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Papers: 6 Jun 2020 - 12 Jun 2020

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Cellular circuits in the brain and their modulation in acute and chronic pain.

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics and imaging technological tools in rodent models with a view towards decoding sensory, affective and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.

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

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mTOR activation by constitutively active serotonin6 receptors as new paradigm in neuropathic pain and its treatment.

Chronic neuropathic pain is a highly disabling syndrome that is poorly controlled by currently available analgesics. Here, we show that painful symptoms and associated cognitive deficits induced by spinal nerve ligation in the rat are prevented by the administration of serotonin 5-HT receptor inverse agonists or by the mTOR inhibitor rapamycin. In contrast, they are not alleviated by the administration of 5-HT receptor neutral antagonists. Likewise, activation of mTOR by constitutively active 5-HT receptors mediates allodynia in oxaliplatin-induced peripheral neuropathy in rats but not mechanical nociception in healthy rats. Furthermore, both painful and co-morbid cognitive symptoms in neuropathic rats are strongly reduced by intrathecal delivery of a cell-penetrating peptide that disrupts 5-HT receptor/mTOR physical interaction. Collectively, these findings demonstrate a deleterious influence of non-physiological mTOR activation by constitutively active spinal 5-HT receptors upon painful and cognitive symptoms in neuropathic pains of different etiologies. They suggest that targeting the constitutive activity of 5-HT receptors with inverse agonists or disrupting the 5-HT receptor/mTOR interaction might be valuable strategies for the alleviation of neuropathic pain and cognitive co-morbidities.

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Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors.

Pain is a source of substantial discomfort. Abnormal activity in both the zona incerta (ZI) and posterior complex of the thalamus (Po) are implicated in neuropathic pain, but their exact roles remain unclear. In particular, the precise cell types and molecular mechanisms of the ZI-Po circuit that regulate nociception are largely uncharacterized. Here, we found that parvalbumin (PV)-positive neuronal projections from the ventral ZI (ZIv) to the Po (ZIv-Po) are critical for promoting nocifensive behaviors, whereas selectively inhibiting ZIv-Po activity reduces nocifensive withdrawal responses. Furthermore, cannabinoid type 1 receptors (CBRs) are expressed specifically at ZIv-Po axon terminals in this circuit, and cannabinoids attenuate nocifensive responses through presynaptic inhibition. Selective inhibition of the ZIv-Po circuit or administration of cannabinoids into the Po are sufficient to ameliorate pathological pain. These findings identify the critical role of the ZIv-Po circuit and its modulation by endocannabinoids in controlling nocifensive behaviors.

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GCaMP as an indirect measure of electrical activity in rat trigeminal ganglion neurons.

While debate continues over whether somatosensory information is transmitted via labeled line, population coding, frequency coding, or some combination therein, researchers have begun to address this question at the level of the primary afferent by using optical approaches that enable the assessment of neural activity in hundreds to even thousands of neurons simultaneously. However, with limited availability of tools to optically assess electrical activity in large populations of neurons, researchers have turned to genetically encoded Ca indicators (GECIs) including GCaMP to enable the detection of increases in cytosolic Ca concentrations as a correlate for neuronal activity. One of the most widely used GECIs is GCaMP6, which is available in three different versions tuned for sensitivity (GCaMP6s), speed (GCaMP6f), or a balance of the two (GCaMP6m). In order to determine if these issues were unique to GCaMP6 itself, or if they were inherent to more than one generation of GCaMP, we also characterized jGCaMP7. In the present study, we sought to determine the utility of the three GCaMP6 isoforms to detect changes in activity in primary afferents at frequencies ranging from 0.1-30 Hz. Given the heterogeneity of sensory neurons, we also compared the performance of each GCaMP6 isoform in subpopulations of neurons defined by properties used to identify putative nociceptive afferents: cell body size, isolectin B4 (IB4) binding, and capsaicin sensitivity. Finally, we compared results generated with GCaMP6 with that generated from neurons expressing the next generation of GCaMP, jGCaMP7s and jGCaMP7f. A viral approach, with AAV9-CAG-GCaMP6s/m/f, was used to drive GECI expression in acutely dissociated rat trigeminal ganglion (TG) neurons, and neural activity was driven by electrical field stimulation. Infection efficiency with the AAV serotype was high >95 %, and the impact of GCaMP6 expression in TG neurons over the period of study (<10 days) on the regulation of intracellular Ca, as assessed with fura-2, was minimal. Having confirmed that the field stimulation evoked Ca transients were dependent on Ca influx secondary to the activation of action potentials and voltage-gated Ca channels, we also confirmed that the signal-to-noise ratio for each of the isoforms was excellent, enabling detection of a single spike in>90% of neurons. However, the utility of the GCaMP6 isoforms to enable an assessment of the firing frequency let alone changes in firing frequency of each neuron was relatively limited and isoform specific: GCaMP6s and 6m had the lowest resolution, enabling detection of spikes at 3 Hz in 15% and 32% of neurons respectively, but it was possible to resolve discrete single spikes up to 10 Hz in 36% of GCaMP6f neurons. Unfortunately, using other parameters of the Ca transient, such as magnitude of the transient or the rate of rise, did not improve the range over which these indicators could be used to assess changes in spike number or firing frequency. Furthermore, in the presence of ongoing neural activity, it was even more difficult to detect a change in firing frequency. The frequency response relationship for the increase in Ca was highly heterogeneous among sensory neurons and was influenced by both the GCaMP6 isoform used to assess it, the timing between the delivery of stimulation trains (inter-burst interval), and afferent subpopulation. Notably, the same deficiencies were observed with jGCaMP7s and 7f in resolving the degree of activity as were present for the GCaMP6 isoforms. Together, these data suggest that while both GCaMP6 and jGCaMP7 are potentially useful tools in sensory neurons to determine the presence or absence of neural activity, the ability to discriminate changes in firing frequency ≥ 3 Hz is extremely limited. As a result, GECIs should probably not be used in sensory neurons to assess changes in activity within or between subpopulations of neurons.

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Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

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Different neuronal populations mediate inflammatory pain analgesia by exogenous and endogenous opioids.

Mu-opioid receptors (MORs) are crucial for analgesia by both exogenous and endogenous opioids. However, the distinct mechanisms underlying these two types of opioid analgesia remains largely unknown. Here, we demonstrate that analgesic effects of exogenous and endogenous opioids on inflammatory pain are mediated by MORs expressed in distinct subpopulations of neurons in mouse. We found that the exogenous opioid-induced analgesia of inflammatory pain is mediated by MORs in Vglut2 glutamatergic but not GABAergic neurons. In contrast, analgesia by endogenous opioids is mediated by MORs in GABAergic rather than Vglut2 glutamatergic neurons. Furthermore, MORs expressed at the spinal level is mainly involved in the analgesic effect of morphine in acute pain, but not in endogenous opioid analgesia during chronic inflammatory pain. Thus, our study revealed distinct mechanisms underlying analgesia by exogenous and endogenous opioids, and laid the foundation for further dissecting the circuit mechanism underlying opioid analgesia.

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Sex-Specific Disruption of Distinct mPFC Inhibitory Neurons in Spared-Nerve Injury Model of Neuropathic Pain.

The medial prefrontal cortex (mPFC) modulates a range of behaviors, including responses to noxious stimuli. While various pain modalities alter mPFC function, our understanding of changes to specific cell types underlying pain-induced mPFC dysfunction remains incomplete. Proper activity of cortical GABAergic interneurons is essential for normal circuit function. We find that nerve injury increases excitability of layer 5 parvalbumin-expressing neurons in the prelimbic (PL) region of the mPFC from male, but not female, mice. Conversely, nerve injury dampens excitability in somatostatin-expressing neurons in layer 2/3 of the PL region; however, effects are differential between males and females. Nerve injury slightly increases the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) in layer 5 parvalbumin-expressing neurons in males but reduces frequency of sEPSCs in layer 2/3 somatostatin-expressing neurons in females. Our findings provide key insight into how nerve injury drives maladaptive and sex-specific alterations to GABAergic circuits in cortical regions implicated in chronic pain.

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Mutational analysis of ProTx-I and the novel venom peptide Pe1b provide insight into residues responsible for selective inhibition of the analgesic drug target Na1.7.

Management of chronic pain presents a major challenge, since many currently available treatments lack efficacy and have problems such as addiction and tolerance. Loss of function mutations in the SCN9A gene lead to a congenital inability to feel pain, with no other sensory deficits aside from anosmia. SCN9A encodes the voltage-gated sodium (Na) channel 1.7 (Na1.7), which has been identified as a primary pain target. However, in developing Na1.7-targeted analgesics, extreme care must to be taken to avoid off-target activity on other Na subtypes that are critical for survival. Since spider venoms are an excellent source of Na channel modulators, we screened a panel of spider venoms to identify selective Na1.7 inhibitors. This led to identification of two novel Na modulating venom peptides (β/μ-theraphotoxin-Pe1a and β/μ-theraphotoxin-Pe1b (Pe1b) from the arboreal tarantula Phormingochilus everetti. A third peptide isolated from the tarantula Bumba pulcherrimaklaasi was identical to the well-known ProTx-I (β/ω-theraphotoxin-Tp1a) from the tarantula Thrixopelma pruriens. A tethered toxin (t-toxin)-based alanine scanning strategy was used to determine the Na1.7 pharmacophore of ProTx-I. We designed several ProTx-I and Pe1b analogues, and tested them for activity and Na channel subtype selectivity. Several analogues had improved potency against Na1.7, and altered specificity against other Na channels. These analogues provide a foundation for development of Pe1b as a lead molecule for therapeutic inhibition of Na1.7.

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FcγRI-coupled signaling in peripheral nociceptors mediates joint pain in a rat model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is often accompanied by joint pain and inflammation. Previous studies demonstrated that functional FcγRI was expressed in dorsal root ganglion neurons, and might contribute to pain in rodent models of antigen-induced arthritis (AIA). This study was performed to elucidate the roles of nociceptive neuronal FcγRI-coupled signaling in the development of joint pain in AIA.

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Association of Migraine With Aura and Other Risk Factors With Incident Cardiovascular Disease in Women.

Migraine with aura is known to increase the risk of cardiovascular disease (CVD). The absolute contribution of migraine with aura to CVD incidence in relation to other CVD risk factors remains unclear.

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IL-6 induced upregulation of T-type Ca currents and sensitization of DRG nociceptors is attenuated by MNK inhibition.

Phosphorylation of the 5' cap-binding protein eIF4E by MAPK interacting kinases MNK1/2 is important for nociceptor sensitization and the development of chronic pain. IL-6 induced DRG nociceptor excitability is attenuated in mice lacking eIF4E phosphorylation, in MNK1/2 mice and by the nonselective MNK1/2 inhibitor cercosporamide. Here, we sought to better understand the neurophysiological mechanisms underlying how IL-6 causes nociceptor excitability via MNK-eIF4E signaling using the highly selective MNK inhibitor eFT508 . Dorsal root ganglion (DRG) neurons were cultured from male and female ICR mice, 4-7 weeks old. DRG cultures were treated with vehicle, IL-6, eFT508 (pretreat) followed by IL-6 or eFT508 alone. Whole-cell patch clamp recordings were done on small diameter neurons (20-30 pF) to measure membrane excitability in response to ramp depolarization. One hr IL-6 treatment resulted in increased action potential firing compared to vehicle at all ramp intensities, an effect that was blocked by pretreatment with eFT508. Basic membrane properties, including resting membrane potential, input resistance and rheobase, were similar across groups. Latency to the first action potential in the ramp protocol was lower in the IL-6 group, and rescued by eFT508 pretreatment. We also found that the amplitudes of T-type voltage-gated calcium channels (VGCCs) were increased in the DRG following IL-6 treatment, but not in the eFT508 co-treatment group. Our findings are consistent with a model wherein MNK-eIF4E signaling controls the translation of signaling factors that regulate T-type VGCCs in response to IL-6 treatment. Inhibition of MNK with eFT508 disrupts these events, thereby preventing nociceptor hyperexcitability.

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Fentanyl but not Morphine Interacts with Non-Opioid Recombinant Human Neurotransmitter Receptors and Transporters.

Synthetic opioids, including fentanyl and its analogues, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the U.S. has increased, and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite, morphine, induce respiratory depression that can be treated with the mu opioid receptor (MOR) antagonist, naloxone. With higher or more rapid dosing, fentanyl, more than morphine, causes chest wall rigidity, and can also induce rapid onset laryngospasm. Because non-MORs could mediate differing clinical manifestations, we examined the interactions of fentanyl and morphine at recombinant human neurotransmitter transporters, G protein-coupled receptors, and the NMDA glutamate receptor. Both drugs were agonists at MOR, kappa, and delta opioid receptors. Morphine had little or no affinity at other human receptors and transporters (Ki or IC value >100μM). However, fentanyl had Ki values of 1,407nM and 1,100nM at α1A and α1B adrenoceptor subtypes, respectively, Ki values of 1,049nM and 1,670nM at dopamine D4.4 and D1 receptor subtypes, respectively, and also blocked [H]neurotransmitter uptake by the vesicular monoamine transporter 2 (VMAT2) (IC = 911nM). Pharmacokinetic models indicate that these Ki and IC values are pharmacologically relevant. Fentanyl had little affinity for other receptors or transporters. Thus, noradrenergic disposition at specific receptor subtypes in relevant organs may play a role in respiratory and cardiothoracic effects of fentanyl. Data suggest that less selective fentanyl receptor pharmacology could play a role in the different clinical effects of morphine compared to fentanyl, including fentanyl-induced deaths following illicit use. SIGNIFICANCE STATEMENT: The synthetic opioid, fentanyl, induces different clinical effects including rapid onset muscular rigidity, vocal cord closure and rapid death, than the heroin metabolite, morphine. Our data indicate for the first time that the two drugs have very different effects at recombinant human neurotransmitter receptors and transporters that might explain those clinical differences.

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Placebo-induced pain reduction is associated with negative coupling between brain networks at rest.

Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between two resting-state networks in placebo but not control participants. Specifically, networks comprised the bilateral somatosensory cortex and posterior insula, as well as the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the anterior insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, and there was no significant relation with expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a theoretical model where placebo analgesia might affect processing within a descending pain-modulatory network, potentially segregating it from somatosensory regions that may code for painful experiences.

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Altered resting activity patterns and connectivity in individuals with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder that typically occurs in the limbs, usually the upper limb. CRPS usually develops from a peripheral event but its maintenance relies on changes within the central nervous system. While functional abnormalities in the thalamus and primary somatosensory cortex (S1) of the brain are some of the most consistently reported brain findings in CRPS, the mechanisms are yet to be explored in full, not least of all how these two regions interact and how they might relate to clinical deficits, such as the commonly reported poor tactile acuity in this condition. This study recruited 15 upper-limb CRPS subjects and 30 healthy controls and used functional magnetic resonance imaging (fMRI) to investigate infra-slow oscillations (ISOs) in critical pain regions of the brain in CRPS. As hypothesised, we found CRPS was associated with increases in resting signal intensity ISOs (0.03-0.06 Hz) in the thalamus contralateral to the painful limb in CRPS subjects. Interestingly, there was no such difference between groups in S1, however CRPS subjects displayed stronger thalamo-S1 functional connectivity than controls, and this was related to pain. As predicted, CRPS subjects displayed poor tactile acuity on the painful limb which, interestingly, was also related to thalamo-S1 functional connectivity strength. Our findings provide novel evidence of altered patterns of resting activity and connectivity in CRPS which may underlie altered thalamocortical loop dynamics and the constant perception of pain.

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CD3 T cells are critical for the resolution of comorbid inflammatory pain and depression-like behavior.

Chronic pain and depression often co-occur. The mechanisms underlying this comorbidity are incompletely understood. Here, we investigated the role of CD3 T cells in an inflammatory model of comorbid persistent mechanical allodynia, spontaneous pain, and depression-like behavior in mice.

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Differential Expression of Acid – Sensing Ion Channels in Mouse Primary Afferents in Naïve and Injured Conditions.

Injury and inflammation cause tissue acidosis, which is a common feature of various painful conditions. Acid-Sensing Ion channels (ASICs) are amongst the main excitatory channels activated by extracellular protons and expressed in the nervous system. Six transcripts of ASIC subunits including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4 are encoded by four genes (Asic1-4) and have been identified in rodents. Most ASIC subunits are present at substantial levels in primary sensory neurons of dorsal root ganglia (DRG) except for ASIC4. However, their expression pattern in DRG neurons remains largely unclear, mainly due to the lack of antibodies with appropriate specificity. In this study, we examined in detail the expression pattern of ASIC1-3 subunits, including splice variants, in different populations of DRG neurons in adult mice using an hybridization technique (RNAscope) with high sensitivity and specificity. We found that in naïve condition, all five subunits examined were expressed in the majority of myelinated, NF200-immunoreactive, DRG neurons (NF200). However, ASIC subunits showed a very different expression pattern among non-myelinated DRG neuronal subpopulations: ASIC1 and ASIC3 were only expressed in CGRP-immunoreactive neurons (CGRP), ASIC2a was mostly expressed in the majority of IB4-binding neurons (IB4), while ASIC2b was expressed in almost all non-myelinated DRG neurons. We also found that at least half of sensory neurons expressed multiple types of ASIC subunits, indicating prevalence of heteromeric channels. In mice with peripheral nerve injury, the expression level of ASIC1a and ASIC1b in L4 DRG and ASIC3 in L5 DRG were altered in CGRP neurons, but not in IB4 neurons. Furthermore, the pattern of change varied among DRGs depending on their segmental level, which pointed to differential regulatory mechanisms between afferent types and anatomical location. The distinct expression pattern of ASIC transcripts in naïve condition, and the differential regulation of ASIC subunits after peripheral nerve injury, suggest that ASIC subunits are involved in separate sensory modalities.

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Acupuncture Treatment Modulates the Connectivity of Key Regions of the Descending Pain Modulation and Reward Systems in Patients with Chronic Low Back Pain.

Chronic low back pain (cLBP) is a common disorder with unsatisfactory treatment options. Acupuncture has emerged as a promising method for treating cLBP. However, the mechanism underlying acupuncture remains unclear. In this study, we investigated the modulation effects of acupuncture on resting state functional connectivity (rsFC) of the periaqueductal gray (PAG) and ventral tegmental area (VTA) in patients with cLBP. Seventy-nine cLBP patients were recruited and assigned to four weeks of real or sham acupuncture. Resting state functional magnetic resonance imaging data were collected before the first and after the last treatment. Fifty patients completed the study. We found remission of pain bothersomeness in all treatment groups after four weeks, with greater pain relief after real acupuncture compared to sham acupuncture. We also found that real acupuncture can increase VTA/PAG rsFC with the amygdala, and the increased rsFC was associated with decreased pain bothersomeness scores. Baseline PAG-amygdala rsFC could predict four-week treatment response. Our results suggest that acupuncture may simultaneously modulate the rsFC of key regions in the descending pain modulation (PAG) and reward systems (VTA), and the amygdala may be a key node linking the two systems to produce antinociceptive effects. Our findings highlight the potential of acupuncture for chronic low back pain management.

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Does type 2 diabetes increase the risk of musculoskeletal pain? Cross-sectional and longitudinal analyses of UK biobank data.

We investigated cross-sectional associations and whether type 2 diabetes increases the risk of musculoskeletal pain after adjusting for the presence of important comorbidities.

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Effectiveness and optimal dosage of exercise training for chronic non-specific neck pain: A systematic review with a narrative synthesis.

Clinical guidelines make vague recommendations as to exercise training (ET) type and dosage to manage chronic non-specific neck pain (CNSNP).

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Sleep disturbance as a moderator of the association between physical activity and later pain onset among American adults aged 50 and over: evidence from the Health and Retirement Study.

To examine whether sleep disturbance modifies the association between physical activity and incident pain.

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The Effects of a Pain Psychology and Neuroscience Self-Evaluation Internet Intervention: A Randomized Controlled Trial.

Many patients' chronic musculoskeletal pain is strongly influenced by central nervous system processes such as sensitization or amplification. Education about pain neuroscience can change patients' beliefs but has less consistent effects on pain outcomes. Patients may have greater clinical benefits if the educational intervention is personalized, and they evaluate various psychosocial risk factors with respect to their pain. We developed and tested a brief, internet-based Pain Psychology and Neuroscience (PPN) self-evaluation intervention.

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Current and emerging systemic treatments targeting the neural system for chronic pruritus.

Pruritus is a debilitating symptom that significantly affects the quality of life of patients who suffer from it. Many current and emerging systemic treatments targeting the neural system have been successful in treating itch of various underlying etiologies.

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Changes in opioid receptors, opioid peptides and morphine antinociception in mice subjected to early life stress.

Recent studies have shown that the endogenous opioid system is considerably affected by early life stress such as child abuse. Here, we investigated whether early life stress changes the endogenous opioid receptors and their peptides, and if such stress impacts morphine antinociception. We used mice affected by maternal separation and social isolation (MSSI) as an early life stress model. In the tail-flick test, 10-week-old MSSI mice showed a significant decrease in morphine antinociception compared to age-matched control mice. The number of c-Fos-positive cells increased in the periaqueductal gray (PAG), nucleus accumbens, and thalamus of control mice after the morphine injections, whereas hardly any positive cells were detected in the same areas of MSSI mice. The expression of μ- and κ-opioid receptor (MOR and KOR, respectively) messenger RNA (mRNA) was significantly decreased in the PAG of MSSI mice, whereas KOR expression was significantly increased in the amygdala of MSSI mice. The expression of δ-opioid receptor (DOR) mRNA was significantly reduced in the PAG and rostral ventromedial medulla of MSSI mice compared to control mice. Moreover, the lack of morphine antinociception was observed in 18-week-old MSSI mice. Our findings suggest that the supraspinal opioid system may be affected by early life stress exposure, and that this exposure may impact morphine antinociception.

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Mechano growth factor interacts with nucleolin to protect against cisplatin-induced neurotoxicity.

Mechano growth factor (MGF) is an alternatively spliced form of insulin-like growth factor-1 (IGF-1) that has shown to be neuroprotective against 6-hydroxydopamine toxicity and ischemic injury in the brain. MGF also induces neural stem cell proliferation in the hippocampus and preserves olfactory function in aging mice. Cisplatin is a chemotherapy drug that induces peripheral neuropathy in 30-40% of treated patients. Our studies were designed to see if MGF would protect dorsal root ganglion (DRG) neurons from cisplatin-induced neurotoxicity and to identify potential mechanisms that may be involved. Expression of endogenous MGF in adult DRG neurons in vivo ameliorated cisplatin-induced thermal hyperalgesia. Exogenous MGF and MGF with a cysteine added to the N-terminus (CMGF) also protected embryonic DRG neurons from cisplatin-induced cell death in vitro. Mass spectroscopy analysis of proteins bound to MGF showed that nucleolin is a key-binding partner. Antibodies against nucleolin prevented the neuroprotective effect of MGF and CMGF in culture. Both nucleolin and MGF are located in the nucleolus of DRG neurons. RNAseq of RNA associated with MGF indicated that MGF may be involved in RNA processing, protein targeting and transcription/translation. Nucleolin is an RNA binding protein that is readily shuttled between the nucleus, cytoplasm and plasma membrane. Nucleolin and MGF may work together to prevent cisplatin-induced neurotoxicity. Exploring the known mechanisms of nucleolin may help us better understand the mechanisms of cisplatin toxicity and how MGF protects DRG neurons.

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Osteoarthritis Pain Model Induced by Intra-Articular Injection of Mono-Iodoacetate in Rats.

The current animal models of osteoarthritis (OA) can be divided into spontaneous models and induced models, both of which aim to simulate the pathophysiological changes of human OA. However, as the main symptom in the late stage of OA, pain affects the patients' daily life, and there are not many available models. The mono-iodoacetate (MIA)-induced model is the most widely used OA pain model, mainly used in rodents. MIA is an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, which causes chondrocyte death, cartilage degeneration, osteophyte, and measurable changes in animal behavior. Besides, expression changes of matrix metalloproteinase (MMP) and pro-inflammatory cytokines (IL1 β and TNF α) can be detected in the MIA-induced model. Those changes are consistent with OA pathophysiological conditions in humans, indicating that MIA can induce a measurable and successful OA pain model. This study aims to describe the methodology of intra-articular injection of MIA in rats and discuss the resulting pain-related behaviors and histopathological changes.

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Safety and Efficacy of Fremanezumab for the Prevention of Migraine: A Meta-Analysis From Randomized Controlled Trials.

Fremanezumab (TEV-48125) is a fully-humanized immunoglobulin G isotype 2a selective monoclonal antibody that potently binds to calcitonin gene-related peptide (CGRP). It is one of the novel therapeutic drugs for the prevention of migraine, which is one of the most common neurological diseases worldwide. Several controlled trials have been conducted to investigate the safety and efficacy of fremanezumab, however, there is no systematic review of the existing literature has been performed. Hence, in our study, we performed a meta-analysis to investigate the safety and efficacy of fremanezumab for the prevention of migraine. Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to August 2019 for randomized controlled trials (RCTs). Five RCTs with 3,379 patients were finally included in our study. We pooled 3,379 patients from 5 RCTs; the primary endpoints were mean monthly migraine and headache days, baseline to week 12. We found that fremanezumab led to a significant reduction in migraine days ( < 0.0001) and headache days ( < 0.0001) during 12 weeks compared with placebo. Moreover, after using fremanezumab, the risk of at least one adverse event (AE) ( = 0.001) and AE related to the trial regimen ( = 0.0005) significantly increased compared with the placebo. Fremanezumab showed good efficacy for the prevention of migraine. The administration of fremanezumab can cause some mild adverse events but no serious adverse events.

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Opioid Use Trajectories after Thoracic Surgery among Veterans in the United States.

Opioid use has increased to epidemic levels over the past decade within the United States, particularly among vulnerable populations. This retrospective study aimed to evaluate rates of prolonged opioid use in the Veteran population after thoracic surgery and identify specific risk clusters.

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Capsaicin-Induced Skin Desensitization Differentially Affects A-Delta and C-Fiber-Mediated Heat Sensitivity.

Localized neuropathic pain can be relieved following the topical application of high-concentration capsaicin. This clinical effect is thought to be related to the temporary desensitization of capsaicin- and heat-sensitive epidermal nociceptors. The objective of the present study was to examine whether the changes in thermal sensitivity induced by high-concentration topical capsaicin can be explained entirely by desensitization of capsaicin-sensitive afferents. For this purpose, we characterized, in 20 healthy human volunteers, the time course and spatial extent of the changes in sensitivity to thermal stimuli preferentially activating heat-sensitive A-fiber nociceptors, heat-sensitive C-fiber afferents, and cool-sensitive A-fiber afferents. The volar forearm was treated with a high-concentration capsaicin patch for 1 h. Transient heat, warm and cold stimuli designed to activate Aδ- and C-fiber thermonociceptors, C-fiber warm receptors, and Aδ-fiber cold receptors were applied to the skin before and after treatment at days 1, 3, and 7. Reaction times, intensity ratings, and quality descriptors were collected. The stimuli were applied both within the capsaicin-treated skin and around the capsaicin-treated skin to map the changes in thermal sensitivity. We found that topical capsaicin selectively impairs heat sensitivity without any concomitant changes in cold sensitivity. Most interestingly, we observed a differential effect on the sensitivity to thermal inputs conveyed by Aδ- and C-fibers. Reduced sensitivity to Aδ-fiber-mediated heat was restricted to the capsaicin-treated skin, whereas reduced sensitivity to C-fiber-mediated heat extended well beyond the treated skin. Moreover, the time course of the reduced sensitivity to C-fiber-mediated input was more prolonged than the reduced sensitivity to Aδ-fiber-mediated input.

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Efficacy and acceptability of pharmacological and non-pharmacological interventions for non-specific chronic low back pain: a protocol for a systematic review and network meta-analysis.

Despite the enormous financial and humanistic burden of chronic low back pain (CLBP), there is little consensus on what constitutes the best treatment options from a multitude of competing interventions. The objective of this network meta-analysis (NMA) is to determine the relative efficacy and acceptability of primary care treatments for non-specific CLBP, with the overarching aim of providing a comprehensive evidence base for informing treatment decisions.

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High sensitivity C-reactive protein and risk of migraine in a 11-year follow-up with data from the Nord-Trøndelag health surveys 2006-2008 and 2017-2019.

Several previous studies have reported a cross-sectional association between elevated high sensitivity C-reactive protein (hs-CRP) and migraine. The aim of this population-based follow-up study was to investigate the influence of hs-CRP at baseline on the risk of developing migraine 11 years later.

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Small molecule drugs for the treatment of pruritus in patients with atopic dermatitis.

Chronic pruritus is a cardinal symptom of the inflammatory skin disease atopic dermatitis (AD). Pathogenic mechanisms in the periphery, spinal cord and the brain have been implicated in AD-related pruritus. Therefore, both systemic and topical administration of drugs could potentially provide relief. Despite efforts to elucidate the mechanisms behind AD-related pruritus and the relative contribution of peripheral nervous system and central nervous system (CNS), specific and successful treatment options have not yet been developed. Several small molecule drugs are currently being investigated to treat AD and AD-related pruritus. These small molecule drugs can be applied systemically but also topically, as they are able to penetrate into the skin due to their small size. Small molecule drugs specifically targeting peripheral itch transmission, e.g. peripherally selective κ-opioid receptors agonists and neurokinin 1 receptors antagonists, have so far been unable to improve AD-related pruritus when applied systemically, possibly because of the lack of CNS activity. Current evidence from clinical and preclinical trials with centrally acting or peripherally selective oral κ-opioid receptors agonists implies that CNS activity is required for an antipruritic effect. CNS activity is, however, directly associated with CNS-mediated side-effects. On the other hand, topical application of small molecules with anti-inflammatory activity such as Janus kinase inhibitors and phosphodiesterase 4 inhibitors, and also of κ-opioid receptor agonists, has shown promising results regarding their ability to reduce AD-related pruritus. In conclusion, topical application of anti-inflammatory compounds appears to be a highly promising strategy for the treatment of AD-related pruritus.

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Effects of neurofeedback in the management of chronic pain: A systematic review and meta-analysis of clinical trials.

Neurofeedback provides real-time feedback about neurophysiological signals to patients, thereby encouraging modulation of pain-associated brain activity. This review aims to evaluate the effectiveness and safety of neurofeedback in alleviating pain and pain-associated symptoms in chronic pain patients.

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Chronic pain diagnosis in refugee torture survivors: A prospective, blinded diagnostic accuracy study.

An estimated 87% of torture survivors experience chronic pain such as brachial plexopathy from upper extremity suspension or lumbosacral plexus injury from leg hyperextension. However, a vast majority of pain is undetected by evaluators due to a lack of diagnostic tools and confounding psychiatric illness. This diagnostic gap results in exclusive psychological treatment rather than multimodal therapies, substantially limiting rehabilitation. We hypothesized that the United Nations Istanbul Protocol (UNIP) would have a sensitivity of approximately 15% for pain detection, and that the use of a validated pain screen would improve its sensitivity by at least 29%, as compared to the reference standard (pain specialist evaluation).

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Genetics of migraine aura: an update.

Migraine is a common brain disorder with a large genetic component. Of the two main migraine types, migraine with aura and migraine without aura, the genetic underpinning in the former is least understood. Given the evidence from epidemiological studies in cohorts and families that the genetic contribution is highest in migraine with aura, this seems paradoxical. Various genetic approaches have been applied to identify genetic factors that confer risk for migraine. Initially, so-called candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) tested variants in any gene in an hypothesis-free manner. Whereas GWAS in migraine without aura, or the more general diagnosis migraine have already identified dozens of gene variants, the specific hunt for gene variants in migraine with aura has been disappointing. The only GWAS specifically investigating migraine with aura yielded only one single associated single nucleotide polymorphism (SNP), near MTDH and PGCP, with genome-wide significance. However, interrogation of all genotyped SNPs, so beyond this one significant hit, was more successful and led to the notion that migraine with aura and migraine without aura are genetically more alike than different. Until now, most relevant genetic discoveries related to migraine with aura came from investigating monogenetic syndromes with migraine aura as a prominent phenotype (i.e. FHM, CADASIL and FASPS). This review will highlight the genetic findings relevant to migraine with aura.

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Effects of a person-centred approach in a school setting for adolescents with chronic pain – The HOPE randomized controlled trial.

Chronic pain among adolescents is common but effective interventions applicable in a school setting are rare. Person-centred care (PCC) is a key factor in improving health by engaging people as partners in their own care.

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Within- and between-session reliability of secondary hyperalgesia induced by electrical high-frequency stimulation.

An increasing number of studies are focusing on secondary hyperalgesia to better understand central sensitization, as this phenomenon may play an important role in persistent pain. Recent studies have shown that, compared to the classical high frequency stimulation protocol (HFS) at 100 Hz, a protocol using 42 Hz stimulation induces a more intense and a larger area of secondary hyperalgesia (SH).

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Increased immediate early gene activation in the basolateral amygdala following persistent peripheral inflammation.

Chronic pain results in a variety of neural adaptations, many of which are maladaptive and result in hypersensitivity to pain. In humans, this hypersensitivity can be debilitating and treatment options are limited. Fortunately, there are numerous animal models that mimic clinical populations and have the potential to aid in the evaluation of underlying mechanisms and ultimately the development of better treatments. One of these is the complete Freund's adjuvant (CFA)-model of chronic inflammatory pain. In rodents, this model requires the injection of CFA into the hindpaw, muscle, or joint, which induces inflammation similar to what might be found in individuals with rheumatoid arthritis or tendonitis. While the mechanistic effects CFA on the spinal cord are well established, less is known about the effects of CFA on the brain. Thus, in this study, neuronal activation, as measured by c-Fos immunocytochemistry, in brain regions important to control of pain was evaluated. Animals that received CFA treatment, and tested 3 days later for mechanical allodynia and edema, had an increase in the number of c-Fos immunopositive cells in the basolateral amygdala, but not in any of the other brain regions that were evaluated. Given that the basolateral amygdala is known to be important for pain-related emotional responses, these data suggest that the CFA-model may provide an opportunity to further explore how pain affects this brain region at a mechanistic level, which in turn may shed light on what may be occurring in clinical populations.

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A pharmacological interactome between COVID-19 patient samples and human sensory neurons reveals potential drivers of neurogenic pulmonary dysfunction.

The SARS-CoV-2 virus infects cells of the airway and lungs in humans causing the disease COVID-19. This disease is characterized by cough, shortness of breath, and in severe cases causes pneumonia and acute respiratory distress syndrome (ARDS) which can be fatal. Bronchial alveolar lavage fluid (BALF) and plasma from mild and severe cases of COVID-19 have been profiled using protein measurements and bulk and single cell RNA sequencing. Onset of pneumonia and ARDS can be rapid in COVID-19, suggesting a potential neuronal involvement in pathology and mortality. We hypothesized that SARS-CoV-2 infection drives changes in immune cell-derived factors that then interact with receptors expressed by the sensory neuronal innervation of the lung to further promote important aspects of disease severity, including ARDS. We sought to quantify how immune cells might interact with sensory innervation of the lung in COVID-19 using published data from patients, existing RNA sequencing datasets from human dorsal root ganglion neurons and other sources, and a genome-wide ligand-receptor pair database curated for pharmacological interactions relevant for neuro-immune interactions. Our findings reveal a landscape of ligand-receptor interactions in the lung caused by SARS-CoV-2 viral infection and point to potential interventions to reduce the burden of neurogenic inflammation in COVID-19 pulmonary disease. In particular, our work highlights opportunities for clinical trials with existing or under development rheumatoid arthritis and other (e.g. CCL2, CCR5 or EGFR inhibitors) drugs to treat high risk or severe COVID-19 cases.

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Transcranial Direct Current Stimulation (tDCS) Combined With Therapeutic Exercise in Chronic Low Back Pain: Protocol of a Randomized Controlled Trial.

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The role of erenumab in the treatment of migraine.

Calcitonin gene related peptide (CGRP) monoclonal antibodies (mAbs) have been the first class of specifically developed preventive treatments for migraine. Clinical trials data suggest superiority of the CGRP mAbs to placebo in terms of prevention of migraine symptoms, migraine-specific quality of life and headache related disability. Treatment-related side effects overall did not differ significantly from placebo and discontinuation rate due to side effects has been low across the clinical trials, perhaps in view of their peripheral mode of action. Along with their route and frequency of administration, these novel class of drugs may constitute an improvement compared with the established arsenal of migraine treatments. Erenumab is a fully human antibody and the only mAb acting on the CGRP pathway by blocking its receptor. It is the first of the CGRP mAb class approved by the US Food and Drug Administration (May 2018) and the European Medicines Agency (July 2018). Erenumab exists in two different doses (70 mg and 140 mg) and it is administered with monthly subcutaneous injections. This review summarises erenumab pharmacological characteristics, clinical trials data, focusing on the potential role of this treatment in clinical practice.

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Evidence for a novel subcortical mechanism for posterior cingulate cortex atrophy in HIV peripheral neuropathy.

We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.

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Commentary on “A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial”.

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Lasmiditan mechanism of action – review of a selective 5-HT agonist.

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT receptors. The discovery that the serotonin 1F (5-HT) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT receptors, the activation of 5-HT receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

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Comparison of efficacy of a supervised versus non-supervised physical therapy exercise program on the pain, functionality and quality of life of patients with non-specific chronic low-back pain: a randomized controlled trial.

To compare the effectiveness of supervised physical therapy program versus non-supervised on pain, functionality, fear of movement and quality of life in patients with non-specific chronic low back pain.

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Reliability, Discriminative and Prognostic Validity of the MultiDimensional Symptom Index in Musculoskeletal Trauma.

The MultiDimensional Symptom Index (MSI) is a 10-item parallel score frequency x interference patient reported outcome for use in clinical pain research. This manuscript describes the results of evaluations related to measurement stability, discriminative accuracy when screening for major depressive disorder (MDD), and prognostic validity when predicting recovery trajectories following acute musculoskeletal (MSK) trauma.

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Methadone for postoperative analgesia: contribution of N-methyl-D-aspartate receptor antagonism: A randomised controlled trial.

Over the past number of years, N-methyl-D-aspartate (NMDA) inhibitory drugs, like ketamine, have been introduced as adjuvant treatments for postoperative acute pain, within a multimodal approach. A further extension of this strategy could be the use of opioids with NMDA receptor (NMDAr) antagonism activity for control of postoperative pain. Methadone has a unique pharmacodynamic profile: it is both a μ-agonist and an NMDAr-blocker.

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Targeting nitric oxide production in microglia with novel imidazodiazepines for non-sedative pain treatment.

The goal of this research is the identification of new treatments for neuropathic pain. We characterized the GABAergic system of immortalized mouse and human microglia using electrophysiology and qRT-PCR. Cells from both species exhibited membrane current changes in response to γ-aminobutyric acid, with an EC50 of 260 nM and 1940 nM, respectively. Human microglia expressed high levels of the γ-aminobutyric acid type A receptor (GABAAR) α3 subunit, which can assemble with β1 and γ2/δ subunits to form functional GABAARs. Mouse microglia contained α2, α3 and α5, in addition to β1-3, γ1-2 and δ, mRNA, enabling a more diverse array of GABAARs than human microglia. Benzodiazepines are well-established modulators of GABAAR activity, prompting a screen of a library of diverse benzodiazepines in microglia for cellular effects. Several active compounds were identified by reduction of nitric oxide (NO) in interferon gamma and lipopolysaccharide activated microglia. However, further investigation with GABAAR antagonists flumazenil, picrotoxin, and bicuculline demonstrated that GABAARs were not linked to the NO response. A screen of 48 receptors identified the κ-opioid receptor and to a lesser extent the µ-opioid receptor as molecular targets, with opioid receptor antagonist norbinaltorphimine reversing benzodiazepine induced reduction of microglial NO. Functional assays identified the downregulation of inducible NO synthase as the mode of action of imidazodiazepines MP-IV-010 and GL-IV-03. Like other κ-opioid receptor agonists, GL-IV-03 reduced the agitation response in both phases of the formalin nociception test. However, unlike other κ-opioid receptor agonists, MP-IV-010 and GL-IV-03 did not impair sensorimotor coordination in mice. Thus, MP-IV-010 and GL-IV-03 represent a new class of non-sedative drug candidates for inflammatory pain.

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Cluster headache therapies: pharmacology and mode of action.

Cluster headache (CH) is the most common trigeminal autonomic cephalalgia with a significant need for novel treatment options. While the use of most of the acute CH medications is supported by clinical trials and based on a pathophysiological concept for the generation of pain, the scientific evidence for preventive CH medications is very limited.

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A Real-World Analysis of Patient Characteristics, Treatment Patterns, and Level of Impairment in Patients With Migraine Who are Insufficient Responders vs Responders to Acute Treatment.

The objective of this study was to examine if patients with migraine who responded sufficiently to acute treatment were significantly different from those who did not in terms of patient characteristics, treatment patterns, and patient level of impairment, and to identify characteristics associated with insufficient response.

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Integrative approaches to treating pain in sickle cell disease: Pre-clinical and clinical evidence.

Sickle cell disease (SCD) is a genetic disorder characterized by hemolysis, end-organ damage, inflammation, and pain. Recurrent and unpredictable episodes of acute pain due to vaso-occlusive crises are a unique feature of SCD. Many patients also develop lifelong chronic pain. Opioids are the primary method of pain treatment in SCD; however, continued use is associated with several adverse effects. Integrative approaches to treating pain in SCD are increasingly being explored to prevent the side effects associated with opioids. In this review, we highlight the mechanisms of pain in SCD and describe mechanism-based integrative approaches for treating pain.

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The effect of painful laser stimuli on EEG gamma-band activity in migraine patients and healthy controls.

Gamma-band oscillations (GBOs) induced by nociceptive stimuli were compared between migraine patients and controls in order to further characterize interictal pain processing in the brain of migraineurs. GBOs were related to subjective pain intensity, years of migraine history and migraine attack frequency and the sources of GBOs were investigated.

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Modeling a Nociceptive Neuro-Immune Synapse Activated by ATP and 5-HT in Meninges: Novel Clues on Transduction of Chemical Signals Into Persistent or Rhythmic Neuronal Firing.

Extracellular ATP and serotonin (5-HT) are powerful triggers of nociceptive firing in the meninges, a process supporting headache and whose cellular mechanisms are incompletely understood. The current study aimed to develop, with the neurosimulator NEURON, a novel approach to explore in silico the molecular determinants of the long-lasting, pulsatile nature of migraine attacks. The present model included ATP and 5-HT release, ATP diffusion and hydrolysis, 5-HT uptake, differential activation of ATP P2X or 5-HT3 receptors, and receptor subtype-specific desensitization. The model also tested the role of branched meningeal fibers with multiple release sites. Spike generation and propagation were simulated using variable contribution by potassium and sodium channels in a multi-compartment fiber environment. Multiple factors appeared important to ensure prolonged nociceptive firing potentially relevant to long-lasting pain. Crucial roles were observed in: (i) co-expression of ATP P2X2 and P2X3 receptor subunits; (ii) intrinsic activation/inactivation properties of sodium Nav1.8 channels; and (iii) temporal and spatial distribution of ATP/5-HT release sites along the branches of trigeminal nerve fibers. Based on these factors we could obtain either persistent activation of nociceptive firing or its periodic bursting mimicking the pulsating nature of pain. In summary, our model proposes a novel tool for the exploration of peripheral nociception to test the contribution of clinically relevant factors to headache including migraine pain.

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The fifth cranial nerve in headaches.

The fifth cranial nerve is the common denominator for many headaches and facial pain pathologies currently known. Projecting from the trigeminal ganglion, in a bipolar manner, it connects to the brainstem and supplies various parts of the head and face with sensory innervation. In this review, we describe the neuroanatomical structures and pathways implicated in the sensation of the trigeminal system. Furthermore, we present the current understanding of several primary headaches, painful neuropathies and their pharmacological treatments. We hope that this overview can elucidate the complex field of headache pathologies, and their link to the trigeminal nerve, to a broader field of young scientists.

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Vitamin D Deficiency is Associated With Painful Diabetic Neuropathy.

The aetiology of painful diabetic neuropathy is unclear. We have evaluated vitamin D levels in diabetic patients with and without painful neuropathy. Forty-three patients with type 1 diabetes and painless (DPN) (n = 20) or painful (PDN) (n = 23) neuropathy and 14 non-diabetic healthy control subjects (C) underwent assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal confocal microscopy (CCM) and measurement of serum 25(OH)D. There were no significant differences for age, BMI, HbA1c, lipids, neurological deficits, QST, electrophysiology, intra-epidermal nerve fibre density (IENFD) and corneal nerve morphology between patients with DPN and PDN. Both positive (hyperalgesia and allodynia) and negative symptoms (paraesthesia and numbness) of diabetic neuropathy were greater in PDN compared to DPN (P = 0.009 and P = 0.02 respectively). Serum 25(OH)D level were significantly lower in PDN (24.0 ± 14.1 ng/mL) compared to DPN (34.6 ± 15.0 ng/mL, P = 0.01) and controls (34.1 ± 8.6 ng/mL, P = 0.03). The odds ratio in favour of painful diabetic neuropathy was 9.8 (P = 0.003 (95% CI 2.2-76.4) for vitamin D deficiency (<20 ng/mL) and 4.4 (P = 0.03 [95% CI 1.1-19.8]) for vitamin D insufficiency (<30 ng/mL). This study suggests that vitamin D deficiency and insufficiency are associated with painful diabetic neuropathy. This article is protected by copyright. All rights reserved.

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Spinal actions of the NSAID diclofenac on nociceptive transmission in comparison to the K7 channel opener flupirtine.

NSAIDs are the drugs most commonly used to alleviate pain. Despite being a heterogeneous group of compounds, all of them share a mechanism of action based on blockade of COXs enzymes, which confers them anti-inflammatory and analgesic properties. Diclofenac is a NSAID with preferred activity on COX-2 isozymes, but additionally, other targets may be implicated in its analgesic activity. Among them, diclofenac may facilitate the activity of K7 channels, that have been previously recognized as potential therapeutic targets in analgesia. In this study, the antinociceptive actions of diclofenac acting at the spinal level and the role of K7 channels in its effects were evaluated. Electrophysiological recordings of spinal reflexes and responses of dorsal horn neurons were obtained using in vitro spinal cord preparations from neonatal mice. Diclofenac, applied at clinically relevant concentrations to the entire preparation, depressed wind-up of spinal reflexes with a pattern similar to that of flupirtine, an analgesic with activity as K7 channel opener. Depressant actions of both compounds were strongly reduced after K7 channel blockade with XE-991, indicating the implication of these channels in the observed effects. Flupirtine, but not diclofenac, also reduced action potential firing of dorsal horn neurons in response to electrical activation of nociceptive afferents, suggesting differences in the actions of both compounds on K7 channel configurations present in sensory areas of the cord. Results demonstrate previously unknown central actions of diclofenac on K7 channels located in spinal circuits, expanding the knowledge about its pharmacological actions.

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Brain Network Disruption in Whiplash.

Whiplash-associated disorders frequently develop following motor vehicle collisions and often involve a range of cognitive and affective symptoms, though the neural correlates of the disorder are largely unknown. In this study, a sample of participants with chronic whiplash injuries were scanned by using resting-state fMRI to assess brain network changes associated with long-term outcome metrics.

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The Impact of Posttraumatic Stress Disorder on Clinical Presentation and Psychosocial Treatment Response in Youth with Functional Abdominal Pain Disorders: An Exploratory Study.

Youth with functional abdominal pain disorders (FAPDs) may report high rates of trauma and/or posttraumatic stress disorder (PTSD), which could impact both physical and psychosocial functioning, in addition to psychosocial treatment response. The current study aimed to examine the rates of PTSD in a sample of 89 youth with FAPDs and examine the association between PTSD with physical and psychosocial functioning. The impact of PTSD on psychosocial treatment response in a subsample of youth with FAPDs was also explored. Participants were youth with FAPDs (ages 9-14) enrolled in a larger study examining the effect of a short-term pain and anxiety focused cognitive behavioral therapy (CBT) treatment (Aim to Decrease Anxiety and Pain Treatment (ADAPT)) for youth with FAPDs. Youth were administered a semi-structured diagnostic interview by a trained clinician to confirm the presence of psychological diagnoses, including PTSD. Measures of physical and psychosocial functioning were also completed. Results revealed a high rate of PTSD in youth with FAPDs with 12.4% meeting diagnostic criteria for the disorder. PTSD was associated with several indicators of increased psychosocial impairment and one indicator of physical impairment. Exploratory analyses revealed comorbid PTSD may impact response to a brief CBT intervention targeting pain and anxiety, but more rigorous controlled studies are needed.

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Rescue of HSP70 in Spinal Neurons Alleviates Opioids-Induced Hyperalgesia via the Suppression of Endoplasmic Reticulum Stress in Rodents.

A major unresolved issue in treating pain is the paradoxical hyperalgesia produced by the gold-standard analgesic morphine and other opioids. Endoplasmic reticulum (ER) stress has been shown to contribute to neuropathic or inflammatory pain, but its roles in opioids-induced hyperalgesia (OIH) are elusive. Here, we provide the first direct evidence that ER stress is a significant driver of OIH. GRP78, the ER stress marker, is markedly upregulated in neurons in the spinal cord after chronic morphine treatment. At the same time, morphine induces the activation of three arms of unfolded protein response (UPR): inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1), protein kinase RNA-like ER kinase/eukaryotic initiation factor 2 subunit alpha (PERK/eIF2α), and activating transcription factor 6 (ATF6). Notably, we found that inhibition on either IRE1α/XBP1 or ATF6, but not on PERK/eIF2α could attenuate the development of OIH. Consequently, ER stress induced by morphine enhances PKA-mediated phosphorylation of NMDA receptor subunit 1(NR1) and leads to OIH. We further showed that heat shock protein 70 (HSP70), a molecular chaperone involved in protein folding in ER, is heavily released from spinal neurons after morphine treatment upon the control of K channel. Glibenclamide, a classic K channel blocker that inhibits the efflux of HSP70 from cytoplasm to extracellular environment, or HSP70 overexpression in neurons, could markedly suppress morphine-induced ER stress and hyperalgesia. Taken together, our findings uncover the induction process and the central role of ER stress in the development of OIH and support a novel strategy for anti-OIH treatment.

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Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination.

Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aβ mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.

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A Step Towards a Better Understanding of Pain Phenotypes: Latent Class Analysis in Chronic Pain Patients Receiving Multimodal Inpatient Treatment.

The number of non-responders to treatment among patients with chronic pain (CP) is high, although intensive multimodal treatment is broadly accessible. One reason is the large variability in manifestations of CP. To facilitate the development of tailored treatment approaches, phenotypes of CP must be identified. In this study, we aim to identify subgroups in patients with CP based on several aspects of self-reported health.

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Calcitonin Gene-Related Peptide Receptor Antagonists (Gepants) for the Acute Treatment of Nausea in Episodic Migraine: A Systematic Review and Meta-Analysis.

To synthesize the evidence on the efficacy of calcitonin gene-related peptide receptor antagonists (gepants) from all clinical trials addressing nausea treatment for episodic migraine.

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Current Perspectives on Sex Differences in Tension Type Headache.

Clinical and experimental evidence supports the presence of several gender differences in the pain experience.

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The Role of the Cannabinoid System in Pain Control: Basic and Clinical Implications.

The purpose of this review is to provide a comprehensive update of the different known components of the endogenous cannabinoid system and the mechanisms of action, as it applies to analgesia.

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Differences in EEG patterns between tonic and high frequency spinal cord stimulation in chronic pain patients.

To investigate the differences in neural patterns between spinal cord stimulation (SCS) waveforms (60-Hz tonic vs 10-KHz high frequency stimulation, HFS) and their correlation to stimulation-induced pain relief.

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A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice.

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.

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How effective and efficient are different exercise patterns in reducing back pain?

Exercise is considered an effective intervention to relieve chronic back pain. However, it is still unknown whether specific exercise patterns vary in terms of their efficiency and effectiveness.

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Safe Opioid Storage and Disposal: A Survey of Patient Beliefs and Practices.

To evaluate knowledge, practices, and beliefs of US patients receiving prescription opioids regarding opioid storage, disposal, and diversion.

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Immunohistochemistry Analysis of Itch and Pain Mediators in Nonmelanoma Skin Cancer.

Patients with nonmelanoma skin cancer (NMSC) may experience symptoms of itch and pain, which we previously reported to be associated with overall degree of inflamation . Specific mediators underlying itch and pain in NMSCs have not been studied, so immunohistochemistry was performed for mediators involved in these pathways. 60 subjects from a tissue repository were included in this study for a total of 50 histopathologically confirmed NMSCs and 10 healthy controls. Participants were asked to rank their current itch and pain intensities at the time and location of biopsy on a 11-point numerical rating scale (NRS).

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Upregulation of Mlxipl induced by cJun in the spinal dorsal horn after peripheral nerve injury counteracts mechanical allodynia by inhibiting neuroinflammation.

Mlxipl regulates glucose metabolism, lipogenesis and tumorigenesis and has a wide-ranging impact on human health and disease. However, the role of Mlxipl in neuropathic pain remains unknown. In this study, we found that Mlxipl was increased in the ipsilateral L4-L6 spinal dorsal horn after Spared Nerve Injury surgery. Knockdown of Mlxipl in the ipsilateral L4-L6 spinal dorsal horn by intraspinal microinjection aggravated Spared Nerve Injury-induced mechanical allodynia and inflammation in the spinal dorsal horn, on the contrary, overexpression of Mlxipl inhibited mechanical allodynia and inflammation. Subsequently, the rat Mlxipl promoter was analyzed using bioinformatics methods to predict the upstream transcription factor cJun. Luciferase assays and ChIP-qPCR confirmed that cJun bound to the promoter of Mlxipl and enhanced its expression. Finally, we demonstrated that Mlxipl inhibited the inflammatory responses of lipopolysaccharide-induced microglia and that Mlxipl was regulated by the transcription factor cJun. These findings suggested that cJun-induced Mlxipl upregulation in the spinal dorsal horn after peripheral nerve injury provided a protective mechanism for the development and progression of neuropathic pain by inhibiting microglial-derived neuroinflammation. Targeting Mlxipl in the spinal dorsal horn might represent an effective strategy for the treatment of neuropathic pain.

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High-salt diet decreases mechanical thresholds in mice that is mediated by a CCR2-dependent mechanism.

Though it is well-known that a high-salt diet (HSD) is associated with many chronic diseases, the effects of long-term high-salt intake on physiological functions and homeostasis remain elusive. In this study, we investigated whether and how an HSD affects mouse nociceptive thresholds, and myeloid cell trafficking and activation.

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Multidimensional assessment of the effects of erenumab in chronic migraine patients with previous unsuccessful preventive treatments: a comprehensive real-world experience.

erenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments.

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Identification of Candidate Genes Associated with Postherpetic Neuralgia Susceptibility.

Postherpetic neuralgia (PHN) is one of the most common complications of herpes zoster (HZ). Heritable factors have been found to play a role in various clinical pain symptoms. However, the effect of gene variability on the susceptibility of PHN remains poorly understood.

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Associations of Cognitive Fusion and Pain Catastrophizing with Fibromyalgia Impact through Fatigue, Pain Severity, and Depression: An Exploratory Study Using Structural Equation Modeling.

Differences in fibromyalgia impact on functioning exist and appear to be influenced by numerous factors, including symptomatology severity, as well as the cognitive profile of the individual. The contribution of these elements, however, tends to be explored in a fragmented manner. To address this issue, we tested a comprehensive structural equation model in which associations of cognitive fusion and pain catastrophizing with function limitations are investigated through fibromyalgia symptomatology (i.e., fatigue, pain severity, and depression) in 231 women with fibromyalgia. In the model, cognitive fusion and two catastrophizing components (magnification and helplessness) were associated with poorer functioning indirectly through fibromyalgia symptomatology. Only the rumination component of catastrophizing had a direct association with functional limitations. All fibromyalgia symptoms were linked to increased functional limitations. A parsimonious model with significant associations only obtained an excellent fit (S-B = 774.191, df = 543, < 0.001; CFI = 0.943; RMSEA = 0.043; CAIC = -2724.04) and accounted for 50% of the variance of functional limitations. These results suggest that the relationship between psychological cognitive processes, fibromyalgia symptomatology, and functional limitations is complex and support the need for comprehensive models such as the present. The findings are discussed in the context of personalized psychological treatments (i.e., the need to address certain cognitive processes according to the problematic symptomatology or outcome).

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What Works? Processes of Change in a Transdiagnostic Exposure Treatment for Patients with Chronic Pain and Emotional Problems.

We recently developed a transdiagnostic exposure treatment ("the hybrid treatment") for chronic pain patients with concurrent emotional difficulties. This paper investigates the hypothesized treatment processes, specifically: a) if changes on pain-related dysregulation (catastrophizing, fear-avoidance and non-acceptance of pain) and general emotion dysregulation (difficulties to regulate a broad spectrum of emotional responses) mediate effects on outcomes; and b) if mediation is more pronounced for patients who score higher on these processes pre-treatment.

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Increased Experimental Pain Sensitivity in Chronic Pain Patients who developed Opioid Use Disorder.

Although the great majority of patients who take opioids for chronic pain use them appropriately and to good effect, a certain minority will develop the problematic outcome of opioid use disorder (OUD). Patient characteristics associated with the development of OUD in patients with chronic pain have been described, however relatively unexplored is how sensitivity to pain is associated with OUD outcomes.

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Virtual Reality to Relieve Pain in Burn Patients Undergoing Imaging and Treatment.

Pain from burn injuries is among the most excruciating encountered in clinical practice. Pharmacological methods often fail to achieve acceptable level of analgesia in these patients, especially during burn wound dressing and debridement. Virtual reality (VR) distraction is a promising analgesic technique that progressed significantly in the last decade with development of commercially available, low-cost, high-resolution, wide field-of-view, standalone VR devices that can be used in many clinical scenarios. VR has demonstrated clinical benefit as an adjunctive analgesic during burn wound dressing and other painful medical procedures. The technique has proven useful also in preparing patients for magnetic resonance imaging scans, particularly in claustrophobic patients. Modulation of pain-related brain activity at cortical and subcortical levels by VR, and its correlation with subjective improvement in various laboratory and clinical pain experiences has been demonstrated using multiple functional brain imaging studies including functional magnetic resonance imaging and brain perfusion single photon emission computed tomography.

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Capsaicin 8% dermal patch in clinical practice: an expert opinion.

Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP.

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Perioperative Opioid Use Predicts Postoperative Opioid Use and Inferior Outcomes after Shoulder Arthroscopy.

The purpose of this study is to define the impact of preoperative opioid use on post-operative opioid use, patient-reported outcomes and revision rates in a cohort of patients receiving arthroscopic shoulder surgery METHODS: Patients who underwent shoulder arthroscopy were identified from an institutional database. Inclusion criteria were completion of preoperative and postoperative patient reported outcome measures (PROMs) at one-year follow-up, in addition to a questionnaire on use of opioids and number of pills per day. Outcomes assessed included postoperative PROM scores, postoperative opioid use, persistent pain, and achievement of the patient acceptable symptomatic state (PASS). A matched-cohort analysis was performed to evaluate the impact of opioid use on achievement of postoperative outcomes while a multivariate regression was performed to determine additional risk factors. Receiver operating characteristic curves were used to establish threshold values in oral morphine equivalents (OME) that predicted each outcome.

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Comprehensive Evidence-Based Guidelines for Facet Joint Interventions in the Management of Chronic Spinal Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines Facet Joint Interventions 2020 Guidelines.

Chronic axial spinal pain is one of the major causes of significant disability and health care costs, with facet joints as one of the proven causes of pain.

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Antihyperalgesic effects of intrathecal perospirone in a rat model of neuropathic pain.

The descending serotonergic pathway, from the brainstem to spinal cord, modulates various aspects of pain processing. The spinal 5-hydroxytryptamine (5-HT) and 5-HT receptors play pivotal roles in pain modulation. Perospirone is a novel atypical antipsychotic that serves as a 5-hydroxytryptamine (5-HT) receptor agonist, a 5-HT receptor antagonist, and a dopamine D receptor antagonist. Little is known about the effect of perospirone on pain transmission. Here, we explored whether perospirone attenuated neuropathic and inflammatory pain in the spinal cord. A chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. We evaluated the effects of intrathecal administration of perospirone (10, 20, or 40 μg) on mechanical and cold hyperalgesia using the electronic von Frey and cold plate tests, respectively. Normal rats were assessed in terms of inflammatory nociception using the formalin test and for motor coordination employing the rotarod test. To define the mechanism underlying the action of perospirone, the effects of intrathecal pretreatment with the 5-HT receptor antagonist WAY-100635, the 5-HT receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (DOI), and the dopamine D receptor agonist sumanirole on perospirone action were examined using the electronic von Frey test and cold plate test. Perospirone dose-dependently alleviated mechanical and cold hyperalgesia, but not inflammatory nociception in the spinal cord, and affected motor coordination. WAY-100635 reversed the antihyperalgesic action of perospirone significantly, but neither DOI nor sumanirole exhibited such an effect. We conclude that perospirone attenuates mechanical and cold hyperalgesia principally via 5-HT receptor activation in the spinal cord, and the agent is a promising novel candidate for neuropathic pain relief.

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Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors.

Preclinical research using different rodent model systems has largely contributed to the scientific progress in the pain field, however, it suffers from interspecies differences, limited access to human models, and ethical concerns. Human induced pluripotent stem cells (iPSCs) offer major advantages over animal models, i.e., they retain the genome of the donor (patient), and thus allow donor-specific and cell-type specific research. Consequently, human iPSC-derived nociceptors (iDNs) offer intriguingly new possibilities for patient-specific, animal-free research. In the present study, we characterized iDNs based on the expression of well described nociceptive markers and ion channels, and we conducted a side-by-side comparison of iDNs with mouse sensory neurons. Specifically, immunofluorescence (IF) analyses with selected markers including early somatosensory transcription factors (BRN3A/ISL1/RUNX1), the low-affinity nerve growth factor receptor (p75), hyperpolarization-activated cyclic nucleotide-gated channels (HCN), as well as high voltage-gated calcium channels (VGCC) of the Ca2 type, calcium permeable TRPV1 channels, and ionotropic GABA receptors, were used to address the characteristics of the iDN phenotype. We further combined IF analyses with microfluorimetric Ca measurements to address the functionality of these ion channels in iDNs. Thus, we provide a detailed morphological and functional characterization of iDNs, thereby, underpinning their enormous potential as an animal-free alternative for human specific research in the pain field for unveiling pathophysiological mechanisms and for unbiased, disease-specific personalized drug development.

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Psychophysical characterization of burning mouth syndrome – A systematic review and meta-analysis.

Primary burning mouth syndrome (BMS) is an orofacial disease with neuropathic characteristics. Psychophysics, such as quantitative sensory testing (QST) are used to sub-classify neuropathic pain syndromes, but their usefulness in characterizing BMS is not yet clear.

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Changes in Perceived Stress After Yoga, Physical Therapy, and Education Interventions for Chronic Low Back Pain: A Secondary Analysis of a Randomized Controlled Trial.

Perceived stress and musculoskeletal pain are common, especially in low-income populations. Studies evaluating treatments to reduce stress in patients with chronic pain are lacking. We aimed to quantify the effect of two evidence-based interventions for chronic low back pain (cLBP), yoga and physical therapy (PT), on perceived stress in adults with cLBP.

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Randomized Trial of General Strength and Conditioning Versus Motor Control and Manual Therapy for Chronic Low Back Pain on Physical and Self-Report Outcomes.

Exercise and spinal manipulative therapy are commonly used for the treatment of chronic low back pain (CLBP) in Australia. Reduction in pain intensity is a common outcome; however, it is only one measure of intervention efficacy in clinical practice. Therefore, we evaluated the effectiveness of two common clinical interventions on physical and self-report measures in CLBP. Participants were randomized to a 6‑month intervention of general strength and conditioning (GSC; = 20; up to 52 sessions) or motor control exercise plus manual therapy (MCMT; =20; up to 12 sessions). Pain intensity was measured at baseline and fortnightly throughout the intervention. Trunk extension and flexion endurance, leg muscle strength and endurance, paraspinal muscle volume, cardio‑respiratory fitness and self-report measures of kinesiophobia, disability and quality of life were assessed at baseline and 3- and 6-month follow-up. Pain intensity differed favoring MCMT between-groups at week 14 and 16 of treatment (both, = 0.003), but not at 6-month follow‑up. Both GSC (mean change (95%CI): -10.7 (-18.7, -2.8) mm; = 0.008) and MCMT (-19.2 (-28.1, -10.3) mm; < 0.001) had within-group reductions in pain intensity at six months, but did not achieve clinically meaningful thresholds (20mm) within- or between‑group. At 6-month follow-up, GSC increased trunk extension (mean difference (95% CI): 81.8 (34.8, 128.8) s; = 0.004) and flexion endurance (51.5 (20.5, 82.6) s; = 0.004), as well as leg muscle strength (24.7 (3.4, 46.0) kg; = 0.001) and endurance (9.1 (1.7, 16.4) reps; = 0.015) compared to MCMT. GSC reduced disability (-5.7 (‑11.2, -0.2) pts; = 0.041) and kinesiophobia (-6.6 (-9.9, -3.2) pts; < 0.001) compared to MCMT at 6‑month follow-up. Multifidus volume increased within-group for GSC ( = 0.003), but not MCMT or between-groups. No other between-group changes were observed at six months. Overall, GSC improved trunk endurance, leg muscle strength and endurance, self-report disability and kinesiophobia compared to MCMT at six months. These results show that GSC may provide a more diverse range of treatment effects compared to MCMT.

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Pain- and Fatigue-Related Functional and Structural Changes in Ankylosing Spondylitis: An fRMI Study.

Chronic pain and fatigue are two cardinal features of ankylosing spondylitis (AS) and how to effectively treat these conditions continues to be a challenge. The underlying mechanisms and the relationship between AS-related pain and fatigue remain poorly understood. The present study was conducted, therefore, to explore the brain functional and structural changes associated with pain and fatigue in AS. A total of 65 AS patients (48 men and 17 women; 32.33 ± 8.6 years) and 53 age- and sex-matched controls were enrolled in the study. The patients underwent clinical assessment based on Total Back Pain scores, Fatigue Severity Scale, Bath Ankylosing Spondylitis Disease Activity Index, (BASDAI), high-sensitivity C-reactive Protein (hsCRP), erythrocyte sedimentation rate (ESR), and Beck Depression Inventory (BDI). Using 3T magnetic resonance imaging (3T-MRI), we analyzed the brain functional (connectivity and nodal properties) and structural (covariance and gray matter volumes) differences between AS patients and controls. Furthermore, we extracted the values of the significantly changed regions in the AS cohort and explored their association with pain and fatigue. In AS patients, there were functional and structural abnormalities distributed in the default mode network (DMN), salience network (SN), sensory/somatomotor network (SMN), dorsal attention network (DAN), task control network (TCN), and visual network, and some regions showed both types of changes. Among these, the functional connectivity (FC) between the left insula and medial prefrontal cortex, the betweenness centrality of the left medial prefrontal cortex and the gray matter volume of the right putamen tracked both pain and fatigue. In addition, pain was related to within-DMN FC disruption and nodal function / gray matter volumes changes in DMN, SN, and the visual network, while fatigue mainly involved the SMN, DAN, and TCN. Moreover, certain changes were also related to BASDAI and inflammation level. This study offers new insights into understanding the neural mechanism of AS-related pain and fatigue, and could help to stratify patients based on the correlation features and ultimately move towards a personalized therapy.

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Quantitative Sensory Testing in Adolescents with Co-occurring Chronic Pain and Obesity: A Pilot Study.

Factors such as gender, ethnicity, and age affect pain processing in children and adolescents with chronic pain. Although obesity has been shown to affect pain processing in adults, almost nothing is known about pediatric populations. The aim of this pilot study was to explore whether obesity alters sensory processing in adolescents with chronic pain. Participants were recruited from a chronic pain clinic (Chronic Pain (CP), = 12 normal weight; Chronic Pain + Obesity (CPO), = 19 overweight/obesity) and from an obesity clinic (Obesity alone (O), = 14). The quantitative sensory testing protocol included assessments of thermal and mechanical pain thresholds and perceptual sensitization at two sites with little adiposity. The heat pain threshold at the hand was significantly higher in the CPO group than in either the CP or O groups. Mechanical pain threshold (foot) was significantly higher in the CPO group than the CP group. No differences were found on tests of perceptual sensitization. Correlations between experimental pain and clinical pain parameters were found for the CPO group, but not for the CP group. This preliminary study provides important lessons learned for subsequent, larger-scale studies of sensory processing for youth with co-occurring chronic pain and obesity.

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Post-Discharge Pain Management After Thoracic Surgery – A Patient-Centered Approach.

Postoperative analgesia is paramount to recovery following thoracic surgery, and opioids play an invaluable role in this process. Yet, current one-size-fits-all prescribing practices produce large quantities of unused opioids, increasing the risk of nonmedical use and overdose. Here, we hypothesized that patient and perioperative characteristics, including 24-hour before discharge opioid intake, could inform more appropriate post-discharge prescriptions after thoracic surgery.

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A Qualitative Evaluation of the Pain Management VA-ECHO Program Using the RE-AIM Framework: The Participant’s Perspective.

Veterans frequently seek chronic pain care from their primary care providers (PCPs) who may not be adequately trained to provide pain management. To address this issue the Veterans Health Administration (VHA) Office of Specialty Care adopted the Specialty Care Access Network Extension for Community Healthcare Outcomes (VA-ECHO née SCAN-ECHO). The VA-ECHO program offered training and mentoring by specialists to PCPs and their staff. VA-ECHO included virtual sessions where expertise was shared in two formats: (1) didactics on common pain conditions, relevant psychological disorders, and treatment options and (2) real-time consultation on patient cases. VA-ECHO participants' perspectives were obtained using a semi-structured interview guide designed to elicit responses based on the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. A convenience sampling was used to recruit PCPs and non-physician support staff participants. Non-physicians from rural VHA sites were purposively sampled to gain diverse perspectives. This qualitative study yielded data on each RE-AIM domain except reach. Program reach was not measured as it is outside the scope of this study. Respondents reported program effectiveness as gains in knowledge and skills to improve pain care delivery. Effective incorporation of learning into practice was reflected in respondents' perceptions of improvements in: patient engagement, evidenced-based approaches, appropriate referrals, and opioid use. Program adoption included how participating health care systems selected trainees from a range of sites and roles to achieve a wide reach of pain expertise. Participation was limited by time to attend and facilitated by institutional support. Differences and similarities were noted in implementation between hub sites. Maintenance was revealed when respondents noted the importance of the lasting relationships formed between fellow participants. This study highlights VA-ECHO program attributes and unintended consequences. These findings are expected to inform future use of VA-ECHO as a means to establish a supportive consultation network between primary and specialty care providers to promote the delivery evidence-based pain management practices.

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Role of fragile X mental retardation protein in chronic pain.

Chronic pain has detrimental effects on one's quality of life. However, its treatment options are very limited, and its underlying pathogenesis remains unclear. Recent research has suggested that fragile X mental retardation protein is involved in the development of chronic pain, making it a potential target for prevention and treatment. The current review of literature will examine the function of fragile X mental retardation protein and its associated pathways, through which we hope to gain insight into how fragile X mental retardation protein may contribute to nociceptive sensitization and chronic pain.

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Relationship between pain, fatigue, and physical activity levels during a technology-based physical activity intervention.

The majority of individuals with spinal cord injury (SCI) experience chronic pain. Chronic pain can be difficult to manage because of variability in the underlying pain mechanisms. More insight regarding the relationship between pain and physical activity (PA) is necessary to understand pain responses during PA. The objective of this study is to explore possible relationships between PA levels and secondary conditions including pain and fatigue. Prospective cohort analysis of a pilot study. Community. Twenty individuals with SCI took part in the study, and sixteen completed the study. Mobile-health (mHealth) based PA intervention for two-months during the three-month study. Chronic Pain Grade Scale (CPGS) questionnaire, The Wheelchair User's Shoulder Pain Index (WUSPI), Fatigue Severity Scale (FSS), and PA levels measured by the mHealth system. A positive linear relationship was found between light-intensity PA and task-specific pain. However, the relationship between moderate-intensity PA and pain interference was best represented by a curvilinear relationship (polynomial regression of second order). Light-intensity PA showed positive, linear correlation with fatigue at baseline. Moderate-intensity PA was not associated with fatigue during any phase of the study. Our results indicated that PA was associated with chronic pain, and the relationship differed based on intensity and amount of PA performed. Further research is necessary to refine PA recommendations for individuals with SCI who experience chronic pain. ClinicalTrials.gov identifier: NCT03773692.

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The efficacy and safety of valproate medications for migraine in adults: a meta-analysis.

Many parallel-group studies of migraine prophylaxis using valproate medications were reported in recent decades. This meta-analysis assessed the efficacy and safety of valproate medications for migraine prophylaxis in adults.

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Clinical Validation of a Multi-Biomarker Assay for the Evaluation of Chronic Pain Patients in a Cross-Sectional, Observational Study.

Chronic pain assessment and post-treatment evaluation continues to be challenging due to a lack of validated, objective tools to measure patient outcomes. Validation of mechanistic pain biomarkers would allow clinicians to objectively identify abnormal biochemistry contributing to painful symptoms.

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Opioid-induced Somatic Activation: Prevalence in a Population of Patients With Chronic Pain.

Context and objective Opioids have heterogeneous side effects including a well-known effect of sedation; however, the opposing effect of stimulation, or somatic activation, has been largely ignored or overlooked. The objective of this study is to determine the prevalence of opioid-induced somatic activation (OISA). Methods We conducted a retrospective chart review of 189 patients seen by a single clinical psychiatrist/pain specialist. During the initial encounter, the clinician took a standardized history of every opioid currently or previously taken by the patients, and enquired if the patients had experienced a somatically activating or sedating effect per opioid. Results Patients recalled an average exposure to 5.1 opioids (SD: 1.9). Ninety-one patients (48.1%; mean: 1.6) reported somatic activation, while 118 (62.4%; mean: 1.7) reported sedation from at least one opioid. Fifty-eight patients (30.7%) identified at least one opioid as activating, and another as sedating. The distribution of OISA did not significantly differ by gender, race, primary pain diagnosis, or depression. The distribution of OISA by oxycodone significantly differed compared to morphine sulfate (27.3% vs 8.9%; p: 0.005), while sedation did not (29.0% vs 24.3%; p: 0.46). Conclusions In this study, we quantified the previously unstudied phenomenon of OISA. This phenomenon appears dependent on opioid type with some opioids, such as oxycodone, appearing more likely to have this effect. Given current concerns about the risks of opioids in high-risk populations, future studies are needed to study this phenomenon to arrive at an accurate determination of the potential risks and benefits of OISA.

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