonic acid (AA) and linoleic acid (LA).Statistical analyses assessed the association of oxylipins with headache severity (primary outcome, measured by headache question on NSI) as well as associations between oxylipins and total NSI or SWLS scores. Among oxylipins, 4-hydroxy-DHA and 19,20-epoxy-docosapentaenoate (DHA derivatives) were inversely associated with headache severity, and 11-hydroxy-9-epoxy-octadecenoate (an LA derivative) was positively associated with headache severity. These findings support a potential for DHA-derived oxylipins as prognostic biomarkers for development of chronic PTH.

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Localized sympathectomy reduces peripheral nerve regeneration and pain behaviors in 2 rat neuropathic pain models.

Previous studies have shown that the peripheral nerve regeneration process is linked to pain in several neuropathic pain models. Other studies show that sympathetic blockade may relieve pain in some pain models and clinical conditions. This study examined reduction in peripheral nerve regeneration as one possible mechanism for relief of neuropathic pain by sympathetic blockade. A "microsympathectomy," consisting of cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, reduced mechanical hypersensitivity in 2 different rat neuropathic pain models. In the spinal nerve ligation model, in which some functional regeneration and reinnervation of the ligated spinal nerve can be observed, microsympathectomy reduced functional and anatomical measures of regeneration as well as expression of growth-associated protein 43 (GAP43), a regeneration-related protein. In the spared nerve injury model, in which functional reinnervation is not possible and the futile regeneration process results in formation of a neuroma, microsympathectomy reduced neuroma formation and GAP43 expression. In both models, microsympathectomy reduced macrophage density in the sensory ganglia and peripheral nerve. This corroborates previous work showing that sympathetic nerves may locally affect immune function. The results further highlight the challenge of improving pain in neuropathic conditions without inhibiting peripheral nerve regeneration that might otherwise be possible and desired.

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Postnatal maturation of spinal dynorphin circuits and their role in somatosensation.

Inhibitory interneurons in the adult spinal dorsal horn (DH) can be neurochemically classified into subpopulations that regulate distinct somatosensory modalities. Although inhibitory networks in the rodent DH undergo dramatic remodeling over the first weeks of life, little is known about the maturation of identified classes of GABAergic interneurons, or whether their role in somatosensation shifts during development. We investigated age-dependent changes in the connectivity and function of prodynorphin (DYN)-lineage neurons in the mouse DH that suppress mechanosensation and itch during adulthood. In vitro patch clamp recordings revealed a developmental increase in primary afferent drive to DYN interneurons and a transition from exclusive C-fiber monosynaptic input to mixed A-fiber and C-fiber innervation. Although most adult DYN interneurons exhibited tonic firing as expected from their inhibitory phenotype, neonatal and adolescent DYN cells were predominantly classified as phasic or single-spiking. Importantly, we also found that most of the inhibitory presynaptic terminals contacting lamina I spinoparabrachial projection neurons (PNs) originate from DYN neurons. Furthermore, inhibitory synaptic input from DYN interneurons onto PNs was weaker during the neonatal period, likely reflecting a lower number of GABAergic terminals and a reduced probability of GABA release compared to adults. Finally, spinal DYN interneurons attenuated mechanical sensitivity throughout development, but this population dampened acute nonhistaminergic itch only during adulthood. Collectively, these findings suggest that the spinal "gates" controlling sensory transmission to the brain may emerge in a modality-selective manner during early life due to the postnatal tuning of inhibitory synaptic circuits within the DH.

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The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli.

Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurons innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 after surgery, designated "late"-stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs sham-operated, day 14; P < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, dorsal root ganglia in vivo imaging of genetically encoded calcium indicators and Markov Cluster Analysis were used to analyse 1748 late-stage CIBP (n = 10) and 757 sham-operated (n = 9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour, (1) 3 times as many sensory afferents responded (repeated-measures analysis of variance: P < 0.0001 [vs sham]); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs sham): P < 0.0001); and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats, and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.

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Placebo hypoalgesia: racial differences.

No large-cohort studies that examine potential racial effects on placebo hypoalgesic effects exist. To fill this void, we studied placebo effects in healthy and chronic pain participants self-identified as either African American/black (AA/black) or white. We enrolled 372 study participants, 186 with a diagnosis of temporomandibular disorder (TMD) and 186 race-, sex-, and age-matched healthy participants to participate in a placebo experiment. Using a well-established paradigm of classical conditioning with verbal suggestions, each individual pain sensitivity was measured to calibrate the temperatures for high- and low-pain stimuli in the conditioning protocol. These 2 temperatures were then paired with a red and green screen, respectively, and participants were told that the analgesic intervention would activate during the green screens to reduce pain. Participants then rated the painfulness of each stimulus on a visual analog scale ranging from 0 to 100. Racial influences were tested on conditioning strength, reinforced expectations, and placebo hypoalgesia. We found that white participants reported greater conditioning effects, reinforced relief expectations, and placebo effects when compared with their AA/black counterparts. Racial effects on placebo were observed in TMD, although negligible, short-lasting, and mediated by conditioning strength. Secondary analyses on the effect of experimenter-participant race and sex concordance indicated that same experimenter-participant race induced greater placebo hypoalgesia in TMDs while different sex induced greater placebo hypoalgesia in healthy participants. This is the first and largest study to analyze racial effects on placebo hypoalgesia and has implications for both clinical research and treatment outcomes.

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Sex differences in the development of anxiodepressive-like behavior of mice subjected to sciatic nerve cuffing.

We investigated the contribution of nucleus locus ceruleus (LC) to the development of pain-associated affective behavior. Mice of both sexes were subjected to sciatic nerve cuffing, a model of peripheral nerve injury, and monitored for 45 days. Although the thermal and mechanical thresholds were equally decreased in both males and females, only the male mice developed anxiodepressive-like behavior, which was complemented by suppressed hippocampal neurogenesis. Furthermore, the LC activity was lower in males when compared with females subjected to sciatic cuffing. Next, we used a chemogenetic approach to modulate the activity of LC projections to the dentate gyrus of the hippocampus in females without cuffs and in males with sciatic cuffs. Sustained inhibition of the LC projections to the dentate gyrus for 15 days induced anxiodepressive-like behavior and reduced the hippocampal neurogenesis in females. Activation of the LC projections to the dentate gyrus for 15 days prevented the development of anxiodepressive-like behavior and increased the hippocampal neurogenesis in males with cuffs. In sum, we demonstrated that the LC projections to the hippocampus link the sensory to the affective component of neuropathic injury and that the female mice are able to dissociate the nociception from affect by maintaining robust LC activity. The work provides evidence that sex differences in LC response to pain determine the sex differences in the development of pain phenotype.

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Enhanced mindfulness-based stress reduction in episodic migraine: a randomized clinical trial with magnetic resonance imaging outcomes.

We aimed to evaluate the efficacy of an enhanced mindfulness-based stress reduction (MBSR+) vs stress management for headache (SMH). We performed a randomized, assessor-blind, clinical trial of 98 adults with episodic migraine recruited at a single academic center comparing MBSR+ (n = 50) with SMH (n = 48). MBSR+ and SMH were delivered weekly by group for 8 weeks, then biweekly for another 8 weeks. The primary clinical outcome was reduction in headache days from baseline to 20 weeks. Magnetic resonance imaging (MRI) outcomes included activity of left dorsolateral prefrontal cortex (DLPFC) and cognitive task network during cognitive challenge, resting state connectivity of right dorsal anterior insula to DLPFC and cognitive task network, and gray matter volume of DLPFC, dorsal anterior insula, and anterior midcingulate. Secondary outcomes were headache-related disability, pain severity, response to treatment, migraine days, and MRI whole-brain analyses. Reduction in headache days from baseline to 20 weeks was greater for MBSR+ (7.8 [95% CI, 6.9-8.8] to 4.6 [95% CI, 3.7-5.6]) than for SMH (7.7 [95% CI 6.7-8.7] to 6.0 [95% CI, 4.9-7.0]) (P = 0.04). Fifty-two percent of the MBSR+ group showed a response to treatment (50% reduction in headache days) compared with 23% in the SMH group (P = 0.004). Reduction in headache-related disability was greater for MBSR+ (59.6 [95% CI, 57.9-61.3] to 54.6 [95% CI, 52.9-56.4]) than SMH (59.6 [95% CI, 57.7-61.5] to 57.5 [95% CI, 55.5-59.4]) (P = 0.02). There were no differences in clinical outcomes at 52 weeks or MRI outcomes at 20 weeks, although changes related to cognitive networks with MBSR+ were observed. Enhanced mindfulness-based stress reduction is an effective treatment option for episodic migraine.

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Hippocampal glutamatergic synapses impairment mediated novel-object recognition dysfunction in rats with neuropathic pain.

Cognitive impairment is one of the most common complications associated with chronic pain. Almost 20% of chronic pain patients suffer from cognitive impairment, which may substantially influence their quality of life. Levels of major excitatory neurotransmitters in the central nervous system and alterations in the glutamatergic system may influence cognitive function and the pain sensory pathway. In this study, we adopted the spared nerve injury model to establish the progress of chronic pain and investigated the mechanism underlying the cognitive aspect related to it. At behavioral level, using the novel-object recognition test, mechanical hypersensitivity was observed in peripheral nerve-injured rats because they exhibited recognition deficits. We showed a dramatic decrease in hippocampal glutamate concentration using nuclear magnetic resonance and reduced glutamatergic synaptic transmission using whole-cell recordings. These were associated with deficient hippocampal long-term potentiation induced by high-frequency stimulation of the Schaffer collateral afferent. Ultra-high-performance liquid chromatography revealed lower levels of D-serine in the hippocampus of the spared nerve injury rats and that D-serine treatment could restore synaptic plasticity and cognitive dysfunction. The reduction of excitatory synapses was also increased by administering D-serine. These findings suggest that chronic pain has a critical effect on synaptic plasticity linked to cognitive function and may built up a new target for the development of cognitive impairment under chronic pain conditions.

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Physical disuse contributes to widespread chronic mechanical hyperalgesia, tactile allodynia, and cold allodynia through neurogenic inflammation and spino-parabrachio-amygdaloid pathway activation.

Physical disuse could lead to a state of chronic pain typified by complex regional pain syndrome type I due to fear of pain through movement (kinesiophobia) or inappropriate resting procedures. However, the mechanisms by which physical disuse is associated with acute/chronic pain and other pathological signs remain unresolved. We have previously reported that inflammatory signs, contractures, disuse muscle atrophy, spontaneous pain-like behaviors, and chronic widespread mechanical hyperalgesia based on central plasticity occurred after 2 weeks of cast immobilization in chronic post-cast pain (CPCP) rat model. In this study, we also demonstrated dystrophy-like changes, both peripheral nociceptive signals and activation of the central pain pathway in CPCP rats. This was done by the following methods: (1) vascular permeability (Evans blue dye) and inflammatory- and oxidative stress-related messenger RNA changes (real-time quantitative polymerase chain reaction); (2) immunofluorescence of pERK and/or c-Fos expression in the spino-parabrachio-amygdaloid pathway; and (3) blockade of nociceptive-related signals using sciatic nerve block. Furthermore, we demonstrated tactile allodynia using an optogenetic method in a transgenic rat line (W-TChR2V4), cold allodynia using the acetone test, and activation of dorsal horn neurons in the chronic phase associated with chronic mechanical hyperalgesia using c-Fos immunofluorescence. In addition, we showed that nociceptive signals in the acute phase are involved in chronic pathological pain-like behaviors by studying the effects of sciatic nerve block. Thus, we conclude that physical disuse contributes to dystrophy-like changes, spontaneous pain-like behavior, and chronic widespread pathological pain-like behaviors in CPCP rats after 2 weeks of cast immobilization.

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Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models.

Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced antinociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid antinociception in cancer-induced bone pain in female BALB/c mice and chemotherapy-induced peripheral neuropathy in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours, pain behaviors were evaluated after analgesic drug treatment. Heat shock protein 90 inhibition in the brain or systemically completely blocked morphine and oxymorphone antinociception in chemotherapy-induced peripheral neuropathy; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin antinociception. We also found that the Hsp90 isoform Hsp90α and the cochaperone Cdc37 were responsible for the observed changes in opioid antinociception. By contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid antinociception in cancer-induced bone pain. These results demonstrate that Hsp90 inhibitors block opioid antinociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.

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Structural abnormalities in the temporalis musculo-aponeurotic complex in chronic muscular temporomandibular disorders.

Some forms of chronic pain are thought to be driven and maintained by nociceptive input, which can drive plasticity within nociceptive pathways. We have previously identified abnormalities along the entire nociceptive pathway in chronic myalgic temporomandibular disorders (mTMD), including the trigeminal nerves, brainstem pathways, and in the thalamus and somatosensory cortex. These data suggest that there is a peripheral nociceptive drive in mTMD, but the source of this nociceptive activity remains unknown. Here, our aim was to determine whether structural abnormalities exist in the muscles of mastication of patients with chronic mTMD. Specifically, we tested whether the volume of the temporalis muscle and its tendon-aponeurosis complex (TAC, a structure that dissipates forces in a muscle) in mTMD patients differ compared to age- and sex-matched controls. To do so, we segmented these structures on T1-weighted structural magnetic resonance images. We found that muscle volumes in mTMD were not different to controls. However, the mTMD group had significantly smaller volumes of the bilateral temporalis TAC, and thus a smaller TAC-to-muscle volume ratio. These findings were consistent across 2 independent cohorts of 17 mTMD patients, compared to 17 age- and sex-matched controls. We propose a model where reduced TAC-to-muscle ratio could result in a predisposition to muscle tissue injury. In sum, abnormalities of the temporalis muscles in mTMD supports our hypothesis that chronic mTMD pathophysiology may be related to peripheral nociceptive barrage originating from the muscles of mastication.

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Increasing gender differences in the prevalence and chronification of orofacial pain in the population.

Although a fluctuating pattern of orofacial pain across the life span has been proposed, data on its natural course are lacking. The longitudinal course of orofacial pain in the general population was evaluated using data from routine dental check-ups at all Public Dental Health services in Västerbotten, Sweden. In a large population sample, 2 screening questions were used to identify individuals with pain once a week or more in the orofacial area. Incidence and longitudinal course of orofacial pain were evaluated using annual data for 2010 to 2017. To evaluate predictors for orofacial pain remaining over time, individuals who reported pain on at least 2 consecutive dental check-ups were considered persistent. A generalized estimating equation model was used to analyze the prevalence, accounting for repeated observations on the same individuals. In total, 180,308 individuals (equal gender distribution) were examined in 525,707 dental check-ups. More women than men reported orofacial pain (odds ratio 2.58, 95% confidence interval [CI] 2.48-2.68), and there was a significant increase in the prevalence of reported pain from 2010 to 2017 in both women and men. Longitudinal data for 135,800 individuals were available for incidence analysis. Women were at higher risk of both developing orofacial pain (incidence rate ratio 2.37; 95% CI 2.25-2.50) and reporting pain in consecutive check-ups (incidence rate ratio 2.56; 95% CI 2.29-2.87). In the northern Swedish population studied, the prevalence of orofacial pain increases over time and more so in women, thus indicating increasing differences in gender for orofacial pain.

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Patients’ experience with and perspectives on neuromodulation for pain: a systematic review of the qualitative research literature.

Chronic pain has far-reaching impacts on a person's life and on society more broadly. After failure or intolerance of conservative treatments, neuromodulation may be an option for a subgroup of patients. However, little is known about the patient experience of neuromodulation. We conducted a systematic review of published qualitative research on patient experience with neuromodulation for chronic pain. Four databases were searched: MEDLINE, EMBASE, Psych INFO, and all EMB reviews, from inception to December 4, 2019. We used narrative synthesis to identify key findings from the included studies. The data were qualitatively analyzed using a modified constant comparative analysis to identify key themes across the studies. Seven thousand five hundred forty-two unique citations were retrieved. Sixty-four abstracts were selected by the reviewers and continued to full-text review. After full-text review, 57 studies were excluded with 7 studies included in this systematic review. The included studies were of high quality. Four broad themes emerged: (1) living with chronic pain, (2) expectations, (3) managing challenges, and (4) regaining normalcy. Neuromodulation should be part of an overall pain management plan that may include the need for ongoing emotional and psychosocial support. A deeper knowledge of the patient experience with neuromodulation will assist care teams in providing meaningful support to patients. The results of this study suggest that further research is needed to support neuromodulation as an option for patients living with chronic pain.

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Spinal caspase-6 regulates AMPA receptor trafficking and dendritic spine plasticity via netrin-1 in postoperative pain following orthopedic surgery for tibial fracture in mice.

Chronic postoperative pain hinders functional recovery after bone fracture and orthopedic surgery. Recently reported evidence indicates that caspase-6 is important in excitatory synaptic plasticity and pathological pain. Meanwhile, netrin-1 controls post-synaptic recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and synaptogenesis. The present work aimed to examine whether caspase-6 and netrin-1 contribute to fracture-induced postoperative allodynia. A mouse model of tibial fracture by intramedullary pinning was generated for inducing postoperative pain. Then, paw withdrawal threshold, spinal caspase-6 activity, netrin-1 secretion, AMPAR trafficking, and spine morphology were examined. Caspase-6 inhibition and netrin-1 knockdown by shRNA were performed to elucidate the pathogenetic mechanism of allodynia and its prevention. Whole-cell patch-clamp recording was carried out to assess caspase-6's function in spinal AMPAR-induced current. Tibial fractures after orthopedic operation initiated persistent postsurgical mechanical and cold allodynia, accompanied by increased spinal active caspase-6, netrin-1 release, GluA1-containing AMPAR trafficking, spine density and AMPAR-induced current in dorsal horn neurons. Caspase-6 inhibition reduced fracture-associated allodynia, netrin-1 secretion and GluA1 trafficking. Netrin-1 deficiency impaired fracture-caused allodynia, post-synaptic GluA1 recruitment and spine plasticity. The specific GluA2-lacking AMPAR antagonist NASPM also dose-dependently prevented postoperative pain. The reduction of fracture-mediated postoperative excitatory synaptic AMPAR current in the dorsal horn by caspase-6 inhibition was compromised by recombinant netrin-1. Exogenous caspase-6 induced pain hypersensitivity, reversing by netrin-1 knockdown or co-application of NASPM. Thus, spinal caspase-6 modulation of GluA1-containing AMPAR activation and spine morphology through netrin-1 secretion is important in the development of fracture-related postsurgical pain in the mouse.

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Modality-specific facilitation of non-injurious sharp mechanical pain by topical capsaicin.

We had previously shown that a "blunt blade" stimulator can mimic the non-injurious strain phase of incisional pain, but not its sustained duration. Here we tested, whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this non-invasive surrogate model of intraoperative pain. Altogether 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the "blunt blade" (0.25 x 4 mm) on normal skin (n=36) and on skin pretreated by a high concentration capsaicin patch (8%, Qutenza®; n=36). These data were compared with an experimental incision (n=40) using quantitative and qualitative pain ratings by numerical rating scale and SES Pain Perception Scale descriptors. Capsaicin-sensitization increased blade-induced pain magnitude and duration significantly (both p<0.05), but it failed to fully match the sustained duration of incisional pain. In normal skin, the SES pattern of pain qualities elicited by the blade matched incision in pain magnitude and pattern of pain descriptors. In capsaicin-treated skin, the blade acquired a significant facilitation only of the perceived heat pain component (p<0.001), but not of mechanical pain components. Thus, capsaicin morphed the descriptor pattern of the blade to become more capsaicin-like, which is probably explained best by peripheral sensitization of the TRPV1 receptor. Quantitative sensory testing (QST) in capsaicin-sensitized skin revealed hyperalgesia to heat and pressure stimuli, and loss of cold and cold pain sensitivity. These findings support our hypothesis that the blade models the early tissue-strain related mechanical pain phase of surgical incisions.

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Trigeminal Neuralgia Diffusivities using Gaussian Process Classification and Merged Group Tractography.

Imaging of trigeminal neuralgia (TN) has demonstrated key DTI based diffusivity alterations in the trigeminal nerve, however imaging has primarily focused on the peripheral nerve segment due to previous limitations in reliably segmenting small fiber bundles across multiple subjects. We used Selective Automated Group Integrated Tractography (SAGIT) to study 36 TN subjects (right sided pain) and 36 sex matched controls, to examine the trigeminal nerve (CN V), pontine decussation (TPT), and thalamocortical fibers (S1). GP classifiers were trained by scrolling a moving window over CN V, TPT, and S1 tractography centroids. Fractional anisotropy (FA), generalized FA (GFA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) metrics were evaluated for both groups, analyzing TN vs. control groups and affected vs. unaffected sides. Classifiers that performed at greater-or-equal-to 70% accuracy were included. GP classifier consistently demonstrated bilateral trigeminal changes, differentiating them from controls with an accuracy of 80%. Affected and unaffected sides could be differentiated from each other with 75% accuracy. Bilateral TPT could be distinguished from controls with at least 85% accuracy. TPT left-right classification achieved 98% accuracy. Bilateral S1 could be differentiated from controls, where the affected S1 RD classifier achieved 87% accuracy. This is the first TN study that combines group-wise merged tractography, machine learning classification, and analysis of the complete trigeminal pathways from the peripheral fibers to S1 cortex. This analysis demonstrates that TN is characterized by bilateral abnormalities throughout the trigeminal pathway compared with controls, as well as abnormalities between affected and unaffected sides.

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The predictive value of quantitative sensory testing: a systematic review on chronic postoperative pain and the analgesic effect of pharmacological therapies in patients with chronic pain.

Studies have suggested that quantitative sensory testing (QST) might hold a predictive value for development of chronic postoperative pain and the response to pharmacological interventions.This review systematically summarizes the current evidence on the predictive value of QST for chronic postoperative pain and the effect of pharmacological interventions. The main outcome measures were posttreatment pain intensity, pain relief, presence of moderate-to-severe postoperative pain, responders of 30% and 50% pain relief or validated questionnaires of pain and disability.A systematic search of MEDLINE and EMBASE yielded 25 studies on surgical interventions and 11 on pharmacological interventions. Seventeen surgical and 11 pharmacological studies reported an association between preoperative or pre-treatment QST and chronic postoperative pain or analgesic effect. The most commonly assessed QST modalities were pressure stimuli (17 studies), temporal summation of pain (TSP, 14 studies) and conditioned pain modulation (CPM, 16 studies). Of those, the dynamic QST parameters TSP (50%) and CPM (44%) were most frequently associated with chronic postoperative pain and analgesic effects. A large heterogeneity in methods for assessing TSP (n=4) and CPM (n=7) was found. Overall, most studies demonstrated low-to-moderate levels of risk of bias in study design, attrition, prognostic factors, outcome, and statistical analyses.This systematic review demonstrates that TSP and CPM show the most consistent predictive values for chronic postoperative pain and analgesic effect, but the heterogeneous methodologies reduce the generalizability and hence call for methodological guidelines.

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Endoplasmic reticulum stress in the dorsal root ganglia regulates large-conductance potassium channels and contributes to pain in a model of multiple sclerosis.

Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4-phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca transients in putative DRG nociceptors. We went on to assess disease-mediated changes in the functional properties of Ca -sensitive BK-type K channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

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A longitudinal examination of the interpersonal fear avoidance model of pain: the role of intolerance of uncertainty.

Youth with chronic pain and their parents face uncertainty regarding their diagnosis, treatment, and prognosis. Given the uncertain nature of chronic pain, and high comorbidity of anxiety among youth, intolerance of uncertainty (IU) may be critical to the experience of pediatric chronic pain. This study longitudinally examined major tenets of the Interpersonal Fear Avoidance Model of Pain, and included parent and youth IU as key factors in the model. Participants included 152 youth with chronic pain (Mage=14.23 years; 72% female) and their parents (93% female). At baseline, parents and youth reported on their IU and catastrophic thinking about youth pain; youth reported on their fear of pain, pain intensity, and pain interference; and parents reported on their protective responses to child pain. Youth reported on their pain interference three months later. Cross-lagged panel models, controlling for baseline pain interference, showed that greater parent IU predicted greater parent pain catastrophizing which, in turn, predicted greater parent protectiveness, greater youth fear of pain, and subsequently greater youth 3-month pain interference. Youth IU had a significant indirect effect on 3-month pain interference via youth pain catastrophizing and fear of pain. The results suggest that parent and youth IU contribute to increases in youth pain interference over time via increased pain catastrophizing, parent protectiveness, and youth fear of pain. Thus, parent and youth IU play important roles as risk factors in the maintenance of pediatric chronic pain over time and may be important targets for intervention.

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Activation of the Notch signaling pathway in the anterior cingulate cortex is involved in the pathological process of neuropathic pain.

Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain.We adopted western boltting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague Dawley rats.Levels of the Notch intracellular domain (NICD) were increased in ACC on day 7 after chronic constriction injury (CCI) surgery or spared nerve injury (SNI). Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased while the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA (shRNA)-Notch reduced NICD expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perception were also alleviated in rats subjected to CCI or SNI. This process was mainly mediated by the downstream effector Hes1, but not Hes5.Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.

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Prevalence of chronic pain in opioid-maintained patients using the capture-recapture method: a nationwide population-based study.

Few studies all based on classical surveys have provided prevalence estimates of chronic pain (CP) in opioid-maintained patients (OMPs) but often had a limited patient sample size and a great variability in the prevalence estimates. This study sought to assess the prevalence of CP in the exhaustive population of OMPs using the capture-recapture method applied to the French nationwide healthcare database. Capture-recapture methods are increasingly used to estimate the prevalence of chronic conditions but have never been used in the specific context of CP in OMPs. Three large medical-administrative sources were used: the prescription drug database (A-list), the national hospital discharge database (M-list), and the pain center database (C-list). Between 2015-2016, 160,429 OMPs ≥15 years old were identified and age- and sex-matched with 160,429 non-OMPs. All patients treated with analgesic drugs for ≥6months (A-list) or diagnosed with CP (M and C-list) were included. Capture-recapture analyses were performed to yield CP estimates with their 95% confidence intervals [95% CI] using log-linear models. In 2015-2016, 12,765 OMPs and 2,938 non-OMPs with CP were captured. Most patients were male (67%) in OMPs and non-OMPs; median ages for OMPs and non-OMPs were 46 (interquartile range: 38-51) and 48 (41-53) years, respectively. The CP prevalence estimated in OMPs and non-OMPs ranged from 23.6% [14.9-46.2] to 32.1% [28.6-36.3] and from 7.28% [3.98-18.4] to 9.32% [7.42-12.1], respectively. This first study on CP in the exhaustive population of OMPs using the capture-recapture method demonstrated a high prevalence of CP in OMPs, three to four-fold than in the general population.

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NINDS Strategies for Enhancing the Diversity of Neuroscience Researchers.

Neuroscience is one of the fastest growing fields and highlights the excitement about research, but it also demonstrates the impact that our large scientific community can make in prioritizing equity and inclusion throughout science. I discuss strategies at multiple systemic levels where opportunities and interventions could be implemented to enhance neuroscience workforce diversity.

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Depolarization-dependent C-Raf signaling promotes hyperexcitability and reduces opioid sensitivity of isolated nociceptors after spinal cord injury.

Chronic pain caused by spinal cord injury (SCI) is notoriously resistant to treatment, particularly by opioids. After SCI, dorsal root ganglion neurons show hyperactivity and chronic depolarization of resting membrane potential (RMP) that is maintained by cAMP signaling through PKA and EPAC. Importantly, SCI also reduces the negative regulation by Gαi of adenylyl cyclase and its production of cAMP, independent of alterations in G protein-coupled receptors and/or G proteins. Opioid reduction of pain depends upon coupling of opioid receptors to Gαi/o family members. Combining high-content imaging and cluster analysis, we show that in male rats SCI decreases opioid responsiveness in vitro within a specific subset of small-diameter nociceptors that bind isolectin B4. This SCI effect is mimicked in nociceptors from naïve animals by a modest 5 min depolarization of RMP (15 mM K; -45 mV), reducing inhibition of cAMP signaling by mu-opioid receptor agonists DAMGO and morphine. Disinhibition and activation of C-Raf by depolarization-dependent phosphorylation are central to these effects. Expression of an activated C-Raf reduces sensitivity of adenylyl cyclase to opioids in non-excitable HEK293 cells, while inhibition of C-Raf or treatment with the hyperpolarizing drug retigabine restores opioid responsiveness and blocks spontaneous activity of nociceptors after SCI. Inhibition of ERK downstream of C-Raf also blocks SCI-induced hyperexcitability and depolarization, without direct effects on opioid responsiveness. Thus, depolarization-dependent C-Raf and downstream ERK activity maintain a depolarized resting membrane potential and nociceptor hyperactivity after SCI, providing a self-reinforcing mechanism to persistently promote nociceptor hyperexcitability and limit the therapeutic effectiveness of opioids.Chronic pain induced by spinal cord injury (SCI) is often permanent and debilitating, and usually refractory to treatment with analgesics, including opioids. SCI-induced pain in a rat model has been shown to depend upon persistent hyperactivity in primary nociceptors (injury-detecting sensory neurons), associated with a decrease in the sensitivity of adenylyl cyclase production of cAMP to inhibitory Gαi proteins in dorsal root ganglia. This study shows that SCI and one consequence of SCI — chronic depolarization of resting membrane potential — decrease sensitivity to opioid-mediated inhibition of cAMP and promote hyperactivity of nociceptors by enhancing C-Raf activity. ERK activation downstream of C-Raf is necessary for maintaining ongoing depolarization and hyperactivity, demonstrating an unexpected positive feedback loop to persistently promote pain.

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Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor.

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala, -MePhe, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2.

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Transcript expression of vesicular glutamate transporters in rat dorsal root ganglion and spinal cord neurons: Impact of spinal blockade during hindpaw inflammation.

Studies in mouse, and to a lesser extent in rat, have revealed the neuroanatomical distribution of vesicular glutamate transporters (VGLUTs) and begun exposing the critical role of VGLUT2 and VGLUT3 in pain transmission. In the present study in rat we used specific riboprobes to characterize the transcript expression of all three VGLUTs in lumbar dorsal root ganglia (DRGs) and in the thoracolumbar, lumbar and sacral spinal cord. We show for the first time in rat a very discrete VGLUT3 expression in DRGs and in deep layers of the dorsal horn. We confirm the abundant expression of VGLUT2, both in DRGs and the spinal cord, including presumable motorneurons in the latter. As expected, VGLUT1 was present in many DRG neuron profiles, and in the spinal cord was mostly localized to neurons in the dorsal nucleus of Clarke. In rats with a 10-day long hindpaw inflammation, increased spinal expression of VGLUT2 transcript was detected by qRT-PCR, and intrathecal administration of the non-selective VGLUT inhibitor Chicago Sky Blue 6B resulted in reduced mechanical and thermal allodynia for up to 24 hours. In conclusion, our results provide a collective characterization of VGLUTs in rat DRGs and the spinal cord, demonstrate increased spinal expression of VGLUT2 during chronic peripheral inflammation, and support the use of spinal VGLUT blockade as a strategy for attenuating inflammatory pain.

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Low plasma levels of calcitonin gene-related peptide in persistent post-traumatic headache attributed to mild traumatic brain injury.

To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI).

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Mechanisms of Mindfulness Meditation, Cognitive Therapy, and Mindfulness-based Cognitive Therapy for Chronic Low Back Pain.

This study evaluated theoretically derived mechanisms and common therapeutic factors to test their role in accounting for pain-related outcome change during group-delivered cognitive therapy (CT), mindfulness meditation (MM) and mindfulness-based cognitive therapy (MBCT) for chronic low back pain.

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Neuromodulation, Specialized Proresolving Mediators, and Resolution of Pain.

The current crises in opioid abuse and chronic pain call for the development of nonopioid and nonpharmacological therapeutics for pain relief. Neuromodulation-based approaches, such as spinal cord stimulation, dorsal root ganglion simulation, and nerve stimulation including vagus nerve stimulation, have shown efficacy in achieving pain control in preclinical and clinical studies. However, the mechanisms by which neuromodulation alleviates pain are not fully understood. Accumulating evidence suggests that neuromodulation regulates inflammation and neuroinflammation-a localized inflammation in peripheral nerves, dorsal root ganglia/trigeminal ganglia, and spinal cord/brain-through neuro-immune interactions. Specialized proresolving mediators (SPMs) such as resolvins, protectins, maresins, and lipoxins are lipid molecules produced during the resolution phase of inflammation and exhibit multiple beneficial effects in resolving inflammation in various animal models. Recent studies suggest that SPMs inhibit inflammatory pain, postoperative pain, neuropathic pain, and cancer pain in rodent models via immune, glial, and neuronal modulations. It is noteworthy that sham surgery is sufficient to elevate resolvin levels and may serve as a model of resolution. Interestingly, it has been shown that the vagus nerve produces SPMs and vagus nerve stimulation (VNS) induces SPM production in vitro. In this review, we discuss how neuromodulation such as VNS controls pain via immunomodulation and neuro-immune interactions and highlight possible involvement of SPMs. In particular, we demonstrate that VNS via auricular electroacupuncture effectively attenuates chemotherapy-induced neuropathic pain. Furthermore, auricular stimulation is able to increase resolvin levels in mice. Thus, we propose that neuromodulation may control pain and inflammation/neuroinflammatioin via SPMs. Finally, we discuss key questions that remain unanswered in our understanding of how neuromodulation-based therapies provide short-term and long-term pain relief.

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Baseline Characteristics of a Dyadic Cohort of Mothers with Chronic Pain and Their Children.

A growing body of research has demonstrated a robust link between parental chronic pain and child pain and psychological function. Although the association between parent and child pain is strong, there are limited data to understand environmental and behavioral processes that account for the association and how this develops over time. This longitudinal cohort study was designed to understand potential mechanisms that confer risk or resilience for chronic pain among child offspring of mothers with chronic pain.

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Protective role of neuronal and lymphoid cannabinoid CB receptors in neuropathic pain.

Cannabinoid CB receptor (CB) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB, however the involvement of CB from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB agonist JWH133 in wild-type and knockout mice lacking CB in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB knockouts and was increased in mice defective in neuronal CB knockouts suggestive of increased spontaneous pain. Interestingly, CB-positive lymphocytes infiltrated the injured nerve and possible CBtransfer from immune cells to neurons was found. Lymphocyte CBdepletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CBthat protects against spontaneous and evoked neuropathic pain.

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En pointe: dancers report their pain less variably than do controls.

The subjective nature of pain and the lack of a gold standard for objective measurement hinders effective assessment, diagnosis, and treatment. Some individuals, such as professional dancers, are better in assessing and reporting bodily sensations. This observational study aimed to assess whether dancers report their pain less variably, than other people do. After consenting, subjects completed the Focused Analgesia Selection Task (FAST), which assesses subjects' variability of pain reports. FAST outcomes, ICC and R reflect the magnitude of variability of pain reports observed. In addition, subjects underwent a taste task, which similarly assesses variability of tastes (salty and sweet) intensity reports and completed the Multidimensional Assessment of Interoceptive Awareness (MAIA) questionnaire. Thirty-three professional dancers and thirty-three healthy aged-matched controls were recruited. The dancers exhibited less variability of pain reports then controls (P=0.013), but not in case of tastes-reports. Years of practice was positively correlated with pain reporting variability (r=0.447, P=0.009, and r=0.380, P=0.029; for FAST ICC and R, respectively). MAIA sub-scores correlated with pain reporting variability: R and ICC with emotional awareness (r=0.260, P=0.040, and r=0.274, P=0.030, respectively), and R with trusting [r=0.254, P=0.044]). Perspective The difference between dancers and controls in the magnitude of variability of pain reports is probably due to the dancers' extensive training, which focuses on attention to body signals. Our results suggest that training can improve subjective pain reports, which are essential for quality clinical care.

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Gene coexpression patterns predict opiate-induced brain-state transitions.

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.

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Plasma Concentrations of Select Inflammatory Cytokines Predicts Pain Intensity 48 Hours Post-shoulder Muscle Injury.

The relationship between elevated inflammatory cytokine levels and peak pain intensity following acute musculoskeletal injury has not been fully elucidated in high risk subgroups. Identifying the role that these cytokines have on pain responses may help with developing tailored therapeutic approaches.

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Pain behaviour assessments by gait and weight bearing in surgically induced osteoarthritis and inflammatory arthritis.

Osteoarthritis (OA) is the most common cause of joint pain. Animal models and relevant assays for measurement of pain-related behaviours are important tools for studies of mechanisms inducing and sustaining pain in OA. The aim of this study was to evaluate two different assessments of weight bearing; stationary and during locomotion, and to explore their feasibility to detect analgesic effects in vivo. Two fundamentally different mouse models of joint arthritis were investigated; surgical transection of the anterior cruciate ligament (ACLT) resulting in destabilization of the joint with subsequent structural deterioration resembling OA, and monoarthritis induced by injection of Complete Freund´s Adjuvant (CFA) into the ankle joint capsule.

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Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Sickle cell disease (SCD) is characterized by chronic pain and episodic acute pain caused by vasoocclusive crises, often requiring high doses of opioids for prolonged periods. In humanized mouse models of SCD, a synthetic cannabinoid has been found to attenuate both chronic and acute hyperalgesia. The effect of cannabis on chronic pain in adults with SCD is unknown.

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Central Nervous System Targets: Supraspinal Mechanisms of Analgesia.

While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving "analgesic" therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood-brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.

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Acceptance and Commitment Therapy for Primary Headache Sufferers: A Randomized Controlled Trial of Efficacy.

Prevention of headaches via avoidance of triggers remains the main behavioral treatment suggestion for headache management despite trigger avoidance resulting in increases in potency, lifestyle restrictions, internal locus of control decreases, pain exacerbation and maintenance. New approaches, such as Acceptance and Commitment Therapy (ACT), instead emphasize acceptance and valued living as alternatives to avoidance. Though ACT is an empirically supported treatment for chronic pain, there is limited evidence for headache management whilst preliminary outcome studies are afflicted with methodological limitations. This study compared an ACT-based group headache-specific intervention to wait-list control, in a randomized clinical trial, on disability, distress, medical utilization, functioning and quality of life. 94 individuals with primary headache (84% women; Mage=43 years; 87.35% migraine diagnosis) were randomized into two groups (47 in each). Assessments occurred: before, immediately after, and at 3-months following treatment end. Only the ACT group was additionally assessed at 6- and 12-months follow-up. Results (intent to treat analyses corroborated by linear-mixed-model analyses) showed substantial improvements in favor of ACT compared to control, on disability, quality of life, functional status, and depression at 3-, 6-, and 12-month follow-up. Improvements were maintained in the ACT group at 6- and 12-month follow-up. At 3-month follow-up, clinical improvement occurred in headache-related disability (63%) and 65% in quality of life in ACT vs. 37% & 35% in control. These findings offer new evidence for the utility and efficacy of ACT in localized pain conditions and yields evidence for both statistical and clinical improvements over a years' period. Perspective: An Acceptance and Commitment Therapy approach focusing on acceptance and values-based activities, was found to improve disability, functioning and quality of life among patients with primary headaches. Trial registration: Clinical trials.gov registry (NCT02734992).

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Acute and chronic stress prevents responses to pain in zebrafish: evidence for stress-induced analgesia.

The state of an animal prior to the application of a noxious stimulus can have a profound effect on their nociceptive threshold and subsequent behaviour. In mammals, the presence of acute stress preceding a painful event can have an analgesic effect whereas the presence of chronic stress can result in hyperalgesia. While considerable research has been conducted on the ability of stress to modulate mammalian responses to pain, relatively little is known about fish. This is of particular concern given that zebrafish () are an extensively used model organism subject to a wide array of invasive procedures where the level of stress prior to experimentation could pose a major confounding factor. This study, therefore, investigated the impact of both acute and chronic stress on the behaviour of zebrafish subjected to a potentially painful laboratory procedure, the fin clip. In stress-free individuals, those subjected to the fin clip spent more time in the bottom of the tank, had reduced swimming speeds and less complex swimming trajectories; however, these behavioural changes were absent in fin-clipped fish that were first subject to either chronic or acute stress, suggesting the possibility of stress-induced analgesia (SIA). To test this, the opioid antagonist naloxone was administered to fish prior to the application of both the stress and fin-clip procedure. After naloxone, acutely stressed fin-clipped zebrafish exhibited the same behaviours as stress-free fin-clipped fish. This indicates the presence of SIA and the importance of opioid signalling in this mechanism. As stress reduced nociceptive responses in zebrafish, this demonstrates the potential for an endogenous analgesic system akin to the mammalian system. Future studies should delineate the neurobiological basis of stress-induced analgesia in fish.

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Radiofrequency denervation for chronic back pain: a systematic review and meta-analysis.

To assess the effectiveness of radiofrequency denervation (RD) of lumbosacral anatomical targets for the management of chronic back pain.

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Static mechanical allodynia in post-surgical neuropathic pain after breast cancer treatments.

Objectives Static mechanical allodynia (SMA), i. e., pain caused by normally non-painful static pressure, is a prevalent manifestation of neuropathic pain (NP). Although SMA may significantly affect the patient's daily life, it is less well studied in the clinical context. We aimed to characterize SMA in women with chronic post-surgical NP (CPSNP) after breast cancer surgery. Our objective was to improve understanding of the clinical picture of this prevalent pain condition. This is a substudy of a previously published larger cohort of patients with intercostobrachial nerve injury after breast cancer surgery (Mustonen et al. Pain. 2019;160:246-56). Methods We studied SMA in 132 patients with CPSNP after breast cancer surgery. The presence, location, and intensity of SMA were assessed at clinical sensory examination. The patients gave self-reports of pain with the Brief Pain Inventory (BPI). We studied the association of SMA to type of surgery, oncological treatments, BMI, other pains, and psychological factors. General pain sensitivity was assessed by the cold pressor test. Results SMA was prevalent (84%) in this cohort whereas other forms of allodynia were scarce (6%). Moderate-to-severe SMA was frequently observed even in patients who reported mild pain in BPI. Breast and the side of chest were the most common locations of SMA. SMA was associated with breast surgery type, but not with psychological factors. Severe SMA, but not self-reported pain, was associated with lower cold pain tolerance. Conclusions SMA is prevalent in post-surgical NP after breast cancer surgery and it may represent a distinct NP phenotype. High intensities of SMA may signal the presence of central sensitization. Implications SMA should be considered when examining and treating patients with post-surgical NP after breast cancer surgery.

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Salience network functional connectivity is spatially heterogeneous across sensorimotor cortex in healthy humans.

The salience network is responsive during a range of conditions requiring immediate behavioral responses, including pain processing. Resting-state functional connectivity of the salience network to the sensorimotor cortex is altered in chronic pain. However, little is understood about their fundamental communication in the absence of pain. In this study, we mapped salience network resting-state functional connectivity across sensorimotor cortex in healthy individuals. Using electromyography and task-based functional magnetic resonance imaging (fMRI), we first localized distinct regions-of-interest across sensorimotor cortex in medial (gluteal), intermediate (shoulder), and lateral (hand) areas. We then used resting-state fMRI for two cohorts (primary and replication) of healthy individuals from public repositories to map salience network resting-state functional connectivity across sensorimotor cortex. Both the primary and replication cohorts exhibited significant heterogeneity in salience network resting-state functional connectivity across the sensorimotor regions-of-interest. Using a cortical flatmap to visualize the entire sensorimotor surface, we observed similar heterogeneity in both cohorts. In general, the somatotopic representation of proximal body regions (trunk/face) had higher salience network resting-state functional connectivity compared to distal body regions (upper/lower limbs). We conclude that sensorimotor cortex is spatially heterogeneous in its interaction with the salience network in healthy individuals.

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Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort.

Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients.

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Development and preliminary validation of the Chronic Pain Acceptance Questionnaire for Clinicians.

Background and Aims Higher chronic pain acceptance is associated with lower pain and disability. Clinician beliefs are associated with patients' beliefs. This study therefore aimed to develop the Chronic Pain Acceptance Questionnaire for Clinicians (CPAQ-C) to measure clinicians' beliefs regarding the importance of levels of acceptance in patients with chronic pain, and to examine the questionnaire's psychometric properties. Methods Phase one: the CPAQ-C was adapted from the Chronic Pain Acceptance Questionnaire. Data on 162 completed questionnaires were analysed using Rasch analysis. Phase Two: the cohort completed the Healthcare Providers Pain and Impairment Relationship Scale, and the association (Pearson's correlation co-efficient) between these questionnaires examined to assist CPAQ-C validation. Twenty-four participants completed the CPAQ-C one-week later. Test re-test reliability was examined using intraclass correlation co-efficient (2,1) and standard error of measurement. Phase Three: to examine responsiveness 17 clinicians attending a workshop on Acceptance and Commitment Therapy completed the CPAQ-C before and immediately after the workshop, and six-months later. The Skillings Mack test was used to determine whether CPAQ-C scores differed across different timepoints. Results Rasch analysis supported two subscales: activity engagement and pain willingness. Five poorly functioning items were excluded. There was good correlation between the CPAQ-C and Healthcare Providers Pain and Impairment Relationship Scale (-.54). The CPAQ-C demonstrated good reliability (ICC (2,1): .81; standard error of measurement: 4.76). There was significant improvement in CPAQ-C scores following the workshop (p=<.001). Conclusions The CPAQ-C appears a valid, reliable and responsive measure of clinicians' beliefs regarding the importance of levels of acceptance in patients with chronic pain. Implications Where the CPAQ-C reveals that clinicians have low perceived levels of importance regarding acceptance in patients with chronic pain those clinicians may benefit from specific education, however, this requires further examination.

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A novel clinical applicable bed-side tool for assessing conditioning pain modulation: proof-of-concept.

Background and aims In recent years, focus on assessing descending pain modulation or conditioning pain modulation (CPM) has emerged in patients with chronic pain. This requires reliable and simple to use bed-side tools to be applied in the clinic. The aim of the present pilot study was to develop and provide proof-of-concept of a simple clinically applicable bed-side tool for assessing CPM. Methods A group of 26 healthy volunteers participated in the experiment. Pressure pain thresholds (PPT) were assessed as test stimuli from the lower leg before, during and 5 min after delivering the conditioning tonic painful pressure stimulation. The tonic stimulus was delivered for 2 min by a custom-made spring-loaded finger pressure device applying a fixed pressure (2.2 kg) to the index finger nail. The pain intensity provoked by the tonic stimulus was continuously recorded on a 0-10 cm Visual Analog Scale (VAS). Results The median tonic pain stimulus intensity was 6.7 cm (interquartile range: 4.6-8.4 cm) on the 10 cm VAS. The mean PPT increased significantly (P = 0.034) by 55 ± 126 kPa from 518 ± 173 kPa before to 573 ± 228 kPa during conditioning stimulation. When analyzing the individual CPM responses (increases in PPT), a distribution of positive and negative CPM responders was observed with 69% of the individuals classified as positive CPM responders (increased PPTs = anti-nociceptive) and the rest as negative CPM responders (no or decreased PPTs = Pro-nociceptive). This particular responder distribution explains the large variation in the averaged CPM responses observed in many CPM studies. The strongest positive CPM response was an increase of 418 kPa and the strongest negative CPM response was a decrease of 140 kPa. Conclusions The present newly developed conditioning pain stimulator provides a simple, applicable tool for routine CPM assessment in clinical practice. Further, reporting averaged CPM effects should be replaced by categorizing volunteers/patients into anti-nociceptive and pro-nociceptive CPM groups. Implications The finger pressure device provided moderate-to-high pain intensities and was useful for inducing conditioning stimuli. Therefore, the finger pressure device could be a useful bed-side method for measuring CPM in clinical settings with limited time available. Future bed-side studies involving patient populations are warranted to determine the usefulness of the method.

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Chronic mechanical hypersensitivity in experimental autoimmune encephalomyelitis is regulated by disease severity and neuroinflammation.

Chronic pain severely affects quality of life in more than half of people living with multiple sclerosis (MS). A commonly-used model of MS, experimental autoimmune encephalomyelitis (EAE), typically presents with hindlimb paralysis, neuroinflammation and neurodegeneration. However, this paralysis may hinder the use of pain behavior tests, with no apparent hypersensitivity observed post-peak disease. We sought to adapt the classic actively-induced EAE model to optimize its pain phenotype. EAE was induced with MOG/CFA and 100-600ng pertussis toxin (PTX), and mice were assessed for mechanical, cold and thermal sensitivity over a 28-day period. Spinal cord tissue was collected at 14 and 28 days post-injection to assess demyelination and neuroinflammation. Only mice treated with 100ng PTX exhibited mechanical hypersensitivity. Hallmarks of disease pathology, including demyelination, immune cell recruitment, cytokine expression, glial activation, and neuronal damage were higher in EAE mice induced with moderate (200ng) doses of pertussis toxin, compared to those treated with low (100ng) levels. Immunostaining demonstrated activated astrocytes and myeloid/microglial cells in both EAE groups. These results indicate that a lower severity of EAE disease may allow for the study of pain behaviors while still presenting with disease pathology. By using this modified model, researchers may better study the mechanisms underlying pain.

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Mu-opioids suppress GABAergic synaptic transmission onto orbitofrontal cortex pyramidal neurons with subregional selectivity.

The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.Considering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.

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Inhibition of M/K7 Currents Contributes to Chloroquine-Induced Itch in Mice.

M/K7 potassium channels play a key role in regulation of neuronal excitability. Modulation of neuronal excitability of primary sensory neurons determines the itch sensation induced by a variety of itch-causing substances including chloroquine (CQ). In the present study, we demonstrate that suppression of M/K7 channel activity contributes to generation of itch in mice. CQ enhances excitability of the primary sensory neurons through inhibiting M/K7 potassium currents in a Ca influx-dependent manner. Specific M/K7 channel opener retigabine (RTG) or tannic acid (TA) not only reverses the CQ-induced enhancement of neuronal excitability but also suppresses the CQ-induced itch behavior. Systemic application of RTG or TA also significantly inhibits the itch behavior induced by a variety of pruritogens. Taken together, our findings provide novel insight into the molecular basis of CQ-induced itch sensation in mammals that can be applied to the development of strategies to mitigate itch behavior.

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Early childhood onset migraine – A serious long-term condition.

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Neuropathy and primary headaches affect different subgroups of inflammatory bowel disease patients.

Peripheral neuropathies (PN) and primary headaches (PH) are common comorbidities in inflammatory bowel disease (IBD) patients. We aimed to evaluate whether PN and PH affect the same subgroups of IBD patients.

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Gene therapies to reduce chronic pain: are we there yet?

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An update on acute and preventive treatments for migraine in children and adolescents.

Migraine is diagnosed in 5% of children in the United States by the age of ten. The estimated prevalence for children with migraine is 10%. It has become increasingly important to diagnose children and adolescents with migraine as they are disabling. Children are more likely to miss school and activities due to headaches compared to other children. In addition, poor management and treatment in children and adolescents could potentially lead to an increase in migraine in adults.

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Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019).

TRPA1 is a non-selective cation channel predominantly expressed in sensory neurons, and functions as an irritant sensor for a plethora of noxious external stimuli and endogenous ligands associated with cell damage. Due to its involvement in pain, itch, and respiratory syndromes, TRPA1 has been pursued as a promising drug target.

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Patients with chronic migraine without history of medication overuse are characterized by a peculiar white matter fiber bundle profile.

We investigated intracerebral fiber bundles using a tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) data to verify microstructural integrity in patients with episodic (MO) and chronic migraine (CM).

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Role of Calcitonin Gene-Related Peptide in Nociceptive Modulation in Anterior Cingulate Cortex of Naïve Rats and Rats With Inflammatory Pain.

It is known that calcitonin gene-related peptide (CGRP) plays a key role in pain modulation in the brain. There are high expressions of CGRP and CGRP receptor in anterior cingulate cortex (ACC), an important brain structure in pain modulation. The present study explored the role and mechanisms of CGRP and CGRP receptor in nociceptive modulation in ACC in naïve rats and inflammatory rats. Administration of different does of CGRP in ACC induced significant antinociception in a dose-dependent manner in both naïve rats and rats with inflammatory pain. The CGRP-induced antinociception was attenuated by injection of the CGRP receptor antagonist CGRP8-37 in ACC. Interestingly, both CGRP-induced antinociception and CGRP receptor expression decreased in ACC in rats with inflammatory pain compared with naïve rats. Knockdown of CGRP receptor in ACC by siRNA targeting to CGRP receptor attenuated both the CGRP receptor expression and the CGRP-induced antinociception significantly in rats. These findings demonstrate that CGRP and CGRP receptor participate in nociceptive modulation in ACC in rats, inhibiting CGRP receptor expression induces decrease in CGRP-induced antinociception in ACC.

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Differential expression of Na/K/Cl cotransporter 1 in neurons and glial cells within the superficial spinal dorsal horn of rodents.

Although convincing experimental evidence indicates that Na/K/Cl cotransporter 1 (NKCC1) is involved in spinal nociceptive information processing and in the generation of hyperalgesia and allodynia in chronic pain states, the cellular distribution of NKCC1 in the superficial spinal dorsal horn is still poorly understood. Because this important piece of knowledge is missing, the effect of NKCC1 on pain processing is still open to conflicting interpretations. In this study, to provide the missing experimental data, we investigated the cellular distribution of NKCC1 in the superficial spinal dorsal horn by immunohistochemical methods. We demonstrated for the first time that almost all spinal axon terminals of peptidergic nociceptive primary afferents express NKCC1. In contrast, virtually all spinal axon terminals of nonpeptidergic nociceptive primary afferents were negative for NKCC1. Data on the colocalization of NKCC1 with axonal and glial markers indicated that it is almost exclusively expressed by axon terminals and glial cells in laminae I-IIo. In lamina IIi, however, we observed a strong immunostaining for NKCC1 also in the dendrites and cell bodies of PV-containing inhibitory neurons and a weak staining in PKCγ-containing excitatory neurons. Our results facilitate further thinking about the role of NKCC1 in spinal pain processing.

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Association of State-Level Opioid-Reduction Policies With Pediatric Opioid Poisoning.

Opioid-reduction policies have been enacted by US states to address the opioid epidemic. Evidence of an association between policy implementation and decreased rates of pediatric opioid poisoning provides further justification for expanded implementation of these policies.

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Astrocytic NDRG2 is critical in the maintenance of neuropathic pain.

Activation of astrocytes and abnormal synaptic glutamate metabolism are closely associated with the induction and maintenance of neuropathic pain (NP), but the exact mechanism underlying this association remains unclear. N-myc downstream-regulated gene 2 (NDRG2), a novel tumor-suppressor protein and stress-response gene, is involved in the pathogenesis of several neurodegenerative diseases. However, its role in nociceptive transduction has rarely been investigated. Here, we found that NDRG2, which was mainly expressed in the astrocytes in the central nervous system (CNS), was increased in the spinal cord of a spinal nerve ligation (SNL) rat model for NP. Suppression of NDRG2 by intrathecal injection of an NDRG2-RNAi-adenovirus significantly alleviated SNL-induced mechanical and thermal hypersensitivity, as well as elevated astrocytic glutamate transporter 1 (GLT-1) expression and downregulated pro-inflammatory cytokine levels, in the spinal dorsal horn of rats on Day 10 after SNL. Furthermore, in lipopolysaccharide (LPS)-stimulated primary astrocytic cultures derived from neonatal rats, inhibition of NDRG2 significantly reversed both the LPS-induced activation of astrocytes and decreased expression of GLT-1. By contrast, overexpression of NDRG2 by an adenoviral vector carrying NDRG2 resulted in astrocytic activation, aberrant glutamatergic neurotransmission, and spontaneous nociceptive responses in rats. Intrathecal injection of AG490, which is an inhibitor of the Janus tyrosine kinase and signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway, significantly attenuated both mechanical and thermal hyperalgesia, as well as inhibited reactive astrocytes and restored normal expression levels of astrocytic GLT-1, in the spinal dorsal horn of NDRG2-overexpression rats. In conclusion, spinal astrocytic NDRG2 is critical in the maintenance of NP. Moreover, NDRG2 modulates astrocytic activation and inflammatory responses via regulating GLT-1 expression through the JAK/STAT3 signaling pathway. Our findings suggested that NDRG2 could be a novel therapeutic target for the treatment of NP.

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Presynaptic glutamatergic transmission and feedback system of oxytocinergic neurons in the hypothalamus of a rat model of adjuvant arthritis.

The neurohypophysial hormone oxytocin (OXT) is synthesized in the hypothalamic paraventricular and supraoptic nuclei. Recently, some studies have considered OXT to be important in sensory modulation and that the OXT protein is upregulated by acute and chronic nociception. However, the mechanism by which OXT is upregulated in neurons is unknown. In this study, we examined the resting membrane potentials and excitatory postsynaptic currents in OXT-ergic neurons in the paraventricular nucleus in adjuvant arthritis rat model, a model of chronic inflammation, using whole-cell patch-clamping. Transgenic rats expressing OXT and monomeric red fluorescent protein 1 (mRFP1) fusion protein to visualize the OXT-ergic neurons were used, and the OXT-mRFP1 transgenic rat model of adjuvant arthritis was developed by injection of heat-killed . Furthermore, the feedback system of synthesized OXT was also examined using the OXT receptor antagonist L-368,899. We found that the resting membrane potentials and frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-monomeric red fluorescent protein 1 neurons in the paraventricular nucleus were significantly increased in adjuvant arthritis rats. Furthermore, L-368,899 dose-dependently increased the frequency of miniature excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in OXT-ergic neurons. Following bath application of the GABA receptor antagonist picrotoxin and the cannabinoid receptor 1 antagonist AM 251, L-368,899 still increased the frequency of miniature excitatory postsynaptic currents. However, following bath application of the nitric oxide synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride, L-368,899 did not alter the miniature excitatory postsynaptic current frequency. Thus, it is suggested that OXT-ergic neuron activity is upregulated via an increase in glutamate release, and that the upregulated OXT neurons have a feedback system with released endogenous OXT. It is possible that nitric oxide, but not GABA, may contribute to the feedback system of OXT neurons in chronic inflammation.

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Assessment of the anti-hyperalgesic efficacy of J-2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP).

Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio-economic burden internationally. The lifetime prevalence of non-specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of 5 shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague-Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP-5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti-hyperalgesic effects of J-2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J-2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non-significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.

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Relevance of Mitochondrial Dysfunction in the Reserpine-Induced Experimental Fibromyalgia Model.

Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.

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Characterisation of nociception and inflammation observed in a traumatic muscle injury model in rats.

Muscle pain is the most prevalent type of pain in the world, but treatment remains ineffective. Thus, it is relevant to develop trustable animal models to understand the involved pain mechanisms. Therefore, this study characterised the nociception and inflammation in a traumatic muscle injury model in rats. A single blunt trauma impact on the right gastrocnemius muscle of male Wistar rats (250-350 g) was used as model for muscle pain. Animals were divided into four groups (sham/no treatment; sham/diclofenac 1%; injury/no treatment; injury/diclofenac 1%) and the topical treatment with a cream containing 1% monosodium diclofenac (applied at 2, 6, 12, 24, and 46 h after muscle injury; 200 mg/muscle) was used as an anti-inflammatory control. Nociception (mechanical and cold allodynia, or nociceptive score) and locomotor activity were evaluated at 26 and 48 h after injury. Also, inflammatory and oxidative parameters were evaluated in gastrocnemius muscle and the creatine kinase (CK) activity and lactate/glicose levels in rat's serum and plasma, respectively. Muscle injury caused mechanical and cold allodynia, and increased nociceptive scores, without inducing locomotor impairment. This model also increased the inflammatory cells infiltration (seen by myeloperoxidase and N-acetyl-β-D-glucosaminidase activities and histological procedure), nitric oxide, interleukin (IL)-1β, IL-6, and dichlorofluorescein fluorescence in muscle samples; and CK activity and lactate/glicose ratio. The treatment with 1% monosodium diclofenac reduced inflammatory cells infiltration, dichlorofluorescein fluorescence and lactate/glicose levels. Thus, we characterised the traumatic muscle injury as a reproducible model of muscle pain, which makes it possible to evaluate promising antinociceptive and anti-inflammatory therapies.

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Chronic opioid use and risk of cancer in patients with chronic non-cancer pain: A nationwide historical cohort study.

To investigate whether chronic opioid therapy is associated with a higher risk of cancer among non-cancer patients with chronic pain.

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Anti-GD2 induced allodynia in rats can be reduced by pretreatment with DFMO.

Anti-GD2 therapy with dinutuximab is effective in improving the survival of high-risk neuroblastoma patients in remission and after relapse. However, allodynia is the major dose-limiting side effect, hindering its use for neuroblastoma patients at higher doses and for other GD2-expressing malignancies. As polyamines can enhance neuronal sensitization, including development of allodynia and other forms of pathological pain, we hypothesized that polyamine depletion might prove an effective strategy for relief of anti-GD2 induced allodynia.

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The Efficacy of Nerve Growth Factor Antibody for the Treatment of Osteoarthritis Pain and Chronic Low-Back Pain: A Meta-Analysis.

Nerve growth factor (NGF) plays a crucial role in pain modulation and is being considered as a new therapeutic target for pain therapy. The purpose of this meta-analysis was to study the efficacy of anti-NGF antibodies for the treatment of osteoarthritis pain and chronic low-back pain, and to provide evidence and direction for further research and practice.

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Proteomic studies of common chronic pain conditions – a systematic review and associated network analyses.

The lack of biomarkers indicating involved nociceptive and/or pain mechanisms makes diagnostic procedures problematic. Clinical pain research has begun to use proteomics.

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Psychometric Properties of the Multidimensional Impression of Change in a Cohort of Pediatric Pain Patients.

This study assessed the utility of the Multidimensional Patient Impression of Change (MPIC) questionnaire in a pediatric pain population following interdisciplinary treatment.

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Eleven things not to say to healthcare professionals during the COVID-19 pandemic.

On March 11, 2020, the infection caused by the COVID-19 virus was declared a pandemic. Throughout this pandemic, healthcare professionals have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID-19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well-established psychological principles. The first 10 scenarios discussed include 1) lack of understanding regarding the extent of the pandemic, 2) shaming over not seeing patients in person, 3) lack of clear and consistent communication from leadership on pandemic-related practice changes, 4) opinions that personal protective equipment use by healthcare professionals causes fear or is unnecessary, 5) forcing in-person care without appropriate personal protective equipment, 6) the risk of exposure to asymptomatic individuals as it relates to opening clinics, 7) media gag orders, 8) pay and benefit reductions, 9) spreading of misinformation about the COVID-19 pandemic, and 10) workload expectations. The 11th scenario addresses healthcare professionals' psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self-efficacy among healthcare professionals.

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Endometriosis Pain Management: a Review.

The purpose of this review is to summarize the up-to-date pain management options and recommendations for the challenging disease, endometriosis.

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Pediatric Migraine Phenomena and Variants: Don’t Let Them Go Over Your Head.

Primary care providers, general pediatric neurologists, and other related subspecialty providers require a clear understanding of pediatric migraine with typical aura and its variants.

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D2 receptor activation relieves pain hypersensitivity by inhibiting superficial dorsal horn neurons in parkinsonian mice.

Chronic pain is a common and undertreated nonmotor symptom in Parkinson's disease (PD). Although chronic pain is improved by L-dopa in some PD patients, the underlying mechanisms remain unclear. In this study, we established PD mice by unilateral microinjection of 6-OHDA in the medial forebrain bundle to investigate the contribution of spinal cord dopamine receptors to parkinsonian pain hypersensitivity. The von Frey filament tests and thermal pain tests revealed that these PD mice displayed decreased nociceptive thresholds in both hindpaws; intrathecal injection of L-dopa or apomorphine significantly increased the mechanical and thermal nociceptive thresholds, and the analgesic effect was mimicked by ropinirole (a D2 receptor agonist), but not SKF38393 (a D1/D5 receptor agonist), and blocked by sulpiride (a D2 receptor antagonist), but not SKF83566 (a D1/D5 receptor antagonist). Whole-cell recordings in lumber spinal cord slices showed that superficial dorsal horn (SDH) neurons in PD mice exhibited hyperexcitability, including more depolarized resting membrane potentials and more action potentials evoked by depolarizing current steps, which were mitigated by ropinirole. Furthermore, ropinirole inhibited the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in SDH neurons more strongly in PD mice than in control mice. However, sulpiride caused less disinhibition of sEPSCs in PD mice than in control mice. Taken together, our data reveal that pain hypersensitivity in PD mice is associated with hyperexcitability of SDH neurons, and both events are reversed by activation of spinal D2 receptors. Therefore, spinal D2 receptors can be promising therapeutic targets for the treatment of PD pain.

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Involvement between social defeat stress and pain-related behavior in a rat lumbar disk herniation model.

Psychological and social factors are involved in the disability and chronicity of pain. Our study aim was to investigate whether social defeat stress (SDS) as a psychophysical stress affected mechanical withdrawal thresholds in the lumbar disk herniation (LDH) rat model. Changes in microglia and astrocytes, which play important roles in neuropathic pain states, were also investigated.

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MMP-9 regulates CX3CL1/CX3CR1 in the early phase of neuropathic pain in chronic sciatic nerve constriction injury (CCI) rats.

To observe the effects of MMP-9 (matrix metalloproteases-9) on the mechanical allodynia and thermal hyperalgesia and the expression of CX3CL1 (CX3C chemokine ligand 1) protein in the spinal dorsal root ganglion (DRG) in rats with chronic sciatic nerve constriction injury (CCI).

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Efficacy and safety of dupilumab for moderate-to-severe atopic dermatitis: a systematic review for the EAACI Biologicals Guidelines.

This systematic review evaluates the efficacy, safety and economic impact of dupilumab compared to standard of care for uncontrolled moderate-to-severe atopic dermatitis (AD). Pubmed, EMBASE and Cochrane Library were searched for RCTs and health economic evaluations. Critical and important AD-related outcomes were considered. The risk of bias and the certainty of the evidence were assessed using GRADE. Seven RCTs including 1845 subjects > 12 years treated with dupilumab 16 to 52 weeks were evaluated. For adults there is high certainty that dupilumab decreases SCORAD (MD -30,72; 95%CI -34,65% to -26,79%) and EASI-75 (RR 3.09; 95%CI 2.45 to 3.89), pruritus (RR 2.96; 95%CI 2.37 to 3.70), rescue medication (RR 3.46; 95%CI 2.79 to 4.30), sleep disturbance (MD -7.29; 95%CI -8.23 to -6.35), anxiety/depression (MD -3.08; 95% CI -4.41 to -1.75) and improves quality of life (MD -4.80; 95% CI -5.55 to -4.06). The efficacy for adolescents is similar. Dupilumab-related adverse events (AEs) slightly increase (low certainty). The evidence for dupilumab-related serious AE is uncertain. The incremental cost-effectiveness ratio ranged from 28,500 £ (low certainty) to 124,541 US$ (moderate certainty). More data on long term safety are needed both for children and adults, together with more efficacy data in the paediatric population.

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Low-dose methadone for refractory chronic migraine accompanied by medication-overuse headache: a prospective cohort study.

A refractory chronic migraine (RCM) accompanied by medication-overuse headache (MOH) is an extremely disabling disease. Evidence suggests that in selected patients, chronic opioids may be a valuable therapeutic option for RCM. The aim of the present study was to evaluate the effectiveness and safety of prophylaxis with low-dose methadone (LDM) in patients affected by RCM with continuous headache and MOH.

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Signs and symptoms, quality of life and psychosocial data in 1331 post-traumatic trigeminal neuropathy patients seen in two tertiary referral centres in two countries.

Post-traumatic trigeminal neuropathy (PTN) is a disturbance of function or pathological change of the trigeminal nerve branches following trauma and has an important impact on patient's quality of life (QoL).

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Imagined and Actual Acupuncture Effects on Chronic Low Back Pain: A Preliminary Study.

Research suggests that imagined experiences can produce brain responses similar to those produced by actual experiences. Shared brain responses that support both imagination and perception may underlie the functional nature of mental imagery. In a previous study, we combined acupuncture and imagery to develop a new treatment method, video-guided acupuncture imagery treatment (VGAIT). We found that VGAIT significantly increased pain thresholds in healthy subjects. The aim of this study is to extend our previous finding by investigating whether VGAIT can relieve symptoms in patients with chronic low back pain.

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The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652 in First-in-Human and Ascending Multiple Oral Dose Studies in Healthy Subjects.

Inhibitors of fatty acid amide hydrolase (FAAH) increase the levels of endocannabinoids and have shown analgesic and anti-inflammatory activity in animal models. ASP3652 is a peripherally acting FAAH inhibitor in development for the treatment of chronic bladder and pelvic pain disorders. Here we describe the safety, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of ASP3652 administered in healthy non-elderly and elderly male and female volunteers.

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Cognitive and sensorimotor function in participants being treated for trigeminal neuralgia pain.

Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls.

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N-Methyladenosine Demethylase FTO Contributes to Neuropathic Pain by Stabilizing G9a Expression in Primary Sensory Neurons.

Nerve injury-induced change in gene expression in primary sensory neurons of dorsal root ganglion (DRG) is critical for neuropathic pain genesis. N-methyladenosine (mA) modification of RNA represents an additional layer of gene regulation. Here, it is reported that peripheral nerve injury increases the expression of the mA demethylase fat-mass and obesity-associated proteins (FTO) in the injured DRG via the activation of Runx1, a transcription factor that binds to the gene promoter. Mimicking this increase erases mA in euchromatic histone lysine methyltransferase 2 () mRNA (encoding the histone methyltransferase G9a) and elevates the level of G9a in DRG and leads to neuropathic pain symptoms. Conversely, blocking this increase reverses a loss of mA sites in mRNA and destabilizes the nerve injury-induced G9a upregulation in the injured DRG and alleviates nerve injury-associated pain hypersensitivities. FTO contributes to neuropathic pain likely through stabilizing nerve injury-induced upregulation of G9a, a neuropathic pain initiator, in primary sensory neurons.

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Duration and Dosage of Opioids After Spine Surgery: Implications on Outcomes at 1 Year.

Longitudinal Cohort Study OBJECTIVE.: The aim of this study was to determine whether duration of postoperative opioids is associated with long-term outcomes, and if initial postoperative opioid dosage is associated with opioid cessation after spine surgery.

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A test of the fear avoidance model to predict chronic pain outcomes in a polytrauma sample.

Chronic musculoskeletal pain is a complex problem, particularly for individuals with head injury and comorbid psychiatric conditions. The Fear Avoidance Model offers one of the strongest opportunities to conceptualize comorbid traumatic injury and pain, but this model is largely untested.

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Online psychological interventions to reduce symptoms of depression, anxiety, and general distress in those with chronic health conditions: a systematic review and meta-analysis of randomized controlled trials.

Over the past 15 years, there has been substantial growth in web-based psychological interventions. We summarize evidence regarding the efficacy of web-based self-directed psychological interventions on depressive, anxiety and distress symptoms in people living with a chronic health condition.

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Pain-related anxiety, sex, and co-use of alcohol and prescription opioids among adults with chronic low back pain.

Both alcohol and prescription opioid use/misuse are highly prevalent among individuals with chronic pain. Co-use of alcohol and prescription opioids is also common, despite contraindications due to increased risk of negative health effects and mortality. There is evidence that pain-related anxiety (i.e., the tendency to respond to pain with anxiety or fear) may be associated with heavier drinking and prescription opioid use/co-use, and that these associations may be especially salient among men.

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Nociceptin is present in synovial fluid of patients undergoing total knee arthroplasty.

Osteoarthritis is a mechanical abnormality characterized by chronic joint pain associated with degeneration of the articular cartilage, synovitis, and local inflammation, leading to loss of function and pain. A connection exists between the peripheral nervous system and inflammatory joint degeneration. The process by which inflammation is influenced by the nervous system is known as neuroinflammation. One of the neuropeptides involved in peripheral neuroinflammation is nociceptin, a peptide related to the opioid class of substances. Nociceptin has both pro- and anti-inflammatory effects. Some studies show that nociceptin can be measured in synovial fluid, while other studies have not been able to detect it. The presence of nociceptin in synovial fluid could imply a molecular role for the neuropeptide in the joint, both physiologically as well as pathophysiologically. The goal of this pilot study was to determine whether nociceptin was present in the synovial fluid of osteoarthritic knees.

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Disrupted default mode network dynamics in recuperative patients of herpes zoster pain.

Previous studies of herpes zoster (HZ) have focused on acute patient manifestations and the most common sequela, postherpetic neuralgia (PHN), both serving to disrupt brain dynamics. Although the majority of such patients gradually recover, without lingering severe pain, little is known about life situations of those who recuperate or the brain dynamics. Our goal was to determine whether default mode network (DMN) dynamics of the recuperative population normalize to the level of healthy individuals.

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Intradural artery dilation during experimentally induced migraine attacks.

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery, hence vasoreactivity in the intradural arteries during migraine is unknown.Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 tesla MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined.Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (p=0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4 to 5.7 %]. Middle cerebral artery dilated by 9.4 % [95% CI: 7.1 to 11.7 %] and superficial temporal artery by 2.3 % [95% CI: 0.2 to 4.4 %].Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.

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A Phase I, Randomized, Single‑Blind, Placebo‑Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Oral TRV250, a G Protein-Selective Delta Receptor Agonist, in Healthy Subjects.

The delta opioid receptor (DOR) has been identified as a therapeutic target for migraine, with DOR agonists exhibiting low abuse potential compared with conventional µ-opioid agonists. TRV250 is a novel small molecule agonist of the DOR that is preferentially selective for G-protein signaling, with relatively little activation of the β-arrestin2 post-receptor signaling pathway. This selectivity provides reduced susceptibility to proconvulsant activity seen with non-selective DOR agonists. TRV250 significantly reduced nitroglycerin-evoked hyperalgesia in rodents, indicating a potential utility in acute migraine without the risk of seizure activity or abuse potential.

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Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo.

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred within 10 min of dosing. Moreover, the compound showed adequate, absolute oral bioavailability of 29.0%. Finally, CM398 showed promising anti-inflammatory analgesic effects in the formalin model of inflammatory pain in mice. The results collected in this study provide more evidence that selective sigma-2 receptor ligands can be useful tools in the development of novel pain therapeutics and altogether, these data suggest that CM398 is a suitable lead candidate for further evaluation.

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Perioperative pain and addiction interdisciplinary network (PAIN): protocol for the perioperative management of cannabis and cannabinoid-based medicines using a modified Delphi process.

At the conception of this study (January 2019), a literature search by the authors found no evidence-based or consensus perioperative guidelines for patients consuming cannabis products, or for those patients in whom a cannabinoid medication could be considered for perioperative treatment. Currently, there is a large global population that consumes cannabis. The availability of cannabis has also increased this decade with greater legal access to cannabis products in some countries such as USA, Canada, Uruguay, Israel, Australia and Germany. There are recognised possible therapeutic benefits for the use of cannabis in patients with chronic pain, chronic neuropathic pain and chemotherapy-induced nausea and vomiting. There are also potential side effects from cannabis use such as psychosis, cannabis hyperemesis syndrome, misuse disorder and cannabis withdrawal syndrome. There is evidence that cannabis may also affect factors in the perioperative period such as monitoring, quality of analgesia, sleep and opioid consumption. Given the large population of persons using cannabis, the heterogeneity of cannabis products and the paucity (and heterogeneity) of perioperative literature surrounding it, perioperative guidelines for cannabis consuming patients are both lacking and necessary. In this paper, we present the design for a modified Delphi technique that has been started with the intent of deriving cannabis perioperative guidelines from the available medical literature and the consensus of multidisciplinary experts.

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Mu opioid receptors on vGluT2-expressing glutamatergic neurons modulate opioid reward.

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2). We created a transgenic mouse that lacks MORs in vGluT2-expressing neurons (MORflox-vGluT2cre) to demonstrate that MORs on the vGluT2 neurons themselves mediate this synaptic inhibition. We then explored the role of MORs in vGluT2-expressing neurons in opioid-related behaviors. In tests of conditioned place preference, MORflox-vGluT2cre mice did not acquire place preference for a low dose of the opioid, oxycodone, but displayed conditioned place aversion at a higher dose, whereas control mice displayed preference for both doses. In an oral consumption assessment, these mice consumed less oxycodone and had reduced preference for oxycodone compared with controls. MORflox-vGluT2cre mice also failed to show oxycodone-induced locomotor stimulation. These mice displayed baseline withdrawal-like responses following the development of oxycodone dependence that were not seen in littermate controls. In addition, withdrawal-like responses in these mice did not increase following treatment with the opioid antagonist, naloxone. However, other MOR-mediated behaviors were unaffected, including oxycodone-induced analgesia. These data reveal that MOR-mediated regulation of glutamate transmission is a critical component of opioid reward.

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Exploring Associations Between Metabolites and Symptoms of Fatigue, Depression and Pain in Women With Fibromyalgia.

Fibromyalgia (FM) is a chronic noncommunicable disorder characterized by a constellation of symptoms that include fatigue, depression and chronic pain. FM affects 2%-8% of the U.S. population, 2% of the global population, with 61%-90% of FM diagnoses attributed to women. Key causal factors leading to the development and severity of FM-related symptoms have not yet been identified. The purpose of this article is to report relationships among identified metabolites and levels of fatigue, depression, pain severity, and pain interference in a sample of 20 women with FM. In this secondary analysis, we conducted global metabolomic analysis and examined the data for relationships of metabolite levels with self-reported symptoms of fatigue, depression, pain severity, and pain interference. Results revealed six metabolites (6-deoxy-hexose; pantothenic acid; ergothioneine; l-carnitine; n-acetylserotonin; butyrobetaine) and their associated metabolic pathways such as carnitine synthesis, lipid oxidation, tryptophan metabolism, beta-alanine metabolism and pantothenic and Coenzyme-A biosynthesis that were either positively or inversely related to pain severity, pain interference, or both. The preliminary data presented suggest that metabolites representing energy, amino acid, or lipid classification may be associated with pain symptom severity and interference in women with FM. Future work will confirm these findings in a large, comparative cohort, targeting metabolites and metabolite pathways to better understand the relationships of metabolites and symptomology.

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