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Papers: 12 Feb 2022 - 18 Feb 2022

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Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors.

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha () expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.

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Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain.

Activation of microglia in the spinal cord following peripheral nerve injury is critical for the development of long-lasting pain hypersensitivity. However, it remains unclear whether distinct microglia subpopulations or states contribute to different stages of pain development and maintenance. Using single-cell RNA-sequencing, we show that peripheral nerve injury induces the generation of a male-specific inflammatory microglia subtype, and demonstrate increased proliferation of microglia in male as compared to female mice. We also show time- and sex-specific transcriptional changes in different microglial subpopulations following peripheral nerve injury. Apolipoprotein E (Apoe) is the top upregulated gene in spinal cord microglia at chronic time points after peripheral nerve injury in mice. Furthermore, polymorphisms in the APOE gene in humans are associated with chronic pain. Single-cell RNA sequencing analysis of human spinal cord microglia reveals a subpopulation with a disease-related transcriptional signature. Our data provide a detailed analysis of transcriptional states of mouse and human spinal cord microglia, and identify a link between ApoE and chronic pain in humans.

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Chronic paternal morphine exposure increases sensitivity to morphine-derived pain relief in male progeny.

Parental history of opioid exposure is seldom considered when prescribing opioids for pain relief. To explore whether parental opioid exposure may affect sensitivity to morphine in offspring, we developed a "rat pain scale" with high-speed imaging, machine learning, and mathematical modeling in a multigenerational model of paternal morphine self-administration. We find that the most commonly used tool to measure mechanical sensitivity in rodents, the von Frey hair, is not painful in rats during baseline conditions. We also find that male progeny of morphine-treated sires had no baseline changes in mechanical pain sensitivity but were more sensitive to the pain-relieving effects of morphine. Using RNA sequencing across pain-relevant brain regions, we identify gene expression changes within the regulator of G protein signaling family of proteins that may underlie this multigenerational phenotype. Together, this rat pain scale revealed that paternal opioid exposure increases sensitivity to morphine's pain-relieving effects in male offspring.

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Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice.

Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.

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A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain.

Chronic pain is a world-wide clinical challenge. Response to analgesic treatment is limited and difficult to predict. Functional MRI has been suggested as a potential solution. However, while most analgesics target specific neurotransmission pathways, functional MRI-based biomarkers are not specific for any neurotransmitter system, limiting our understanding of how they might contribute to predict treatment response. Here, we sought to bridge this gap by applying Receptor-Enriched Analysis of Functional Connectivity by Targets to investigate whether neurotransmission-enriched functional connectivity mapping can provide insights into the brain mechanisms underlying chronic pain and inter-individual differences in analgesic response after a placebo or duloxetine. We performed secondary analyses of two openly available resting-state functional MRI data sets of 56 patients with chronic knee osteoarthritis pain who underwent pre-treatment brain scans in two clinical trials. Study 1 ( = 17) was a 2-week single-blinded placebo pill trial. Study 2 ( = 39) was a 3-month double-blinded randomized trial comparing placebo to duloxetine, a dual serotonin-noradrenaline reuptake inhibitor. Across two independent studies, we found that patients with chronic pain present alterations in the functional circuit related to the serotonin transporter, when compared with age-matched healthy controls. Placebo responders in Study 1 presented with higher pre-treatment functional connectivity enriched by the dopamine transporter compared to non-responders. Duloxetine responders presented with higher pre-treatment functional connectivity enriched by the serotonin and noradrenaline transporters when compared with non-responders. Neurotransmission-enriched functional connectivity mapping might hold promise as a new mechanistic-informed biomarker for functional brain alterations and prediction of response to pharmacological analgesia in chronic pain.

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Zcchc12-containing nociceptors are required for noxious heat sensation.

Dorsal root ganglion (DRG) neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 (Zcchc12) was reported to be the representative marker for a subtype of Gal-positive (Gal) DRG neurons. However, the characteristics and functions of Zcchc12 neurons are largely unknown. Here, we genetically labelled Zcchc12 neurons in Zcchc12-CreERT2::Ai9 mice, and verified that Zcchc12 represented a new subpopulation of DRG neurons in both sexes. Zcchc12 neurons centrally innervated the superficial laminae in spinal dorsal horn, and peripherally terminated as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Besides, Zcchc12 neurons also formed circumferential endings surround the hair follicles in hairy skin. Functionally, calcium imaging in DRGs revealed that Zcchc12 neurons were polymodal nociceptors and could be activated by mechanical and noxious thermal stimuli. Behavioral tests showed that selective ablation of Zcchc12 DRG neurons reduced the sensitivity to noxious heat in mice. Taken together, we identify a new subpopulation of Zcchc12 nociceptors essential for noxious heat sensation.Zcchc12 represents a new subpopulation of DRG neurons. The characteristics and functions of Zcchc12 neurons are largely unknown. Here we genetically labelled Zcchc12 neurons, and showed that the fibers of Zcchc12 DRG neurons projected to superficial lamina at spinal dorsal horn, and innervated skin as free nerve endings in the epidermis and cluster-shaped fibers in the dermis of footpads and nearby. Functionally, Zcchc12 DRG neurons responded to noxious mechanical and heat stimuli. Ablation of Zcchc12 DRG neurons impaired the sensation of noxious heat in mice. Therefore, we identify a new subpopulatipn of DRG neurons required for noxious heat sensation.

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Patient-Centered Treatment of Chronic Migraine With Medication Overuse: A Prospective, Randomized, Pragmatic Clinical Trial.

Overuse of symptomatic (i.e. acute) medications is common amongst those with chronic migraine. It is associated with developing frequent headaches, medication side effects, and reduced quality of life. The optimal treatment strategy for patients with chronic migraine with medication overuse (CMMO) has long been debated. The study objective was to determine if migraine preventive therapy switching or limiting the frequency of the overused medication was non-inferior to migraine preventive therapy switching from the overused medication to an alternate medication that could be used on 2 days/week.

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Trigeminal sensory modulatory effects of galcanezumab and clinical response prediction.

Galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, is an emerging migraine preventative. We hypothesized that the preventive effects are conveyed via modulation of somatosensory processing and that certain sensory profiles may hence be associated with different clinical responses. We recruited migraine patients (n=26), who underwent quantitative sensory tests (QST) over the right V1 dermatome and forearm at baseline (T0), 2-3 weeks (T1), and one year (T12) after monthly galcanezumab treatment. The clinical response was defined as a reduction of ≥30% in headache frequency based on the headache diary. Predictors for clinical response were calculated using binary logistical regression models. After galcanezumab (T1 vs. T0), the heat pain threshold (HPT) (°C, 44.9 ± 3.4 vs. 43.0 ± 3.3, p=0.013) and mechanical pain threshold (MPT) (log mN, 1.60 ± 0.31 vs. 1.45 ± 0.26, p=0.042) were increased exclusively in the V1 dermatome, but not the forearm. These changes were immediate, did not differ between responders and non-responders, and did not last in one year of follow-up (T12 vs. T0). However, baseline HPT (OR: 2.13, 95% CI: 1.08-4.19, p = 0.029) on the forearm was a robust predictor for a clinical response three months later. In summary, our data demonstrated that galcanezumab modulates pain thresholds specifically in the V1 dermatome, but this modulation is short-lasting and irrelevant to clinical response. Instead, the clinical response may be determined by individual sensibility even before the administration of medication.

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Cortical oscillatory dysrhythmias in visual snow syndrome: a magnetoencephalography study.

Visual snow refers to the persistent visual experience of static in the whole visual field of both eyes. It is often reported by patients with migraine and co-occurs with conditions such as tinnitus and tremor. The underlying pathophysiology of the condition is poorly understood. Previously, we hypothesized that visual snow syndrome may be characterized by disruptions to rhythmical activity within the visual system. To test this, data from 18 patients diagnosed with visual snow syndrome, and 16 matched controls, were acquired using magnetoencephalography. Participants were presented with visual grating stimuli, known to elicit decreases in alpha-band (8-13 Hz) power and increases in gamma-band power (40-70 Hz). Data were mapped to source-space using a beamformer. Across both groups, decreased alpha power and increased gamma power localized to early visual cortex. Data from the primary visual cortex were compared between groups. No differences were found in either alpha or gamma peak frequency or the magnitude of alpha power,  > 0.05. However, compared with controls, our visual snow syndrome cohort displayed significantly increased primary visual cortex gamma power,  = 0.035. This new electromagnetic finding concurs with previous functional MRI and PET findings, suggesting that in visual snow syndrome, the visual cortex is hyperexcitable. The coupling of alpha-phase to gamma amplitude within the primary visual cortex was also quantified. Compared with controls, the visual snow syndrome group had significantly reduced alpha-gamma phase-amplitude coupling,  < 0.05, indicating a potential excitation-inhibition imbalance in visual snow syndrome, as well as a potential disruption to top-down 'noise-cancellation' mechanisms. Overall, these results suggest that rhythmical brain activity in the primary visual cortex is both hyperexcitable and disorganized in visual snow syndrome, consistent with this being a condition of thalamocortical dysrhythmia.

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Facial expressions modulate pain perception in patients with chronic migraine.

First, we investigated whether the exposure to different visual feedback conditions may modulate pain perception by means of visual induced analgesia in patients with chronic migraine. Second, to comprehend the way emotional face expressions could induce visual analgesia, we evaluated the degree of identification with the four experimental conditions.

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The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders.

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord-mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain.

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Perceived injustice in patients with chronic pain: Prevalence, relevance, and associations with long-term recovery and deterioration.

The Injustice Experience Questionnaire (IEQ) assesses the degree to which chronic pain sufferers perceive injustice in relation to their pain. The aim of the current study was to assess the prevalence and relevance of the IEQ and its association to perceived recovery and deterioration in a naturalistic pain clinic population. Data was obtained from the Oslo University Hospital's Pain Registry. Among 2950 patients, the prevalence of low (<19), medium (19-29) and high (30+) IEQ was 39%, 32% and 29% respectively. High levels of injustice were positively associated with a wide range of adverse health outcomes. Differences between those with high vs low levels of IEQ were clinically significant for most health outcomes. A Venn diagram analysis showed considerable, but not complete, overlap between IEQ, pain catastrophizing, psychological distress and severe pain intensity. High IEQ was associated with reduced clinical recovery (OR 0.6, 95%CI 0.4-0.9) and deterioration (OR 3.6, 95%CI 2.1-6.2) at 12-months follow-up, however, not when controlling for pain-related disability and pain intensity. We conclude that perceived injustice is a prevalent and clinically relevant phenomenon in a chronic pain clinic population, and that more knowledge is needed regarding its role as indicator of poor prognosis and target for tailored treatment. PERSPECTIVE: : This article shows that pain-related injustice is both prevalent and relevant in a large naturalistic pain clinic population. Higher levels of injustice were consistently associated with adverse pain outcomes. Injustice could as such be a viable target for treatment of chronic pain, with potential indirect effects on pain and disability.

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Axonal excitability does not differ between painful and painless diabetic or chemotherapy-induced distal symmetrical polyneuropathy in a multi-centre observational study.

Axonal excitability reflects ion channel function and it is proposed that this may be a biomarker in painful (versus painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy induced distal symmetrical polyneuropathy.

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Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of , a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to . The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.

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Patient-Centered Treatment of Chronic Migraine With Medication Overuse: More Is Not Always Better.

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Natural History of Abortive Medication Withdrawal in the Management of Pediatric Medication Overuse Headache.

The objective of this study is to document pain scores during withdrawal of abortive medication in patients diagnosed with medication overuse headache.

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Effects of cluster headache preventatives on mouse hypothalamic transcriptional homeostasis.

To investigate how cluster headache preventatives verapamil, lithium and prednisone affect expression of hypothalamic genes involved in chronobiology.

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NCOR2 is a novel candidate gene for migraine-epilepsy phenotype.

To identify genetic factors predisposing to migraine-epilepsy phenotype utilizing a multi-generational family with known linkage to chr12q24.2-q24.3.

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Selective Agonists and Antagonists of α9 Versus α7 Nicotinic Acetylcholine Receptors.

Nicotinic acetylcholine receptors containing α9 subunits are essential for the auditory function and have been implicated, along with α7-containing nicotinic receptors, as potential targets for the treatment of inflammatory and neuropathic pain. The study of α9-containing receptors has been hampered by the lack of selective agonists. The only α9-selective antagonists previously identified are peptide conotoxins. Curiously, the activity of α7 and α9 receptors as modulators of inflammatory pain appears to not rely strictly on ion channel activation, which led to the identification of α7 "silent agonists" and phosphocholine as an "unconventional agonist" for α9 containing receptors. The parallel testing of the α7 silent agonist -CF-diEPP and phosphocholine led to the discovery that -CF-diEPP was an α9 agonist. In this report, we compared the activity of α7 and α9 with a family of structurally related compounds, most of which were previously shown to be α7 partial or silent agonists. We identify several potent α9-selective agonists as well as numerous potent and selective α9 antagonists and describe the structural basis for these activities. Several of these compounds have previously been shown to be effective in animal models of inflammatory pain, an activity that was assumed to be due to α7 silent agonism but may, in fact, be due to α9 activity. The α9-selective conotoxin antagonists have also been shown to reduce pain in similar models. Our identification of these new α9 agonists and antagonists may prove to be invaluable for defining an optimal approach for treating pain, allowing for reduced use of opioid drugs.

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Bimodal sensory integration in migraine: A study of the effect of visual stimulation on somatosensory evoked cortical responses.

Merging of sensory information is a crucial process for adapting the behaviour to the environment in all species. It is not known if this multisensory integration might be dysfunctioning interictally in migraine without aura, where sensory stimuli of various modalities are processed abnormally when delivered separately. To investigate this question, we compared the effects of a concomitant visual stimulation on conventional low-frequency somatosensory evoked potentials and embedded high-frequency oscillations between migraine patients and healthy volunteers.

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FollowTheSutures: Piloting a new way to administer onabotulinumtoxinA for chronic migraine.

Anatomical and experimental data indicate that onabotulinimtoxin A could be more efficient and cost-effective for treating chronic migraine with injections targeting the cranial sutures, where collaterals from the meninges penetrate the skull.

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Inherited Patients Taking Opioids for Chronic Pain – Considerations for Primary Care.

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Association between dietary acid load and clinical features of migraine headaches among Iranian individuals.

There is limited evidence regarding the possible role of dietary acid load (DAL) in the pathophysiology of migraine headaches. Therefore, we sought to examine DAL in relation to the clinical features of migraine including headache frequency, severity and duration, headache impact test-6 (HIT-6), and serum levels of nitric oxide (NO). In the present cross-sectional study, 262 patients (38 men and 224 women aged 20-50 years) were recruited through a simple random sampling method. Dietary intakes were obtained by using a validated 168-item semi-quantitative food frequency questionnaire (FFQ). DAL was then calculated by two different methods; potential renal acid load (PRAL) and net endogenous acid production (NEAP). In total, 262 patients with a mean (SE) age of 36.1 (0.53) and a BMI of 25.55 (0.21) were included in the current study. After controlling for potential confounders, a higher DAL was positively associated with headache frequency in those with the highest DAL score compared to the lowest (PRAL; β = 2.33; 95% CI 0.78, 3.88; NEAP; β = 1.74; 95% CI 0.13, 3.34). Increasing NEAP from 28.96 to 35.89 resulted in a 3.43 and 2.74 increment in HIT-6 scores in the crude (95% CI 1.35, 5.52) and fully-adjusted models (95% CI 0.40, 5.07), respectively. Moreover, a higher dietary PRAL was significantly associated with migraine-related disability, as shown by HIT-6, in subjects of the third tertile compared to those in the first tertile after controlling for confounders (β = 2.42; 95% CI 0.13, 4.70). In conclusion, our study highlighted the importance of the acid-base properties of a diet in the pathophysiology of migraine headaches. However, further well-designed studies are needed to confirm our findings.

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Influencers in the Somatosensory System: Extrinsic Control of Sensory Neuron Phenotypes.

Somatosensory neurons in dorsal root ganglia (DRG) comprise several main subclasses: high threshold nociceptors/thermoceptors, high- and low-threshold mechanoreceptors, and proprioceptors. Recent years have seen an explosion in the identification of molecules that underlie the functional diversity of these sensory modalities. They also have begun to reveal the developmental mechanisms that channel the emergence of this subtype diversity, solidifying the importance of peripheral instructive signals. Somatic sensory neurons collectively serve numerous essential physiological and protective roles, and as such, an increased understanding of the processes that underlie the specialization of these sensory subtypes is not only biologically interesting but also clinically relevant.

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Sestrin2 overexpression attenuates osteoarthritis pain via induction of AMPK/PGC-1α-mediated mitochondrial biogenesis and suppression of neuroinflammation.

Our previous study indicated that reactive oxygen species (ROS) are critically involved in chronic pain. Sestrin2 (Sesn2), a novel stress-inducible protein, is evidenced to reduce the generation of ROS. The study examined the role of Sesn2 in osteoarthritis (OA) pain and delineated the underlying molecular mechanisms.

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Quality of Labor Analgesia with Dural Puncture Epidural versus Standard Epidural Technique in Obese Parturients: A Double-blind Randomized Controlled Study.

The dural puncture epidural technique may improve analgesia quality by confirming midline placement and increasing intrathecal translocation of epidural medications. This would be advantageous in obese parturients with increased risk of block failure. This study hypothesizes that quality of labor analgesia will be improved with dural puncture epidural compared to standard epidural technique in obese parturients.

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Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice.

Itch, a common clinical symptom of many skin diseases, severely impairs the life quality of patients. Nav1.7, a subtype of voltage-gated sodium channels mainly expressed in primary sensory neurons, is responsible for the amplification of threshold currents that trigger action potential (AP) generation. Gain-of-function mutation of Nav1.7 leads to paroxysmal itch, while pharmacological inhibition of Nav1.7 alleviates histamine-dependent itch. However, the crosstalk between histamine and Nav1.7 that leads to itch is unclear. In the present study, we demonstrated that in the dorsal root ganglion (DRG) neurons from histamine-dependent itch model mice induced by compound 48/80, tetrodotoxin-sensitive (TTX-S) but not TTX-resistant Na currents were activated at more hyperpolarized membrane potentials compared to those on DRG neurons from vehicle-treated mice. Meanwhile, bath application of histamine shifted the activation voltages of TTX-S Na currents to the hyperpolarized direction, increased the AP frequency, and reduced the current threshold required to elicit APs. Further mechanistic studies demonstrated that selective activation of H1 but not H2 and H4 receptors mimicked histamine effect on TTX-S Na channels in DRG neurons. The protein kinase C (PKC) inhibitor GO 8963, but not the PKA inhibitor H89, normalized histamine-sensitized TTX-S Na channels. We also demonstrated that histamine shifted the activation voltages of Na currents to the hyperpolarized direction in Chinese hamster ovary (CHO) cells expressing Nav1.7. Importantly, selective inhibition of Nav1.7 by PF-05089771 significantly relieved the scratching frequency in a histamine-dependent itch model induced by compound 48/80. Taken together, these data suggest that activation of H1 receptors by histamine sensitizes Nav1.7 channels through the PKC pathway in DRG neurons that contributes to histamine-dependent itch.

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Pre-emptive analgesia with methylprednisolone and gabapentin in total knee arthroplasty in the elderly.

The aim of this study is to assess whether administration of gabapentin and methylprednisolone as "pre-emptive analgesia" in a group of patients above 65 years of age would be effective in complex pain management therapy following total knee arthroplasty (TKA). One hundred seventy patients above 65 years were qualified for the study, with exclusion of 10 patients due to clinical circumstances. One hundred sixty patients were randomly double-blinded into two groups: the study group (80 patients) and the control group (80 patients). The study group received as "pre-emptive" analgesia a single dose of 300 mg oral (PO) gabapentin and 125 mg intravenous (IV) methylprednisolone, while the control received a placebo. All patients received opioid and non-opioid analgesic agents perioperatively calculated for 1 kg of total body weight. We measured (1) pain intensity level at rest (numerical rating scale, NRS), (2) life parameters, (3) levels of inflammatory markers (leukocytosis, C reactive protein CRP), and (4) all complications. Following administration of gabapentin and methylprednisolone as "pre-emptive" analgesia, the NRS score at rest was calculated at 6, 12 (p < 0.000001), 18 (p < 0.00004) and 24 (p = 0.005569) h postoperatively. Methylprednisolone with gabapentin significantly decreased the dose of parenteral opioid preparations (p = 0.000006). The duration time of analgesia was significantly longer in study group (p < 0.000001), with CRP values lower on all postoperative days (1, 2 days-p < 0.00001, 3 days-p = 0.00538), and leukocytosis on day 2 (p < 0.0086) and 3 (p < 0.00042). No infectious complications were observed in the first postoperative days; in the control group, one patient manifested transient ischemic attack (TIA). The use of gabapentin and methylprednisolone as a single dose decreased the level of postoperative pain on the day of surgery, the dose of opioid analgesic preparations, and the level of inflammatory parameters without infectious processes.

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Participation of transient receptor potential vanilloid 1 in the analgesic effect of duloxetine for paclitaxel induced peripheral neuropathic pain.

Painful peripheral neuropathy is a common dose-limiting side effect of chemotherapeutic paclitaxel (PTX) treatment. The American Society of Clinical Oncology (ASCO) recommends duloxetine (DUL) as a promising treatment alternative for chemotherapy-induced peripheral neuropathic pain. However, this recommendation lacks a robust theoretical basis and supporting data. To elucidate the involvement of transient receptor potential vanilloid 1 (TRPV1) in the analgesic effect of DUL for PTX-induced neuropathic pain, TRPV1 expression in the lumbar dorsal root ganglion (DRG) and spinal cord was evaluated following intraperitoneal administration of PTX (2mg/kg/day) for four alternate days in rats. Western blot and immunohistochemistry suggested that a cumulative dosage of PTX (8 mg/kg) upregulated TRPV1 expression in the lumbar DRG and spinal dorsal horn (SDH) at day 14 post treatment. TRPV1 upregulation in the DRG was mainly expressed in calcitonin gene-related peptide (CGRP) and IB-4 positive small-size sensory neurons. Additionally, PTX increased CGRP and substance P (SP) expression in the DRG and SDH, induced SDH microglia and astrocyte activation, and upregulated spinal tumor necrosis factor-α (TNF-α) but not IL-1β or IL-10 expression. Behavioral detection showed that PTX-related mechanical and thermal hyperalgesia was significantly inhibited by consecutive administration of DUL 20 mg/kg/day greater than 10 mg/kg/day for 5 days starting at day 10 post PTX injection. Furthermore, DUL (20 mg/kg/day) for 5 days markedly ameliorated PTX-induced TRPV1, CGRP, and SP upregulation in the DRG and SDH, and mitigated PTX-induced spinal cord glia activation and TNF-α expression. Moreover, the pharmacological blockade of TRPV1 resulted in an analgesic effect on PTX-induced hyperalgesia. Collectively, these results suggest that DUL alleviates PTX-induced peripheral neuropathic pain by suppressing TRPV1 upregulation in the lumbar DRG and SDH, which is followed by a reduction in CGRP and SP release, as well as spinal glia activation and TNF-α expression.

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Combining Guided Intervention of Education and Relaxation (GIER) with Remote Electrical Neuromodulation (REN) in the Acute Treatment of Migraine.

Evidence indicates that combining behavioral treatments with pharmacological treatments for migraine prevention improves efficacy, however little is known about the outcomes of combining neuromodulation and behavioral interventions for acute treatment of migraine. Remote Electrical Neuromodulation (REN) is an FDA-cleared non-pharmacological migraine treatment. The current study evaluated the clinical benefits of augmenting REN treatment with a specially tailored behavioral therapy comprised of Guided Intervention of Education and Relaxation (GIER), for the acute treatment of migraine.

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Rapid development of an integrated remote programming platform for neuromodulation systems through the biodesign process.

Treating chronic symptoms for pain and movement disorders with neuromodulation therapies involves fine-tuning of programming parameters over several visits to achieve and maintain symptom relief. This, together with challenges in access to trained specialists, has led to a growing need for an integrated wireless remote care platform for neuromodulation devices. In March of 2021, we launched the first neuromodulation device with an integrated remote programming platform. Here, we summarize the biodesign steps taken to identify the unmet patient need, invent, implement, and test the new technology, and finally gain market approval for the remote care platform. Specifically, we illustrate how agile development aligned with the evolving regulatory requirements can enable patient-centric digital health technology in neuromodulation, such as the remote care platform. The three steps of the biodesign process applied for remote care platform development are: (1) Identify, (2) Invent, and (3) Implement. First, we identified the unmet patient needs through market research and voice-of-customer (VOC) process. Next, during the concept generation phase of the invention step, we integrated the results from the VOC into defining requirements for prototype development. Subsequently, in the concept screening phase, ten subjects with PD participated in a clinical pilot study aimed at characterizing the safety of the remote care prototype. Lastly, during the implementation step, lessons learned from the pilot experience were integrated into final product development as new features. Following final product development, we completed usability testing to validate the full remote care system and collected preliminary data from the limited market release experience. The VOC data, during prototype development, helped us identify thresholds for video quality and needs priorities for clinicians and patients. During the pilot study, one subject reported anticipated remote-care-related adverse events that were resolved without sequelae. For usability analysis following final product development, the failure rates for task completion for both user groups were about 1%. Lastly, during the initial 4 weeks of the limited market release experience, a total of 858 remote care sessions were conducted with a 93% success rate. Overall, we developed a remote care platform by adopting a user-centric approach. Although the system intended to address pre-COVID19 challenges associated with disease management, the unforeseen overlap of the study with the pandemic elevated the importance of such a system and an innovative development process enabled us to advance a patient-centric platform to gain regulatory approval and successfully launch the remote care platform to market.

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Prospective, randomized, multicenter study of intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: 24-Month treatment arm results.

Vertebral endplates, innervated by the basivertebral nerve, can be a source of vertebrogenic low back pain when damaged with inflammation, visible as types 1 or 2 Modic changes. A randomized controlled trial (RCT) compared basivertebral nerve ablation (BVNA) to standard care (SC) showed significant differences between arms at 3 and 6-months. At 12-months, significant improvements were sustained for BVNA. We report results of the BVNA arm at 24-months.

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The distinct longitudinal impact of pain catastrophizing on pain interference among youth living with sickle cell disease and chronic pain.

Youth living with chronic sickle cell disease (SCD) pain are at risk for psychosocial distress and high levels of pain catastrophizing that contribute to functional impairment. This study aimed to identify the unique long-term impact of pain catastrophizing on pain impairment among youth with SCD. Youth with chronic SCD pain (N = 63, 10-18 years old, 58.3% female, 95.1% Black or African American) were recruited within comprehensive SCD clinics and completed a battery of measures at baseline and 4-months follow-up. A linear hierarchical regression examined baseline demographic and clinical characteristics (child SCD genotype, age, and average pain intensity), psychosocial functioning (anxiety, depression), and pain catastrophizing as predictors of pain interference at 4-months follow-up. Pain catastrophizing was the only unique predictor of pain interference at 4-months follow-up. Among youth with chronic SCD pain, pain catastrophizing warrants greater consideration as an important predictor that influences pain management and overall functioning.

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Long-term adherence, safety, and efficacy of repeated onabotulinumtoxinA over five years in chronic migraine prophylaxis.

OnabotulinumtoxinA (BoNTA) demonstrated a positive benefit-risk in chronic migraine (CM) patients in PREEMPT I and II phase III trials and many subsequent real-world studies. We herein aimed at evaluating the adherence to repeated BoNTA over a period of five years, while secondary objectives included the assessment of its long-term safety/efficacy and patients' satisfaction to treatment.

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GADD45A induces neuropathic pain by activating P53 apoptosis pathway in mice.

Neuropathic pain is a common condition with current heights of varying etiology. The therapeutic drugs are also poorly work and often limited by side effects such as dizziness.

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Pain management for necrotizing enterocolitis: getting the balance right.

Adequate pain management for preterm born neonates suffering from the extremely painful disease necrotizing enterocolitis (NEC) is essential, since neonatal exposure to pain is related to negative short-term and long-term consequences. The aim of this study was to describe the current pain management and its effectiveness in NEC patients.

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Opioid-sparing in children with chronic pain who are eligible for palliative care.

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Head and neck cancer survivorship consensus statement from the American Head and Neck Society.

To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship.

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Post-COVID-19 persistent headache: A multicentric 9-months follow-up study of 905 patients.

Headache is a frequent symptoms of coronavirus disease 2019 (COVID-19). Its long-term evolution remains unknown. We aim to evaluate the long-term duration of headache in patients that presented headache during the acute phase of COVID-19.

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New Anti-CGRP Medications in the Treatment of Vestibular Migraine.

Vestibular migraine (VM) is a condition associated with migraine headache, vertigo, dizziness, and balance disturbances. Treatment options are limited. It is unknown if new calcitonin gene-related peptide (CGRP) migraine medications have efficacy in treating VM.

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Invited Commentary: Percutaneous Radiofrequency Ablation of Articular Sensory Nerves for Management of Chronic Pain Due to Osteoarthritis.

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Efficacy and safety of transcutaneous electrical nerve stimulation (TENS) for acute and chronic pain in adults: a systematic review and meta-analysis of 381 studies (the meta-TENS study).

To investigate the efficacy and safety of transcutaneous electrical nerve stimulation (TENS) for relief of pain in adults.

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The role of the capsaicin 8% patch in the treatment of painful diabetic peripheral neuropathy.

Treatment of painful diabetic peripheral neuropathy (PDPN) is challenging and often limited by drug tolerability and adverse effects. This review article focuses on the high-dose (8%) capsaicin patch that allows for improved efficacy and reduced application frequency in comparison to low-dose capsaicin formulations. Systemic absorption is minimal resulting in fewer systemic side effects than first-line oral medications. There is evidence that capsaicin patch treatment is well-tolerated, safe and provides effective pain relief maintained for several weeks; well-powered studies are needed to confirm these findings. The capsaicin 8% patch may benefit patients at high risk for adverse effects from oral medication, polypharmacy or inadequate pain relief from first-line therapies.

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Mechanistic Characterization of the Pharmacological Profile of HS-731, a Peripherally Acting Opioid Analgesic, at the µ-, δ-, κ-Opioid and Nociceptin Receptors.

Accumulated preclinical and clinical data show that peripheral restricted opioids provide pain relief with reduced side effects. The peripherally acting opioid analgesic HS-731 is a potent dual μ-/δ-opioid receptor (MOR/DOR) full agonist, and a weak, partial agonist at the κ-opioid receptor (KOR). However, its binding mode at the opioid receptors remains elusive. Here, we present a comprehensive in silico evaluation of HS-731 binding at all opioid receptors. We provide insights into dynamic interaction patterns explaining the different binding and activity of HS-731 on the opioid receptors. For this purpose, we conducted docking, performed molecular dynamics (MD) simulations and generated dynamic pharmacophores (dynophores). Our results highlight two residues important for HS-731 recognition at the classical opioid receptors (MOR, DOR and KOR), particular the conserved residue 5.39 (K) and the non-conserved residue 6.58 (MOR: K, DOR: W and KOR: E). Furthermore, we assume a salt bridge between the transmembrane helices (TM) 5 and 6 via K227 and E297 to be responsible for the partial agonism of HS-731 at the KOR. Additionally, we experimentally demonstrated the absence of affinity of HS-731 to the nociceptin/orphanin FQ peptide (NOP) receptor. We consider the morphinan phenol Y130 responsible for this affinity lack. Y130 points deep into the NOP receptor binding pocket preventing HS-731 binding to the orthosteric binding pocket. These findings provide significant structural insights into HS-731 interaction pattern with the opioid receptors that are important for understanding the pharmacology of this peripheral opioid analgesic.

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Overview of First-Line and Second-Line Pharmacotherapies for Osteoarthritis with Special Focus on Intra-Articular Treatment.

Osteoarthritis (OA) can be defined as the result of pathological processes of various etiologies leading to damage to the articular structures. Although the mechanism of degenerative changes has become better understood due to the plethora of biochemical and genetic studies, the drug that could stop the degenerative cascade is still unknown. All available forms of OA therapy are based on symptomatic treatment. According to actual guidelines, comprehensive treatment of OA should always include a combination of various therapeutic options aimed at common goals, which are pain relief in the first place, and then the improvement of function. Local treatment has become more common practice, which takes place between rehabilitation and pharmacological treatment in the hierarchy of procedures. Only in the case of no improvement and the presence of advanced lesions visible in imaging tests, should surgery be considered. Currently, an increasing number of studies are being published suggesting that intra-articular injections may be as effective or even more effective than non-steroidal anti-inflammatory drugs (NSAIDs) and result in fewer systemic adverse events. The most commonly used preparations are hyaluronic acid (HA), glucocorticosteroids (GS), and also platelet-rich plasma (PRP) in recent years. This review aims to present the mechanism of action and clinical effectiveness of different pharmacological options in relieving pain and improving functions in OA as well as the emerging approach in intra-articular treatment with PRP.

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Inhibition of phosphodiesterase-4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP-cytokine-Cx43 signaling in mice.

The spinal phosphodiesterase-4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury-induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP-Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.

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Functional Characterization of Mechanosensitive Piezo1 Channels in Trigeminal and Somatic Nerves in a Neuron-on-Chip Model.

Mechanosensitive ion channels, Piezo1 and 2, are activated by pressure and involved in diverse physiological functions, including senses of touch and pain, proprioception and many more. Understanding their function is important for elucidating the mechanosensitive mechanisms of a range of human diseases. Recently, Piezo channels were suggested to be contributors to migraine pain generation. Migraine is typically characterized by allodynia and mechanical hyperalgesia associated with the activation and sensitization of trigeminal ganglion (TG) nerve fibers. Notably, migraine specific medicines are ineffective for other types of pain, suggesting a distinct underlying mechanism. To address, in a straightforward manner, the specificity of the mechanosensitivity of trigeminal vs. somatic nerves, we compared the activity of Piezo1 channels in mouse TG neurons vs. dorsal root ganglia (DRG) neurons. We assessed the functional expression of Piezo1 receptors using a conventional live calcium imaging setup equipped with a multibarrel application system and utilizing a microfluidic chip-based setup. Surprisingly, the TG neurons, despite higher expression of the gene, were less responsive to Piezo1 agonist Yoda1 than the DRG neurons. This difference was more prominent in the chip-based setup, suggesting that certain limitations of the conventional approach, such as turbulence, can be overcome by utilizing microfluidic devices with laminar solution flow.

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Modified Spared Nerve Injury Surgery Model of Neuropathic Pain in Mice.

Spared nerve injury (SNI) is an animal model that mimics the cardinal symptoms of peripheral nerve injury for studying the molecular and cellular mechanism of neuropathic pain in mice and rats. Currently, there are two types of SNI model, one to cut and ligate the common peroneal and the tibial nerves with intact sural nerve, which is defined as SNIs in this study, and another to cut and ligate the common peroneal and the sural nerves with intact tibial nerve, which is defined as SNIt in this study. Because the sural nerve is purely sensory whereas the tibial nerve contains both motor and sensory fibers, the SNIt model has much less motor deficit than the SNIs model. In the traditional SNIt mouse model, the common peroneal and the sural nerves are cut and ligated separately. Here a modified SNIt surgery method is described to damage both common peroneal and sural nerves with only one ligation and one cut with a shorter procedure time, which is easier to perform and reduces the potential risk of stretching the sciatic or tibial nerves, and produces similar mechanical hypersensitivity as the traditional SNIt model.

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The Link between Fibromyalgia Syndrome and Anger: A Systematic Review Revealing Research Gaps.

Anger has been associated with increased pain perception, but its specific connection with Fibromyalgia Syndrome (FMS) has not yet been established in an integrated approach. Therefore, the present systematic review focuses on exploring this connection, and based on this connection, delimiting possible gaps in the research, altogether aimed at improving FMS clinical intervention and guiding future research lines. Anger is considered a basic negative emotion that can be divided into two dimensions: anger-in (the tendency to repress anger when it is experienced) and anger-out (the leaning to express anger through verbal or physical means). The current systematic review was performed based on the guidelines of the PRISMA and Cochrane Collaborations. The Prospective Register of Systematic Reviews (PROSPERO) international database was forehand used to register the review protocol. The quality of chosen articles was assessed and the main limitations and research gaps resulting from each scientific article were discussed. The search included PubMed, Scopus, and Web of Science databases. The literature search identified 13 studies eligible for the systematic review. Levels of anger-in have been shown to be higher in FMS patients compared to healthy participants, as well as patients suffering from other pain conditions (e.g., rheumatoid arthritis). FMS patients had also showed higher levels of state and trait anxiety, worry and angry rumination than other chronic pain patients. Anger seems to amplify pain especially in women regardless FMS condition but with a particularly greater health-related quality of life´s impact in FMS patients. In spite of the relevance of emotions in the treatment of chronic pain, including FMS, only two studies have proposed intervention programs focus on anger treatment. These two studies have observed a positive reduction in anger levels through mindfulness and a strength training program. In conclusion, anger might be a meaningful therapeutic target in the attenuation of pain sensitivity, and the improvement of the general treatment effects and health-related quality of life in FMS patients. More intervention programs directed to reduce anger and contribute to improve well-being in FMS patients are needed.

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Stress-induced analgesia: an evaluation of effects on temporal summation of pain and the role of endogenous opioid mechanisms.

Acute stress reduces responses to static evoked pain stimuli (stress-induced analgesia [SIA]). Whether SIA inhibits temporal summation of pain, a dynamic evoked pain measure indexing central sensitization, has been little studied and mechanisms were not evaluated.

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Intravenous administration of human mesenchymal stem cells derived from adipose tissue and umbilical cord improves neuropathic pain via suppression of neuronal damage and anti-inflammatory actions in rats.

Mesenchymal stem cells (MSCs), which are isolated from adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), or bone marrow, have therapeutic potential including anti-inflammatory and immunomodulatory activities. It was recently reported that MSCs are also effective as a therapeutic treatment for neuropathic pain, although the underlying mechanisms have yet to be resolved. Therefore, in this study, we investigated the effects of human AD- and UC-MSCs on neuropathic pain and its mechanisms using rat models of partial sciatic nerve ligation (PSNL). AD- or UC-MSCs were intravenously administered 4 days after PSNL. Antinociceptive effects were then evaluated using the von Frey and weight-bearing tests. We found that, 3-9 days after the administration of AD- or UC-MSCs to PSNL-exposed rats, both the mechanical threshold and differences in weight-bearing of the right and left hind paws were significantly improved. To reveal the potential underlying antinociceptive mechanisms of MSCs, the levels of activation transcription factor 3- and ionized calcium-binding adapter molecule 1-positive cells were measured by immunohistochemical analysis. AD- and UC-MSCs significantly decreased the levels of these proteins that were induced by PSNL in the dorsal root ganglia. Additionally, UC-MSC significantly improved the PSNL-induced decrease in the myelin basic protein level in the sciatic nerve, indicating that UC-MSC reversed demyelination of the sciatic nerve produced by PSNL. These data suggest that AD- and UC-MSCs may help in the recovery of neuropathic pain via the different regulation; AD-MSCs exhibited their effects via suppressed neuronal damage and anti-inflammatory actions, while UC-MSCs exhibited their effects via suppressed neuronal damage, anti-inflammatory actions and remyelination.

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The influence of message framing on nocebo headaches: Findings from a randomized laboratory design.

Attribute framing presents an ethically sound approach for reducing adverse nocebo effects. In past studies, however, attribute framing has not always decreased nocebo effects. The present study used a sham tDCS procedure to induce nocebo headaches to explore factors that may contribute to the efficacy of attribute framing. Participants (N = 174) were randomized to one of three between-subject conditions: a no-headache instruction (control) condition and two conditions in which headaches were described as either 70% likely (negative framing) to occur or 30% unlikely (positive framing) to occur. Results revealed nocebo headaches in both framing conditions, as compared to the control condition. Attribute framing did not influence headache measures recorded during the sham tDCS task, but framing did have a modest influence on one of two headache items completed after the task. Results suggest that attribute framing could have a stronger influence on delayed nocebo effect measures or retrospective symptom reports; a finding that may explain inconsistencies in the existing framing-nocebo effect literature. Exploratory analyses also revealed that low negative affect was associated with stronger nocebo and attribute framing effects, although these effects were found on only a few headache measures. It is concluded that researchers should further investigate the influence of attribute framing on nocebo headaches as a function of both timing and emotional factors.

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Photobiomodulation (λ=808nm) and Platelet-Rich Plasma (PRP) for the Treatment of Acute Rheumatoid Arthritis in Wistar Rats.

Rheumatoid arthritis (RA) causes inflammation, pain, edema, and articular degradation and its treatment can be based on anti-inflammatory drugs, photobiomodulation (PBM) and/or platelet-rich plasma (PRP) that can decrease cell flow and promote local healing. In the present study, we evaluate the effects of PBM and PRP on acute arthritis in Wistar rats through inflammatory and oxidative stress parameters. Thirty female Wistar rats were assigned to five groups (n=6, each group): Control, Sham, PRP, Laser, and PRP+Laser. For arthritis induction, all animals of groups Sham, PRP, Laser and PRP+Laser received an intraarticular injection of Zymosan® (200µg) in the right knee. Twenty-four hours post-arthritis induction, PRP was prepared and injected (8 × 10 of platelets) in animals of PRP and PRP+Laser groups. PBM was performed in Laser and PRP+Laser groups by single-dose therapy with the GaAlAs laser (λ=808 nm, P=25 mW, fluence=30 J/cm, beam area=0.02 mm, t=33 seconds, E=0.825 J, punctual application). After seven days of induction, serum samples were collected and thiobarbituric acid reactive substances (TBARS), nitric oxide (NO) and catalase activity were analysed. Morphological parameters were measured for inflammation areas, cartilage thickness, and C3 protein expression in knee samples. Statistical analysis was performed with an ANOVA test and Tukey's post-hoc test with a significance level of 5% (<0.05). NO was lower in the treated groups compared to the Sham group, and TBARS did not show any differences, while catalase showed greater activity between PRP+Laser versus PRP (<0.05). Inflammatory areas and cartilage thickness were lower in the treated groups compared to Sham (<0.05), while no differences in C3 protein expression was observed. PBM associated with PRP is better for anti-inflammatory and joint preservation by morphological aspects and NO levels that concern a potential clinical application.

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Assessing Movement-Evoked Pain.

One of the most common and nuanced tasks that nurses perform is pain assessment, particularly in acute postoperative settings where frequent reassessments are needed. Most assessments are limited to obtaining a pain intensity score with little attention paid to the conditions necessitating the assessment or the factors contributing to the pain. Pain is frequently assessed during rest, but seldom during periods of movement or activity, which is a crucial omission given that acute postoperative movementevoked pain (MEP) is intense and a common barrier to healing and restoration of function. In addition to physical limitations, MEP can impede cognitive, emotional, and social functioning in ways that can contribute to chronic pain, mood disorders, and disability. Professional and regulatory standards are moving away from a focus on pain intensity to an emphasis on its context, impact on function, and associated distress. Thus, there are many driving forces compelling nurses to integrate MEP assessments into practice to expedite the restoration of biopsychosocial functioning in postoperative patients. The authors discuss the clinical significance of a MEP assessment as well as protocols and tools for completing such assessments.

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Encoding signs of orofacial neuropathic pain from facial expressions in mice.

To evaluate the effects of mental nerve injury in the facial reactions elicited by mechanical stimulation of different intensities and detect and quantify spontaneous facial pain-like expressions during a period free of stimuli, as signs of evoked and spontaneous pain in a mouse model for neuropathic orofacial pain.

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Oxidized linoleic acid metabolites maintain mechanical and thermal hypersensitivity during sub-chronic inflammatory pain.

Inflammatory pain serves as a protective defense mechanism which becomes pathological when it turns into chronic inflammatory pain. This transition is mediated by a variety of peripheral mediators that sensitize nociceptors and increase pain perception in sensory neurons. Besides cytokines, chemokines and growth factors, accumulating evidence shows that oxidized lipids, such as eicosanoids and oxidized linoleic acid metabolites, contribute to this sensitization process. Most notably, the oxidized linoleic acid metabolite and partial TRPV1 agonist 9-HODE (hydroxyoctadecadienoic acid) was shown to be involved in this sensitization process. However, it is still unknown how some of the oxidized linoleic acid metabolites are synthesized in the inflammatory environment and in which phase of inflammation they become relevant. Here we show that the concentrations of oxidized linoleic acid metabolites, especially 9-HODE and 13-HODE, are significantly increased in inflamed paw tissue and the corresponding dorsal root ganglia in the sub-chronic phase of inflammation. Surprisingly, classical inflammatory lipid markers, such as prostaglandins were at basal levels in this phase of inflammation. Moreover, we revealed the cell type specific synthesis pathways of oxidized linoleic acid metabolites in primary macrophages, primary neutrophils and dorsal root ganglia. Finally, we show that blocking the most elevated metabolites 9-HODE and 13-HODE at the site of inflammation in the sub-chronic phase of inflammation, leads to a significant relief of mechanical and thermal hypersensitivity in vivo. In summary, these data offer an approach to specifically target oxidized linoleic acid metabolites in the transition of acute inflammatory pain to chronic inflammatory pain.

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Treatment of nonsurgical refractory back pain with high-frequency spinal cord stimulation at 10 kHz: 12-month results of a pragmatic, multicenter, randomized controlled trial.

Spinal cord stimulation (SCS) at 10 kHz (10-kHz SCS) is a safe and effective therapy for treatment of chronic low-back pain. However, it is unclear from existing evidence whether these findings can be generalized to patients with chronic back pain that is refractory to conventional medical management (CMM) and who have no history of spine surgery and are not acceptable candidates for spine surgery. The authors have termed this condition "nonsurgical refractory back pain" (NSRBP) and conducted a multicenter, randomized controlled trial to compare CMM with and without 10-kHz SCS in this population.

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A dose-escalation clinical trial of intranasal ketamine for uncontrolled cancer-related pain.

Intranasal (IN) ketamine has been shown to be effective in controlling breakthrough chronic pain. However, there are no data evaluating IN ketamine for cancer-related pain. The objective of our study was to determine safety and pharmacology (pharmacokinetics and preliminary efficacy) of IN ketamine for uncontrolled cancer-related pain METHODS: This was a clinical trial of 10 adult patients with uncontrolled cancer-related pain. Each patient received escalating doses of ketamine over four visits, each 2-5 days apart: 10 mg IN at visit 1, 10 mg intravenous (IV) at visit 2, 30 mg IN at visit 3, and 50 mg IN at visit 4. Pain was measured before and after drug administration for up to 4 hours using the 11-point (0-10) Numerical Pain Rating Scale (NPRS).

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Long-Term Effectiveness of Three Anti-CGRP Monoclonal Antibodies in Resistant Chronic Migraine Patients Based on the MIDAS score.

Criteria, including clinical features and effective outcomes, for access and persistence of novel but costly treatments may vary between countries, thus affecting the health of patients. Monoclonal antibodies against the calcitonin gene-related peptide pathway (anti-CGRP mAbs) for migraine treatment are currently prescribed following strict criteria.

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Migraine and tension-type headache in Germany. Prevalence and disease severity from the BURDEN 2020 Burden of Disease Study.

Headache disorders are widespread among women and men in Germany and are primarily associated with restrictions on quality of life. The two most common types of headache disorders are migraine and tension-type headache. In order to gain valid estimates of the prevalence of these conditions, a cross-sectional telephone-based survey was conducted among adults in Germany (N=5,009) between October 2019 and March 2020. The frequency, duration, the characteristics and comorbidities associated with headache were measured using the diagnostic criteria defined in the International Classification of Headache Disorders. 57.5% of women and 44.4% of men in Germany stated that they had had a headache in the last twelve months. 14.8% of women and 6.0% of men meet all of the diagnostic criteria for migraine. Tension-type headache affects 10.3% of women and 6.5% of men. Migraine and tension-type headache are predominantly found among people of working age and steadily decrease with age. Migraine is often accompanied by comorbidities such as depressive symptoms and anxiety disorders. People affected by headache disorders tend to receive very little professional medical care, with only a minority seeking treatment within a year. These results provide a comprehensive picture of the population-related impact of headache disorders and are used in the BURDEN 2020 study to quantify key indicators for burden of disease assessment.

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Sphingosine-1 phosphate receptor 1 contributes to central sensitization in recurrent nitroglycerin-induced chronic migraine model.

Central sensitization is an important pathophysiological mechanism of chronic migraine (CM), and microglia activation in trigeminocervical complex (TCC) contributes to the development of central sensitization. Emerging evidence implicates that blocking sphingosine-1-phosphate receptor 1 (S1PR1) can relieve the development of chronic pain and inhibit the activation of microglia. However, it is unclear whether S1PR1 is involved in the central sensitization of CM. Therefore, the purpose of this study is to explore the role of S1PR1 and its downstream signal transducers and activators of transcription 3 (STAT3) signaling pathway in the CM, mainly in inflammation.

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Intolerance of uncertainty moderates the relationship between catastrophizing, anxiety, and perceived pain in people with chronic nononcological pain.

Substantial empirical evidence has shown that intolerance of uncertainty is a central transdiagnostic feature in psychopathology and it has been suggested to be a pain-related psychological factor contributing to the experience of chronic pain. However, research in this area is virtually nonexistent. The objective of this study was to investigate associations between pain severity, catastrophizing, and anxiety in people with chronic nononcological pain, while assuming that intolerance of uncertainty moderates these relationships.

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Population-Based Study of Nonelective Postpartum Readmissions in Women With Stroke, Migraine, Multiple Sclerosis, and Myasthenia Gravis.

To compare maternal obstetric complications and non-elective readmissions in women with common neurological comorbidities (WWN) versus women without neurological disorders.

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Itch on YouTube: a cross-sectional analysis.

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Rurality impacts pain care for female veterans similarly to male veterans.

Rural disparities exist in access to multidisciplinary pain care with higher rates of opioid prescribing in rural regions. Among Veterans, who have prevalent rates of chronic pain, women often evidence complex presentations, multiple comorbidities, and dissatisfaction with care. This study investigates the impact of rurality on pain care for women specifically, and whether this varies from the impact of rurality for men.

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Red flags in headache care.

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Pain Burden in the CASiRe International Cohort of Sickle Cell Patients: United States and Ghana.

Sickle Cell Disease (SCD) is a genetic blood disorder affecting over 1 million people globally. The aim of this analysis is to explore the pain burden of patients with SCD in two countries: the United States (U.S.) and Ghana.

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The clinical characteristics of familial cluster headache.

A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup.

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Headaches and the use of personal protective equipment in the general population during the COVID-19 pandemic.

Headaches associated with personal protective equipment were reported in health-care workers in previous epidemiological studies.

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Effective interventions to improve long-term physiotherapy exercise adherence among patients with lower limb osteoarthritis. A systematic review.

Osteoarthritis (OA) is a chronic condition. Physiotherapy is known to be beneficial for people with OA. Patient adherence to physiotherapy exercise is essential for the effective management of OA.

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Advances in Neuromodulation for Chronic Pain.

In the past decade, neuromodulation as a treatment option for pain took a huge interest in innovating and developing more effective paradigms to conquer chronic pain syndromes […].

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Ropivacaine-loaded, hydroxypropyl chitin thermo-sensitive hydrogel combined with hyaluronan: an injectable, sustained-release system for providing long-lasting local anesthesia in rats.

Ropivacaine hydrochloride is a commonly used local anesthetic in clinics. However, local injection or continuous infusion of ropivacaine has been associated with several disadvantages. Accordingly, it is important to develop a new controlled release system for local administration of ropivacaine to achieve a prolong anesthetic effect, improve efficacy, and minimize the side effects.

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Endoscopic Lateral Approach for Dorsal Root Ganglion Burst Stimulation: Technical Note and Illustrative Case Series.

Dorsal root ganglion (DRG) stimulation demonstrated superiority over traditional spinal cord stimulation with better pain relief and greater improvement of quality of life. However, leads specifically designed for DRG stimulation are difficult to implant in patients who previously underwent spinal surgery and show epidural scarring at the desired site of implantation because of the reduced stiffness of the lead. Nevertheless, recurrent leg or arm pain after spinal surgery usually manifests as a single level radiculopathy, which should theoretically be amenable to DRG stimulation.

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The MOTION Study: A Randomized Controlled Trial with objective real-world outcomes for lumbar spinal stenosis patients treated with the mild® Procedure 1-Year results.

The purpose of this study is to provide Level-1 objective, real-world outcome data for patients with lumbar spinal stenosis suffering from neurogenic claudication secondary to hypertrophic ligamentum flavum(HLF).

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RGMa signal in Macrophages Induces Neutrophil-related Astrocytopathy in NMO.

Repulsive guidance molecule-a (RGMa) is a glycosylphosphatidylinositol-linked glycoprotein which has multiple functions including axon growth inhibition and immune regulation. However, its role in the pathophysiology of neuromyelitis optica (NMO) is poorly understood. Perivascular astrocytopathy, which is induced by the leakage of aquaporin-4 (AQP4)-specific IgG into the central nervous system parenchyma, is a key feature of NMO pathology. We investigated the RGMa involvement in the pathology of NMO astrocytopathy, and tested a therapeutic potential of humanized anti-RGMa monoclonal antibody (RGMa-mAb).

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Healthcare utilization and costs among patients with chronic migraine, episodic migraine, and tension-type headache enrolled in commercial insurance plans.

To quantify and compare healthcare utilization and costs for patients with chronic migraine (CM), episodic migraine (EM), and tension-type headache (TTH) enrolled in US commercial health plans.

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Cutaneous Allodynia in Migraine: A Narrative Review.

In the present work, we conduct a narrative review of the most relevant literature on cutaneous allodynia (CA) in migraine.

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Mechanical Punctate Pain Thresholds in Patients With Migraine Across Different Migraine Phases: A Narrative Review.

We reviewed the studies of mechanical punctate pain thresholds (MPTs) in patients with migraine and summarized their findings focusing on the differences in MPT measurement and MPTs in different phases of migraine.

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Chronic pain after inguinal hernia repair is a real risk and a major issue.

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Interictal plasma endothelin-1 levels do not change in individuals with episodic and chronic migraine.

Individuals with migraine present ictal elevation of endothelin-1 levels. Migraine can be subclassified into episodic migraine and chronic migraine. Apart from the inconsistent reports on interictal endothelin-1 levels, most studies did not distinguish between episodic migraine and chronic migraine.

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Prevalence of neck pain in migraine: A systematic review and meta-analysis.

Neck pain is a frequent complaint among patients with migraine and seems to be correlated with the headache frequency. Neck pain is more common in patients with chronic migraine compared to episodic migraine. However, prevalence of neck pain in patients with migraine varies among studies.

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Exploring the intersection of adverse childhood experiences, pediatric chronic pain, and rheumatic disease.

While the general relationship between ACEs and the development of chronic pain has become increasingly clear, how ACEs may shape a child's clinical presentation with regards to chronic pain has yet to be fully expounded. We aimed to determine the association between ACEs and clinical manifestations of pediatric chronic pain and explore the interaction of ACEs and pediatric rheumatic disease among youth with chronic pain on health-related outcomes.

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A Bioinformatics Study of Differentially Expressed Genes in Microarrays of Dorsal Root Ganglia from Rat Models of Neuropathic Pain.

BACKGROUND Neuropathic pain is a significant complication of nerve injury. This study aimed to conduct bioinformatics analysis of differentially expressed genes (DEGs) in microarrays of dorsal root ganglia (DRG) from rat models of neuropathic pain, based on 4 GEO datasets: GSE15041, GSE38038, GSE2884, and GSE24982. MATERIAL AND METHODS We retrieved the 4 microarray datasets, which were generated using DRG samples collected in the early and late stages after spinal nerve ligation in rats. The common DEGs (co-DEGs) were identified and then subjected to Gene Ontology, pathway enrichment, and Protein-protein interaction network analyses. Drugs targeting the identified hub genes were analyzed using the Drug Gene Interaction Database. RESULTS We identified 75 early-stage co-DEGs, which were enriched in chromosome segregation and protein catabolic processes, cytosol and extracellular exosome components, and ATP binding function and metabolic pathways. We identified 29 late-stage co-DEGs, which were enriched in protein tetramerization and drug responses, extracellular and membrane raft components, and protein homodimerization and binding functions and calcium signaling pathways. We also identified several hub genes, including Snap25 (synaptosome-associated protein of 25 kDa), Vamp2 (vesicle associated membrane protein 2), and Sf3b1 (splicing factor 3b subunit 1), the first 2 of which can be targeted by botulinum toxin derivatives. SNAP25 plays a role in synaptogenesis and the exocytotic release of neurotransmitters, and VAMP2 participates in neurotransmitter release at a step between docking and fusion. CONCLUSIONS The present study reveals new mechanisms of neuropathic pain and provides key genes, including SNAP25 and VAMP2, for future studies.

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Opioid Consumption in Chronic Pain Patients: Role of Perceived Injustice and Other Psychological and Socioeconomic Factors.

Chronic pain is a complex biopsychosocial phenomenon. Lifestyle, behavioral, socioeconomic, and psychosocial factors such as depression and perceived injustice are often associated with the development of chronic pain and vice versa. We sought to examine the interaction of these factors with opioid intake.

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Salivary MicroRNA Signature for Diagnosis of Endometriosis.

Endometriosis diagnosis constitutes a considerable economic burden for the healthcare system with diagnostic tools often inconclusive with insufficient accuracy. We sought to analyze the human miRNAome to define a saliva-based diagnostic miRNA signature for endometriosis.

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Nobel somatosensations and pain.

The Nobel prices 2021 for Physiology and Medicine have been awarded to David Julius and Ardem Patapoutian "for their discoveries of receptors for temperature and touch", TRPV1 and PIEZO1/2. The present review tells the past history of the capsaicin receptor, covers further selected TRP channels, TRPA1 in particular, and deals with mechanosensitivity in general and mechanical hyperalgesia in particular. Other achievements of the laureates and translational aspects of their work are shortly treated.

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G Protein-Coupled Receptors in Osteoarthritis.

Osteoarthritis (OA) is the most common chronic joint disease characterized, for which there are no available therapies being able to modify the progression of OA and prevent long-term disability. Critical roles of G-protein coupled receptors (GPCRs) have been established in OA cartilage degeneration, subchondral bone sclerosis and chronic pain. In this review, we describe the pathophysiological processes targeted by GPCRs in OA, along with related preclinical model and/or clinical trial data. We review examples of GPCRs which may offer attractive therapeutic strategies for OA, including receptors for cannabinoids, hormones, prostaglandins, fatty acids, adenosines, chemokines, and discuss the main challenges for developing these therapies.

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Gut microbiota and its role in stress-induced hyperalgesia: gender-specific responses linked to different changes in serum metabolites.

Long-term stress causes hyperalgesia; and there are gender differences in the mechanism of pain in male and female individuals. The role of gut microbiota in pain has also been verified. However, whether gut microbiota plays a role in hyperalgesia caused by chronic restraint stress (CRS) with gender differences has not been explored. This study investigated the role of gut microbiota in CRS-induced hyperalgesia gender-specifically through 16S ribosomal RNA (16S rRNA) gene sequencing and untargeted metabolomic analysis using liquid chromatography-mass spectrometry (LC-MS). The study found that both male and female mice experienced hyperalgesia after CRS and antibiotic treatment. 16S rRNA gene sequencing reveals gender differences in the fecal microbiota induced by CRS. The pain threshold decreased after transplanting the fecal microbiota from the male and female CRS group to the corresponding pseudo-germ-free mice. In addition, this study detected gender differences in the host gut microbiota and serum metabolism induced by fecal microbiota transplantation (FMT). Specifically, the different serum metabolites between the pseudo-germ-free mice receiving FMT from the CRS group and those from the control group were mainly involved in bile secretion and steroid hormone biosynthesis for male mice, and in taurine and hypotaurine metabolism and tryptophan metabolism for female mice. In summary, the gut microbiota participates in stress-induced hyperalgesia (SIH) with gender differences by influencing the host's gut microbiota composition and serum metabolism. Therefore, our findings provided insights into developing novel gut microbiota-associated drugs for the management of gender-specific SIH.

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The Balance Between Serving the Community and the Reality of Treating Opioid Use Disorder in Rural Primary Care Practices.

Medication assisted treatment (MAT) is an evidence-based solution to combatting opioid use disorder (OUD); however, MAT is largely unavailable in rural areas. This study investigated clinician and staff perceptions related to OUD and MAT, in particular, buprenorphine treatment, in rural primary care practices. In this qualitative study, we interviewed staff members from 42 practices and analyzed the data using a grounded hermeneutic editing approach. Four key themes emerged: 1) policies and procedures to reduce opioid prescribing were already in place, 2) there was an emotional toll to treating "those types" of patients, 3) there is a lack of local resources for help with chronic pain and buprenorphine treatment, and 4) there is a strong desire to help local patients and community members but hesitancy to engage in buprenorphine treatment. Although there was almost no provision of MAT, many practices were interested in learning more to help their communities.

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A novel approach to vulvodynia using targeted neuromodulation.

Vulvodynia is a debilitating disorder which can prove extremely difficult to treat. Neuromodulation is increasingly becoming a frontline therapy in various chronic pain syndromes. We present a relatively simple surgical technique utilizing targeted neuromodulation leading to the successful treatment of vulvodynia.

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Sex differences in interdisciplinary pain rehabilitation outcomes: a systematic review.

Interdisciplinary pain rehabilitation programs (IPRPs) are evidence-based treatments for chronic pain. Previous research has demonstrated that initial presentations of adult men and women admitted to IPRPs differ, but less is known about sex differences in IPRP treatment outcomes. To summarize and synthesize the current literature base on this topic, a systematic literature review was conducted that asked: are sex differences present in participant outcomes upon completion of interdisciplinary pain rehabilitation programs for cisgender patients? Four core domains of outcome measures were assessed: depression, pain catastrophizing, pain interference, and pain intensity/severity.

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Prolonged Continuous Theta Burst Stimulation to Demonstrate a Larger Analgesia as Well as Cortical Excitability Changes Dependent on the Context of a Pain Episode.

A series of neuropathic pain conditions have a prevalence in older adults potentially associated with declined functioning of the peripheral and/or central nervous system. Neuropathic pain conditions demonstrate defective cortical excitability and intermissions, which raises questions of the impact of pain on cortical excitability changes and when to deliver repetitive transcranial magnetic stimulation (rTMS) to maximize the analgesic effects. Using prolonged continuous theta-burst stimulation (pcTBS), a relatively new rTMS protocol to increase excitability, this study was designed to investigate pcTBS analgesia and cortical excitability in the context of pain. With capsaicin application, twenty-nine healthy participants received pcTBS or Sham stimulation either in the phase of pain initialization (capsaicin applied) or pain ascending (20 min after capsaicin application). Pain intensity was measured with a visual-analogic scale (VAS). Cortical excitability was assessed by motor-evoked potential (MEP) and cortical silent period (CSP) which evaluates corticospinal excitability and GABAergic intracortical inhibition, respectively. Our data on pain dynamics demonstrated that pcTBS produced a consistent analgesic effect regardless of the time frame of pcTBS. More importantly, pcTBS delivered at pain initialization induced a larger pain reduction and a higher response rate compared to the stimulation during pain ascending. We further provide novel findings indicating distinct mechanisms of pcTBS analgesia dependent on the context of pain, in which pcTBS delivered at pain initialization was able to reverse depressed MEP, whereby pcTBS during pain ascending was associated with increased CSP. Overall, our data indicate pcTBS to be a potential protocol in pain management that could be delivered before the initialization of a pain episode to improve rTMS analgesia, potentially through inducing early corticospinal excitability changes that would be suppressed by nociceptive transmission.

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Anti-rheumatic activity of topical nanoemulsion containing bee venom in rats.

Bee Venom (BV) has been used to treat rheumatoid arthritis (RA) for many centuries. However, its clinical use is limited by pain and fear of bee stings/injection. Nanoemulsions (NEs) are nanocarriers that are able to help their content(s) penetrate through the skin. They also act as drug reservoirs on the skin to provide an efficient, sustained-release vehicle.

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Cooled Radiofrequency Ablation for Chronic Joint Pain Secondary to Hip and Shoulder Osteoarthritis.

Osteoarthritis (OA) of the shoulder and hip is a leading cause of physical disability and mental distress. Traditional nonsurgical management alone is often unable to completely address the associated chronic joint pain. Moreover, a large number of patients are not eligible for joint replacement surgery owing to comorbidities or cost. Radiofrequency ablation (RFA) of articular sensory nerve fibers can disrupt the transmission of nociceptive signals by neurolysis, thereby providing long-term pain relief. A subtype of RFA, cooled RFA (CRFA), utilizes internally cooled electrodes to generate larger ablative zones compared with standard RFA techniques. Given the complex variable innervation of large joints such as the glenohumeral and hip joints, a larger ablative treatment zone, such as that provided by CRFA, is desired to capture a greater number of afferent nociceptive fibers. The suprascapular, axillary, and lateral pectoral nerve articular sensory branches are targeted during CRFA of the glenohumeral joint. The obturator and femoral nerve articular sensory branches are targeted during CRFA of the hip. CRFA is a promising tool in the interventionalist's arsenal for management of OA-related pain and symptoms, particularly in patients who cannot undergo, have long wait times until, or have persistent pain following joint replacement surgery. . RSNA, 2022.

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Devices for Episodic Migraine: Past, Present, and Future.

Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15 years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine.

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Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors.

This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.

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Effect of opioids on cancer survival in patients with chronic pain: a propensity score-matched population-based cohort study.

The impact of opioid analgesic use before cancer diagnosis on survival in patients with chronic pain is unclear. Therefore, we designed a propensity score-matched population-based cohort study to compare overall and cancer-related survival of patients with chronic pain who received long-term opioid analgesic treatment with that of those who did not receive such treatment.

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The Mechanism and Function of miRNA in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) disease has been considered as the main cause of low back pain (LBP), which is a very common symptom and the leading cause of disability worldwide today. The pathological mechanism of IDD remains quite complicated, and genetic, developmental, biochemical, and biomechanical factors all contribute to the development of the disease. There exists no effective, non-surgical treatment for IDD nowadays, which is largely related to the lack of knowledge of the specific mechanisms of IDD, and the lack of effective specific targets. Recently, non-coding RNA, including miRNA, has been recognized as an important regulator of gene expression. Current studies on the effects of miRNA in IDD have confirmed that a variety of miRNAs play a crucial role in the process of IDD via nucleus pulposus cells (NPC) apoptosis, abnormal proliferation, inflammatory factors, the extracellular matrix (ECM) degradation, and annulus fibrosus (AF) degeneration. In the past 10 years, research on miRNA has been quite active in IDD. This review summarizes the current research progression of miRNA in the IDD and puts forward some prospects and challenges on non-surgical treatment for IDD.

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Meaning in Life and Pain: The Differential Effects of Coherence, Purpose, and Mattering on Pain Severity, Frequency, and the Development of Chronic Pain.

Meaning in life is consistently associated with better health outcomes across a range of mental and physical domains. However, meaning in life is a complex construct involving three distinct facets: coherence, purpose, and mattering. While these facets have been studied individually in relation to pain, they have not been assessed concurrently to parse out their potential distinct contributions to pain outcomes. We sought to identify the unique relationships of these individual facets of meaning with pain experiences and specify the components associated with pain-related resilience.

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