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Papers: 11 Jul 2020 - 17 Jul 2020

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Uncoupling sodium channel dimers rescues the phenotype of a pain-linked Nav1.7 mutation.

The voltage-gated sodium channel Nav1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in human patients. The hNav1.7/A1632E mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage-gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is interfered with by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain-linked mutation.

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A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of fibromyalgia.

Alterations in cellular energy metabolism have been implicated in chronic pain suggesting a role for mitochondrial DNA (mtDNA). Previous studies reported associations of a limited number of mtDNA polymorphisms with specific pain conditions. In this study, we examined the full mitochondrial genomes of people with a variety of chronic pain conditions. A discovery cohort consisting of 609 participants either with or without a complex persistent pain conditions (CPPC) was examined. mtDNA was subjected to deep sequencing for identification of rare mutations, common variants, haplogroups, and heteroplasmy associated with five CPPCs: episodic migraine, irritable bowel syndrome, fibromyalgia, vulvar vestibulitis, or temporomandibular disorders. The strongest association found was the presence of the C allele at the single nucleotide polymorphism (SNP) m.2352T>C (rs28358579) that significantly increased the risk for fibromyalgia (OR=4.6, P=4.3×10). This relationship was even stronger in women (OR=5.1, P=2.8×10), and m.2352T>C was associated with all other CPPCs in a consistent risk-increasing fashion. This finding was replicated in another cohort (OR=4.3, P=2.6×10) of the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study consisting of 1754 female participants. To gain insight into the cellular consequences of the associated genetic variability, we conducted an assay testing metabolic reprogramming in human cell lines with defined genotypes. The minor allele C was associated with decreased mitochondrial membrane potential under conditions where oxidative phosphorylation is required, indicating a role of oxidative phosphorylation in pathophysiology of chronic pain. Our results suggest that cellular energy metabolism, modulated by m.2352T>C, contributes to fibromyalgia and possibly other chronic pain conditions.

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Molecular and cellular correlates of human nerve regeneration: ADCYAP1/PACAP enhance nerve outgrowth.

We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.

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How Do Physical Therapists Measure Treatment Outcomes in Adults With Chronic Low Back Pain? A Systematic Review.

There is an increasing recognition of the importance of using a conceptual framework covering the full range of relevant health domains and outcome measures addressed by physical therapy modalities in patients with chronic low back pain (CLBP). However, little is known about what outcome domains have been measured and through what measures in physical therapy research.

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Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis.

Widely used for acute pain management, the clinical benefit from perioperative use of gabapentinoids is uncertain. The aim of this systematic review was to assess the analgesic effect and adverse events with the perioperative use of gabapentinoids in adult patients.

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Mechanisms Mediating High Molecular Weight Hyaluronan Induced Anti-hyperalgesia.

We tested the hypothesis that high molecular weight hyaluronan (HMWH) binds to and signals via cluster of differentiation 44 receptor (CD44), to attenuate nociceptor function, in the setting of inflammation. We found that HMWH attenuates prostaglandin E (PGE)-induced mechanical hyperalgesia, in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense to CD44 mRNA and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuate anti-hyperalgesia induced by HMWH. HMWH signaling is dependent on CD44 clustering in lipid rafts, leading to activation of downstream second messenger signaling pathways. Methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts, attenuates HMWH-induced anti-hyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K), also attenuates HMWH-induced anti-hyperalgesia. Our results demonstrate the central role of CD44 in HMWH-induced anti-hyperalgesia and establish its second messengers as novel therapeutic targets for the treatment of pain.We have previously demonstrated that high molecular weight hyaluronan (HMWH) attenuates inflammatory and neuropathic hyperalgesia. In this study we demonstrate that HMWH attenuates PGE-hyperalgesia is mediated by its action at CD44, and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1) and phospholipases (phospholipases Cε and Cγ1), in nociceptors of male and female rats. These findings contribute to our understanding of the anti-hyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.

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Offset analgesia identifies impaired endogenous pain modulation in pediatric chronic pain disorders.

Offset analgesia (OA), a psychophysical test of endogenous pain inhibition, is diminished in many adult chronic pain disorders but OA has not been investigated in youth with chronic pain disorders. The present study assessed OA responses in 30 youth with chronic primary and secondary pain disorders and 32 healthy controls. The OA, control and constant thermal tests were evoked with an individualized noxious heat stimulus of approximately 50/100 mm on a visual analog scale followed by 1°C offset temperature. This study also examined the association of OA responses with two self-report measures of pain sensitivity, the Central Sensitization Inventory (CSI) and Pain Sensitivity Questionnaire (PSQ). Patients exhibited diminished capacity to activate OA with a reduction in ΔeVASc of 53 ± 29% vs. controls 74 ± 24% (P = 0.003) even after multivariate regression adjusting for age, sex and body mass index. Patients also showed decreased ability to habituate to a constant noxious heat stimulus compared to controls (P = 0.021). CSI scores showed excellent predictive accuracy in differentiating patients from controls (AUC= 0.95; 95% CI: 0.91, 0.99) and CSI score ≥ 30 was identified as an optimal cut-off value. PSQ scores did not differentiate patients from controls nor correlate with OA. In this study 60% of youth with chronic pain showed reduced capacity for endogenous pain inhibition.

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Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion.

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. PNI induced afterdischarge in A high threshold mechanoreceptors (AHTMRs), mechanical sensitization (i.e., decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low threshold mechanoreceptors (LTMRs). PNI resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically-insensitive and electrically-unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.

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Testosterone protects against the development of widespread muscle pain in mice.

Chronic widespread pain conditions are more prevalent in women than men suggesting a role for gonadal hormones in the observed differences. Previously, we showed female mice, compared to male, develop widespread, more severe, and longer duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype. We tested if orchiectomy of males prior to induction of an activity-induced pain model produced a female phenotype and if testosterone administration produced a male phenotype in females. Orchiectomy produced longer lasting, more widespread hyperalgesia, similar to females. Administration of testosterone to females or orchiectomized males produced unilateral, shorter lasting hyperalgesia. Prior studies show that the serotonin transporter (SERT) is increased in the nucleus raphe magnus (NRM) in models of chronic pain, and that blockade of SERT in the NRM reduces hyperalgesia. We examined potential sex differences in the distribution of SERT across brain sites involved in nociceptive processing using immunohistochemistry. A sex difference in SERT was found in the NRM in the activity-induced pain model; females had greater SERT-immunoreactivity than males. This suggests testosterone protects against development of widespread, long-lasting muscle pain and that alterations in SERT may underlie the sex differences.

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Mitochondrial bioenergetics, glial reactivity and pain-related behavior can be restored by dichloroacetate treatment in rodent pain models.

Glial reactivity in the dorsal horn of the spinal cord is a hallmark in most chronic pain conditions. Neuroinflammation-associated reactive glia, in particular astrocytes, have been shown to exhibit reduced mitochondrial respiratory function.Here we studied the mitochondrial function at the lumbar spinal cord tissue from Complete Freund's adjuvant (CFA)-induced inflammatory pain rat and chronic constriction injury (CCI) mouse models by high resolution respirometry (HRR). A significant decrease in mitochondrial bioenergetic parameters at the injury-related spinal cord level coincided with highest astrocytosis. Oral administration of dichloroacetate (DCA) significantly increased mitochondrial respiratory function by inhibiting pyruvate dehydrogenase kinase (PDK) and decreased GFAP and Iba-1 immunoreactivity in spinal cord. Importantly, DCA treatment significantly reduced the ipsilateral pain-related behavior without affecting contralateral sensitivity in both pain models. Our results indicate that mitochondrial metabolic modulation with DCA may offer an alternative therapeutic strategy to alleviate chronic and persistent inflammatory pain.

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Analgesic dorsal root ganglionic field stimulation blocks conduction of afferent impulse trains selectively in nociceptive sensory afferents.

Increased excitability of primary sensory neurons after peripheral nerve injury may cause hyperalgesia and allodynia. Dorsal root ganglion field stimulation (GFS) is effective in relieving clinical pain associated with nerve injury and neuropathic pain in animal models. However, its mechanism has not been determined. We examined effects of GFS on transmission of action potentials (APs) from the peripheral to central processes by in vivo single unit recording from lumbar dorsal roots in sham injured rats and rats with tibial nerve injury (TNI) in fiber types defined by conduction velocity. Transmission of APs directly generated by GFS (20Hz) in C-type units progressively abated over 20s, whereas GFS-induced Aβ activity persisted unabated, while Aδ showed an intermediate pattern. Activity generated peripherally by electrical stimulation of the sciatic nerve and punctate mechanical stimulation of the receptive field (glabrous skin) was likewise fully blocked by GFS within 20s in C-type units, whereas Aβ units were minimally affected and a subpopulation of Aδ units were blocked. After tibial nerve injury, the threshold to induce AP firing by punctate mechanical stimulation (von Frey) was reduced, which was reversed to normal during GFS. These results also suggest that C-type fibers, not Aβ, mainly contribute to mechanical and thermal hypersensitivity (von Frey, bush, acetone) after injury. GFS produces use-dependent blocking of afferent AP trains, consistent with enhanced filtering of APs at the sensory neuron T-junction, particularly in nociceptive units.

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A digital health psychological intervention (WebMAP Mobile) for children and adolescents with chronic pain: results of a hybrid effectiveness-implementation stepped wedge cluster randomized trial.

Although psychological treatments benefit youth with chronic pain, treatment is not accessible in most communities. Digital health interventions offer promise for expanding access and reach to this population. Using a stepped wedge cluster randomized trial design, we evaluated effectiveness and implementation of a digital health delivered psychological intervention for pediatric chronic pain. 143 youth, ages 10-17 with chronic pain and a caregiver were recruited from 8 clinics in the United States. Active intervention included access to the WebMAP Mobile App and the WebMAP parent website to learn pain self-management skills. Effectiveness outcomes included pain intensity, disability, and patient global impression of change (PGIC), while Reach, Adoption, Implementation, and Maintenance were implementation outcomes. Results showed that youth in both treatment conditions (WebMAP vs Usual Care) had similar changes over time in pain and disability. Youth in the WebMAP condition perceived greater improvement (PGIC) at post-treatment and follow-up (d's = 0.54 and 0.44, p < .05) compared to youth receiving usual care. Use of the digital health intervention was modest and variable; about 30% of youth and parents completed treatment. Greater engagement (number of completed modules) was associated with significantly greater reductions in pain and disability from pre-treatment to follow-up (d's = -0.57 and -0.38, p < .05). Parents, youth, and providers found treatment acceptable; providers had positive attitudes and demonstrated referrals over a maintenance period. Further research is needed to understand how to enhance treatment engagement with digital health interventions and optimize implementation.

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Intrinsic efficacy of opioid ligands and its importance for apparent bias, operational analysis and therapeutic window.

Evidence from several novel opioid agonists and knockout animals suggest that improved opioid therapeutic window, notably for analgesia versus respiratory depression, can be caused by ligand bias downstream of activation of the mu-opioid receptor (MOR) towards G-protein signaling and away from other pathways such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application of the operational model of agonism are frequently confounded by failure to consider the assumptions of the model. These include failure to account for intrinsic efficacy and ceiling effects in different pathways, distortions introduced by analysis of amplified (G-protein) versus linear (arrestin) signaling mechanisms, and non-equilibrium effects in a dynamic signaling cascade. We show on both theoretical and experimental grounds that reduced intrinsic efficacy that is unbiased across different downstream pathways does produce apparent but erroneous MOR ligand bias towards G-protein signaling, and the weaker the G-protein partial agonism the greater is the apparent bias. Experimentally, such apparently G-protein biased opioids have been shown to exhibit low intrinsic efficacy for G-protein signaling when ceiling effects are properly accounted for. Nevertheless, such agonists do display an improved therapeutic window for analgesia versus respiratory depression. Reduced intrinsic efficacy for G-proteins rather than any supposed G-protein bias provides a more plausible, sufficient explanation for the improved safety. Moreover, genetic models of G-protein biased opioid receptors and replication of previous knockout experiments suggest that reduced or abolished arrestin recruitment does not improve therapeutic window for analgesia versus respiratory depression. SIGNIFICANCE STATEMENT: Efforts to improve safety of mu-opioid analgesics has focused on agonists that show signaling bias for the G-protein pathway versus other signaling pathways. This review provides theoretical and experimental evidence showing that failure to properly consider the assumptions of the operational model of bias commonly leads to large distortions and overestimation of actual bias. We show that low intrinsic efficacy is a major determinant of these distortions and pursuit of appropriately reduced intrinsic efficacy should lead development of safer opioids.

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Pain freedom after 2 hours should be the primary outcome in controlled trials treating migraine attacks.

Pain freedom after 2 hours is the recommended primary endpoint by the International Headache Society in randomized trials investigating drug treatment of acute migraine attacks. In order to demonstrate an early effect of a drug, some drug companies, however, have promoted headache relief (improvement from severe or moderate pain to mild or no pain) at earlier time points than 2 hours as outcome parameter.

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Recombinant production, bioconjugation and membrane binding studies ofPn3a, a selective Na1.7 inhibitor.

Chronic pain is a common and often debilitating condition. Existing treatments are either inefficacious or associated with a wide range of side effects. The progress on developing safer and more effective analgesics has been slow, in large part due to our limited understanding of the physiological mechanisms underlying pain in different diseases. Generation and propagation of action potentials is a central component of pain sensation and voltage-gated sodium channels (Nas) play a critical role in this process. In particular, Na subtype 1.7, has emerged as a promising universal target for the treatment of pain. Recently, a spider venom peptide, μ-TRTX-Pn3a, was found to be a highly selective inhibitor of Na1.7. Here, we report the first recombinant expression method for Pn3a in a bacterial host, which provides an inexpensive route to production. Furthermore, we have developed a method for bio-conjugation of our recombinantly produced Pn3a using sortase A mediated ligation, providing avenues for further pre-clinical development. We demonstrate how heterologous expression in bacteria enables facile isotope labelling of Pn3a, which allowed us to study the membrane binding properties of the peptide by high-resolution solution-state nuclear magnetic resonance (NMR) spectroscopy using a recently developed lipid nanodisc system. The heteronuclear NMR data indicate that the C-terminal region of the peptide undergoes a conformational change upon lipid binding. The membrane binding properties of Pn3a are further validated using isothermal titration calorimetry (ITC), which revealed that Pn3a binds to zwitterionic planar lipid bilayers with thermodynamics that are largely driven by enthalpic contributions.

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Trajectories of post-surgical pain in infants admitted to neonatal intensive care.

The aim of this study was 1) to statistically identify distinct trajectories of pain following surgery in infants less than six months of age, and 2) to compare these trajectories to descriptions of chronic pain in infants in the neonatal intensive care unit (NICU).

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Evaluation of the chronic pain classification: study protocol for an ecological implementation field study in low-, middle-, and high-income countries.

The purpose of the present ecological implementation field study is to evaluate the new classification of chronic pain as implemented in the 11th revision of the () with regard to clinical utility and interrater reliability. To evaluate the classification in a variety of settings, the study will be implemented in different low-, middle-, and high-income countries.

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Toll-Like Receptor 4 in the Rat Caudal Medulla Mediates Tooth Pulp Inflammatory Pain.

The aims of this study were to investigate if Toll-like receptor 4 (TLR4) is expressed in the medullary dorsal horn (MDH) and if medullary application of a TLR4 antagonist (lipopolysaccharides from , LPS-RS) can attenuate changes in nociceptive sensorimotor responses or TLR4 expression that might be evoked by mustard oil (MO) application to the right maxillary first molar tooth pulp. Of 41 adult male Sprague-Dawley rats used in the study, 23 received intrathecal application of the TLR4 antagonist LPS-RS (25 μg/10 μl; LPS-RS group) or isotonic saline (10 μl; vehicle control group) 10 min before pulpal application of MO (95%; 0.2 μl). Bilateral electromyographic (EMG) activities of the anterior digastric and masseter muscles were recorded continuously before and until 15 min after the MO application to the pulp. In 6 of these 23 rats and an additional 18 rats, the caudal medulla containing the ipsilateral and contralateral MDH was removed after euthanasia for subsequent Western Blot analysis of TLR4 expression in LPS-RS ( = 8) and vehicle ( = 8) groups and a naïve group ( = 8). The % change from baseline in the MO-evoked EMG activities within the anterior digastric muscles were significantly smaller in the LPS-RS group than the control group (two-way ANOVA, Bonferroni, < 0.0001). Western Blot analysis revealed similar levels of TLR4 expression in the caudal medulla of the naïve, vehicle and LPS-RS groups. These novel findings suggest that TLR4 signaling in the caudal medulla may mediate MO-induced acute dental inflammatory pain in rats.

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Sustained perturbation in functional connectivity induced by cold pain.

Functional connectivity (FC) perturbations have been reported in multiple chronic pain phenotypes, but the nature of reported changes varies between cohorts and may relate to the consequences of living with chronic-pain related comorbidities, such as anxiety, and depression. Healthy volunteer studies provide opportunities to study the effects of tonic noxious stimulation independently of these sequelae. Connectivity changes in task negative and positive networks, for example, the default mode and salience networks (DMN/SN), respectively, have been described, but how these and other connectivity networks, for example, those governing descending pain control are affected by the presence of tonic, noxious stimulation in healthy, pain-free individuals remains unknown.

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The Development of Adolescent Chronic Pain following Traumatic Brain Injury and Surgery: The Role of Diet and Early Life Stress.

Pain is evolutionarily necessary for survival in that it reduces tissue damage by signaling the body to respond to a harmful stimulus. However, in many circumstances, acute pain becomes chronic, and this is often dysfunctional. Adolescent chronic pain is a growing epidemic with an unknown etiology and limited effective treatment options. Given that the relationship between acute pain and chronic pain is not straightforward, there is a need to better understand the factors that contribute to the chronification of pain. Since early life factors are critical to a variety of outcomes in the developmental and adolescent periods, they pose promise as potential mechanisms that may underlie the transition from acute to chronic pain. This review examines two early life factors: poor diet and adverse childhood experiences (ACEs); they may increase susceptibility to the development of chronic pain following surgical procedures or traumatic brain injury (TBI). Beyond their high prevalence, surgical procedures and TBI are ideal models to prospectively understand mechanisms underlying the transition from acute to chronic pain. Common themes that emerged from the examination of poor diet and ACEs as mechanisms underlying this transition included: prolonged inflammation and microglia activation leading to sensitization of the pain system, and stress-induced alterations to hypothalamic-pituitary-adrenal axis function, where cortisol is likely playing a role in the development of chronic pain. These areas provide promising targets for interventions, the development of diagnostic biomarkers, and suggest that biological treatment strategies should focus on regulating the neuroinflammatory and stress responses in an effort to modulate and prevent the development of chronic pain.

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Chronic pelvic pain patients demonstrate higher catastrophizing in association with pelvic symptoms and comorbid pain diagnoses.

To elucidate the relationship between catastrophization and pelvic pain symptomatology in chronic pelvic pain (CPP) patients using standardized questionnaires.

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Antinociceptive effects ofthe GPR55 antagonist CID16020046 injected into the rat anterior cingulate cortex.

The G-protein coupled receptor, GPR55, modulates nociceptive processing. Given the expression of GPR55 in the anterior cingulate cortex (ACC), a key brain region involved in the cognitive and affective dimensions of pain, the present study tested the hypothesis that GPR55 signalling in the ACC facilitates inflammatory pain behaviour in rats. The expression of GPR55 in the ACC was confirmed by both western blotting and immunostaining, with evidence for neuronal localisation. Microinjection of the selective GPR55 antagonist CID16020046 into the ACC of adult male Sprague-Dawley rats significantly reduced second phase formalin-evoked nociceptive behaviour compared with vehicle-treated controls. CID16020046 administration was associated with a reduction in phosphorylation of extracellular signal-regulated kinase (ERK), a downstream target of GPR55 activation, in the ACC. Intra-ACC administration of CID16020046 prevented the formalin-induced increases in expression of mRNA coding for the immediate early gene and marker of neuronal activity, c-Fos, in the ipsilateral dorsal horn of the spinal cord. Intra-plantar injection of formalin reduced tissue levels of the endogenous GPR55 ligand 2-arachidonoyl-sn-glycero-3-phosphoinositol (2-AGPI) in the ACC, likely reflecting its increased release/utilisation. These data suggest that endogenous activation of GPR55 signalling and increased ERK phosphorylation in the ACC facilitates inflammatory pain via top-down modulation of descending pain control.

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Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study.

Background and aims Pain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response. Methods This is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response. Results For KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02, p < 0.01. R-squared = 0.275. For KOA patients with normal CPM response, general health perception scores were statistically significantly associated with pain scores, F(1, 21) = 5.60, p < 0.05. R-squared = 0.2104. Limitations of this study include methodology details, small sample size and study design characteristics. Conclusions Pain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

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Mirtazapine, an α2 antagonist-type antidepressant reverses pain and lack of morphine analgesia in fibromyalgia-like mouse models.

Treatment for fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain, but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine (Mir), which is presumed to disinhibit 5-HT release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2, postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4-5 days after the cessation of treatments. The repeated Mir-treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of siRNA adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia, but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that Mir could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the anti-hyperalgesia, while other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS-model.

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Chronic morphine induces cyclic adenosine monophosphate formation and hyperpolarization-activated cyclic nucleotide-gated channel expression in the spinal cord of mice.

Chronic morphine exposure persistently activates Gαi/o protein-coupled receptors and enhances adenylyl cyclase (AC) activity, which can increase cyclic adenosine monophosphate (cAMP) production. Direct binding of cAMP to the cytoplasmic site on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels increases the probability of channel opening. HCN channels play a prominent role in chronic pain the disease that shares some common mechanisms with opioid tolerance. This compensatory AC activation may be responsible for the induction of morphine-induced analgesic tolerance. We investigated spinal cAMP formation and expression of HCN2 in the spinal cord, and observed the effect of AC inhibition on the induction of morphine analgesic tolerance. We found that chronic morphine-induced antinociceptive tolerance increased spinal cAMP formation and the expression of spinal HCN2. Inhibition of spinal AC partially blocked chronic morphine-induced cAMP formation and prevented the induction of morphine-induced analgesic tolerance. Inhibition of HCN2 also showed a partial preventive effect on morphine-induced tolerance, hypothermia tolerance and also the right-shift of the dose-response curve. We conclude that repeated morphine treatment increases AC activity and cAMP formation, and also spinal HCN2 expression, blockade of AC or HCN2 can prevent the development of morphine-induced analgesic tolerance.

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Glial cell activation and altered metabolic profile in the spinal-trigeminal axis in a rat model of multiple sclerosis associated with the development of trigeminal sensitization.

Trigeminal neuralgia is often an early symptom of multiple sclerosis (MS), and it generally does not correlate with the severity of the disease. Thus, whether it is triggered simply by demyelination in specific central nervous system areas is currently questioned. Our aims were to monitor the development of spontaneous trigeminal pain in an animal model of MS, and to analyze: i) glial cells, namely astrocytes and microglia in the central nervous system and satellite glial cells in the trigeminal ganglion, and ii) metabolic changes in the trigeminal system. The subcutaneous injection of recombinant MOG protein fragment to Dark Agouti male rats led to the development of relapsing-remitting EAE, with a first peak after 13 days, a remission stage from day 16 and a second peak from day 21. Interestingly, orofacial allodynia developed from day 1 post injection, i.e. well before the onset of EAE, and worsened over time, irrespective of the disease phase. Activation of glial cells both in the trigeminal ganglia and in the brainstem, with no signs of demyelination in the latter tissue, was observed along with metabolic alterations in the trigeminal ganglion. Our data show, for the first time, the spontaneous development of trigeminal sensitization before the onset of relapsing-remitting EAE in rats. Additionally, pain is maintained elevated during all stages of the disease, suggesting the existence of parallel mechanisms controlling motor symptoms and orofacial pain, likely involving glial cell activation and metabolic alterations which can contribute to trigger the sensitization of sensory neurons.

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Severity of Intervertebral Disc Herniation Regulates Cytokine and Chemokine Levels In Patients with Chronic Radicular Back Pain.

The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects.

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Patient Preferences for Osteoarthritis Pain and Chronic Low Back Pain Treatments in the United States: A Discrete-Choice Experiment.

To quantify preferences for attributes of potential analgesic treatments for moderate-to-severe pain associated with osteoarthritis (OA) and/or chronic low back pain (CLBP) as relevant to injectable nerve growth factor (NGF)-inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.

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Optogenetic Activation of Dopamine Receptor D1 and D2 Neurons in Anterior Cingulate Cortex Differentially Modulates Trigeminal Neuropathic Pain.

Anterior cingulate cortex (ACC) is a critical brain center for chronic pain processing. Dopamine signaling in the brain has been demonstrated to contribute to descending pain modulation. However, the role of ACC dopamine receptors in chronic neuropathic pain remains unclear. In this study, we investigated the effect of optogenetic activation of ACC dopamine receptors D1- and D2-expressing neurons on trigeminal neuropathic pain. Chronic constriction injury of infraorbital nerve (CCI-ION) was carried out to induce trigeminal neuropathic pain in mice. We conducted optogenetic stimulation to specifically activate D1- and D2-expressing neurons in the ACC. Western blotting and immunofluorescence staining were used to examine ACC D1 and D2 expression and localization. The von Frey and real-time place preference tests were performed to measure evoked mechanical pain and nonreflexive emotional pain behaviors, respectively. We observed that dopamine receptors D1 and D2 in the ACC are primarily expressed in excitatory neurons and that the D2 receptor is differentially regulated in the early and late phases of trigeminal neuropathic pain. Optogenetic activation of D1-expressing neurons in the ACC markedly exacerbates CCI-ION-induced trigeminal neuropathic pain in both early and late phases, but optogenetic activation of D2-expressing neurons in the ACC robustly ameliorates such pain in its late phase. Our results suggest that dopamine receptors D1 and D2 in the ACC play different roles in the modulation of trigeminal neuropathic pain.

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Is there a reliable brain morphological signature for migraine?

Voxel-based morphometry (VBM) is a popular non-invasive magnetic resonance imaging technique to investigate brain gray matter (GM) differences between groups. Recently, two VBM studies in migraine have been published in The Journal of Headache and Pain. Reviewing the two and those previous published VBM studies, we found considerable variations of the results. Spatially diverse brain regions with decreased and increased GM alterations and null findings have been reported. It is interesting to know whether there is a reliable brain morphological signature for migraine. Coordinate-based meta-analysis (CBMA) is increasingly used to quantitatively pool individual neuroimaging studies to identify consistent and reliable findings. Several CBMA have been conducted, however, their results were inconsistent. The algorithms for CBMA have evolved and more eligible VBM studies in migraine have been published. We therefore conducted an updated CBMA using the latest algorithms for CBMA, seed-based d mapping with permutation of subject images (SDM-PSI). The present CBMA of 32 VBM studies (41 datasets comprising 1252 patients and 1025 healthy controls) found no evidence of consistent GM alterations in migraine. Sensitivity analysis, subgroup meta-analyses, and meta-regression analyses revealed that the result was robust. This negative result indicates that there is no reliable brain morphological signature for migraine. VBM investigations in migraine remain a heterogeneous field. Many potential confounding factors, such as underpowered sample sizes, variations in demographic and clinical characteristics, and differences in MRI scanners, head coils, scanning parameters, preprocessing procedures, and statistical strategies may cause the inconsistences of the results. Future VBM studies are warranted to enroll well-characterized and homogeneous subtype samples with appropriate sample sizes, comprehensively assess comorbidities and medication status, and use well-validated and standardized imaging protocols and processing and analysis pipelines to produce robust and replicable results in migraine.

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Challenges to successful research careers in neurology: How gender differences may play a role.

There has been a substantial rise in the number of women pursuing careers in neurology. However, research has shown that women in neurology have high rates of burnout with gender disparities in burnout and attrition in the field. Recently, there was a call from the National Institutes of Health (NIH), including the National Institute of Neurological Disorders and Stroke (NINDS), asking for input on factors that may limit or discourage grant applications from women. As the recipients of the highly coveted NIH career mentored awards (K-awards) in headache medicine, we applaud the NIH for asking for gender specific feedback and for raising awareness of research showing that female faculty on the Research Track are at increased risk of departure. Using the NIH model for the Responsible Conduct of Research and the tenant of "Nurturing the Fertile Environment", we discuss specific challenges in academic research that may contribute to gender differences in neurology research success. While the rate of women conducting NIH-funded migraine research increased from 23 to 41% over the last 10 years, more women are currently in training compared to independence, with 6/6 of the NIH training grants but only 12/36 of the NIH Research-level grants, held by women in fiscal years 2017-2019. We suggest concrete solutions to these challenges to ensure the success of women in research reaching independence.

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The Cytokine TGF-β Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31 mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-β1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1 CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-β-IL-31 axis with implications for treatment of wound itching.

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Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis.

CGRP Antibodies are high-cost newly licensed migraine preventatives.

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Design of Phase 3 Studies Evaluating Vixotrigine for Treatment of Trigeminal Neuralgia.

Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs.

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Recognizing chronic pain in cerebral palsy.

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Microglia induce the transformation of A1/A2 reactive astrocytes via the CXCR7/PI3K/Akt pathway in chronic post-surgical pain.

Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP.

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Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence.

According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months.

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The α2,3-selective potentiators of GABA receptors, KRM-II-81 and MP-III-80, produce anxiolytic-like effects, and block chemotherapy-induced hyperalgesia, in mice without tolerance development.

Opiate analgesics are one of the treatment options for severe chronic pain, including late-stage cancer, chronic back pain and other disorders. The recent resurgence in opioid overdose has highlighted the serious need for alternative medicines for pain management. While a role for potentiators of α2/3-containing GABA receptors in the modulation of pain has been known for several years, advancements in this area required data from selective compounds. KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3- yl)oxazole) and analogs selectively potentiate GABA receptors containing α2/3 subunits and have recently been shown to attenuate pain behaviors in several acute and chronic pain models in rodents. The present study was designed to ascertain whether KRM-II-81 and the structural analog MP-III-80 (3-ethyl-5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)-1,2,4-oxadiazole) would block chemotherapeutic agent paclitaxel-induced pain in male, C57BL/6 mice. Both compounds significantly inhibited pain behaviors evoked by cold and tactile stimulation in paclitaxel-treated mice as did the neuropathic pain drug gabapentin. Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development; the antihyperalgesic effects of gabapentin showed evidence of tolerance development. KRM-II-81 and MP-III-80 also decreased marble-burying behavior in this mouse strain as did the anxiolytic drug chlordiazepoxide. In contrast to KRM-II-81 and MP-III-80, chlordiazepoxide had motor-impairing effects at anxiolytic-like doses. The data add to the literature documenting that these selective potentiators of α2/3-containing GABA receptors are effective in a host of animal models used to detect novel analgesic drugs. The anxiolytic-like efficacy of these compounds fits well with the comorbidity of anxiety in patients with chronic pain and cancer.

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Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors.

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after 4 and 8 consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on NMDA receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.

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The potential danger of blocking CGRP for treating migraine in CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances and apathy. More than half of mutation carriers suffer from migraine, most often migraine with aura. Recently, a CADASIL patient was treated with a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. Monoclonal antibodies targeting the CGRP system have been demonstrated to be safe, well tolerated, and effective in reducing migraine attacks. There is, however, abundant evidence that CGRP is important in maintaining cardiovascular homeostasis under (patho)physiological conditions. CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia and blockage of the system could, therefore, potentially worsen ischemic events. Therefore, we caution against treating patients with small vessel diseases, such as the monogenic disorder CADASIL, with these drugs until relevant safety data and long term follow up results are available. Alternative preventive migraine treatments in CADASIL may be acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine.

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Pain Neuroscience Education Plus Usual Care Is More Effective Than Usual Care Alone to Improve Self-Efficacy Beliefs in People with Chronic Musculoskeletal Pain: A Non-Randomized Controlled Trial.

Self-efficacy beliefs are associated with less physical impairment and pain intensity in people with chronic pain. Interventions that build self-efficacy beliefs may foster behavioral changes among this population. A non-randomized trial has been carried out to evaluate the effectiveness of pain neuroscience education (PNE) plus usual care in modifying self-efficacy beliefs, pain intensity, pain interference and analgesics consumption in people with chronic musculoskeletal pain. Participants were allocated to an experimental (PNE plus usual care, 49) and a control (usual care alone, 51) group. The primary outcome was self-efficacy beliefs (Chronic Pain Self-Efficacy Scale), and the secondary outcomes were pain intensity, pain interference (Graded Chronic Pain Scale) and analgesics consumption. The participant's pain knowledge (revised Neurophysiology of Pain Questionnaire) after PNE intervention was also assessed to analyze its influence on every outcome measure. All the outcome measures were assessed at the baseline and at four-week and four-month follow-ups. PNE plus usual care was more effective than usual care alone to increase self-efficacy beliefs and decrease pain intensity and pain interference at all follow-up points. No differences between groups were found in terms of analgesics consumption. Knowledge of pain neurophysiology did not modify the effects of PNE plus usual care in any of the outcome measures. These results should be taken with caution because of the non-randomized nature of this design, the limited follow-ups and the uncertainty of the presence of clinical changes in self-efficacy for participants. Larger, methodological sound trials are needed.

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Network Analysis of miRNA and mRNA Changes in the Prelimbic Cortex of Rats With Chronic Neuropathic Pain: Pointing to Inflammation.

Neuropathic pain (NP) is a complex, chronic pain condition caused by injury or dysfunction affecting the somatosensory nervous system. This study aimed to identify crucial mRNAs and microRNAs (miRNAs) in the prelimbic cortex (PL) of NP rats. mRNA and miRNA microarrays were applied in the present study. The miRNA-mRNA regulatory network was constructed by using ingenuity pathway analysis (IPA). A total of 35 differentially expressed (DE) RNAs (24 miRNAs and 10 mRNAs) were identified in the spared nerve injury (SNI) group compared with the control group. The DE miRNA-mRNA network showed that IL-6 and tumor necrosis factor (TNF) were core components. Mir-30c-5p and mir-16-5p were the most connected miRNAs in the network. Interestingly, four mRNAs (Rnase 4, Egr2, Rexo4, and Klf2) with significantly increased expression were abundantly expressed in microglia, which was verified by the real-time quantitative polymerase chain reaction (qPCR). Furthermore, the expression of Rnase4 and Egr2 decreased in M1-polarized macrophages and increased in M2-polarized macrophages. In conclusion, we screened dozens of DE mRNAs and miRNAs in the PL of SNI rats. The core of the DE mRNA and miRNA network pointed to molecules associated with inflammation. Four mRNAs (Rnase4, Egr2, Rexo4, and Klf2) might be the potential markers of M2 polarization.

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Decreased neural inhibitory state in fibromyalgia pain: A cross-sectional study.

Chronic pain is one of the most common and challenging symptoms in fibromyalgia (FM). Currently, self-reported pain is the main criterion used by clinicians assessing patients with pain. However, it is subjective, and multiple factors can affect pain levels. In this study, we investigated the neural correlates of FM pain using conditioned pain modulation (CPM), electroencephalography (EEG), and transcranial magnetic stimulation (TMS).

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Recent Evidence Regarding the Association Between Migraine and Suicidal Behaviors: A Systematic Review.

The review presents a systematic analysis of literature investigating the association between migraine and suicidal behaviors. Migraine is a common neurological disorder. The prevalence of migraines increases with age from adolescence to adulthood in both sexes, and results in a substantial loss of productivity due to missing days of school or work and need for bed rest. Literature prior to 2015 suggests that migraine is a predictor of suicide. Given the worldwide public health interest in suicide prevention, we examined the literature collected from diverse, predominantly non-European, populations post-2015. The databases used in this systematic review included: Medline, PsycINFO, EMBASE (Ovid), Science Direct (Elsevier), Cochrane, and PubMed for all available years of publication from January 2015 onwards. The review included participants aged 16 and over who had been diagnosed with migraines with the following outcome variables: any suicidality, both fatal and non-fatal; suicidal ideation; and suicidal behavior. The database searches yielded a total of 542 citations. Following title and abstract screening, 460 articles were excluded and a total of 21 citations were evaluated. After full-text review and excluding a further 11 non-eligible studies, a total of 10 studies were eligible for inclusion in the systematic review. Current existing research highlights the important association between the increased risk of suicidal behaviors in the clinical and general population among chronic migraineurs with/without aura worldwide. Future studies are needed to facilitate the development of clinical guidelines for risk assessment, targeted interventions, and evidence-based treatment of migraine to reduce the risk of suicide among this vulnerable population.

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Types of Triggers in Migraine – Factor Structure of the Headache Triggers Sensitivity and Avoidance Questionnaire and Development of a New Short Form (HTSAQ-SF).

To examine the factor structure of the Headache Triggers Sensitivity and Avoidance Questionnaire (HTSAQ) and its German version (HTSAQ-G), in order to identify potential different types of triggers. Furthermore, a short form of the questionnaire was developed.

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Remote Electrical Neuromodulation for the Acute Treatment of Migraine in Patients with Chronic Migraine: An Open-Label Pilot Study.

Remote electrical neuromodulation (REN) is a novel acute treatment of migraine. Upper arm peripheral nerves are stimulated to induce conditioned pain modulation (CPM)-an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. The REN device (Nerivio, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. The current study assessed the consistency of response over multiple migraine attacks in people with chronic migraine who are typically characterized with severe pain intensity, high disability, and less robust response to triptans.

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LOW-DOSE NALTREXONE REVERSES FACIAL MECHANICAL ALLODYNIA IN A RAT MODEL OF TRIGEMINAL NEURALGIA.

Trigeminal neuralgia (TN) is a type of neuropathic pain characterized by intense pain; although anticonvulsants are used as an option to relieve pain, adverse side effects can decrease patient adherence. In this context, a low dose of naltrexone is effective in relieving pain in other pain conditions. Thus, the objective of the present study was to evaluate the analgesic effect of low-dose naltrexone on facial mechanical allodynia in a rat model of TN, as well as its effect(s) on biomarkers in the central nervous system (tumor necrosis factor-alpha, brain-derived neurotrophic factor [BDNF], interleukin [IL]-10, and toll-like receptor-4). Fifty-nine adult male Wistar rats (CEUA-HCPA#2017-0575) were allocated to following groups: control; sham-pain + vehicle; sham-pain + carbamazepine (100 mg/kg); sham-pain + naltrexone (0.5 mg/kg); pain + vehicle; pain + carbamazepine; and pain + naltrexone. TN was induced using chronic constriction of the infraorbital nerve. Facial allodynia was assessed using von Frey test. Drugs were administered by gavage 14 days after surgery for 10 days. At baseline, the mechanical threshold was similar between groups (P > 0.05; generalized estimating equation). Seven days after surgery, facial allodynia was observed in sham-TN and pain-TN groups (P < 0.05). Fourteen days after surgery, only pain-TN groups exhibited facial allodynia. The first dose of low-dose naltrexone or carbamazepine partially reversed facial allodynia. After 10 days of treatment, both drugs completely reversed it. Spinal cord levels of BDNF and IL-10 were modulated by low-dose naltrexone. Thus, low-dose naltrexone may be suitable to relieve TN; however, the exact mechanisms need to be clarified.

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A mathematical model for persistent post-CSD vasoconstriction.

Cortical spreading depression (CSD) is the propagation of a relatively slow wave in cortical brain tissue that is linked to a number of pathological conditions such as stroke and migraine. Most of the existing literature investigates the dynamics of short term phenomena such as the depolarization and repolarization of membrane potentials or large ion shifts. Here, we focus on the clinically-relevant hour-long state of neurovascular malfunction in the wake of CSDs. This dysfunctional state involves widespread vasoconstriction and a general disruption of neurovascular coupling. We demonstrate, using a mathematical model, that dissolution of calcium that has aggregated within the mitochondria of vascular smooth muscle cells can drive an hour-long disruption. We model the rate of calcium clearance as well as the dynamical implications on overall blood flow. Based on reaction stoichiometry, we quantify a possible impact of calcium phosphate dissolution on the maintenance of F0F1-ATP synthase activity.

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

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Moving the Needle, the Clinical Perspective.

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Electrophysiology and Structural Connectivity of the Posterior Hypothalamic Region: Much to Learn From a Rare Indication of Deep Brain Stimulation.

Cluster headache (CH) is among the most common and debilitating autonomic cephalalgias. We characterize clinical outcomes of deep brain stimulation (DBS) to the posterior hypothalamic region through a novel analysis of the electrophysiological topography and tractography-based structural connectivity. The left posterior hypothalamus was targeted ipsilateral to the refractory CH symptoms. Intraoperatively, field potentials were captured in 1 mm depth increments. Whole-brain probabilistic tractography was conducted to assess the structural connectivity of the estimated volume of activated tissue (VAT) associated with therapeutic response. Stimulation of the posterior hypothalamic region led to the resolution of CH symptoms, and this benefit has persisted for 1.5-years post-surgically. Active contacts were within the posterior hypothalamus and dorsoposterior border of the ventral anterior thalamus (VAp). Delta- (3 Hz) and alpha-band (8 Hz) powers increased and peaked with proximity to the posterior hypothalamus. In the posterior hypothalamus, the delta-band phase was coupled to beta-band amplitude, the latter of which has been shown to increase during CH attacks. Finally, we identified that the VAT encompassing these regions had a high proportion of streamlines of pain processing regions, including the insula, anterior cingulate gyrus, inferior parietal lobe, precentral gyrus, and the brainstem. Our unique case study of posterior hypothalamic region DBS supports durable efficacy and provides a platform using electrophysiological topography and structural connectivity, to improve mechanistic understanding of CH and this promising therapy.

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Do the commonly used standard questionnaires measure what is of concern to patients with low back pain?

Evaluate whether questionnaires identified all the self-reported patient outcomes raised in focus groups.

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Primary care initiatives focused on the secondary prevention and management of chronic pain: a scoping review of the Australian literature.

The aim of this scoping review was to identify initiatives focused on the secondary prevention and management of chronic pain in Australian primary care to understand options available to Primary Health Networks and to identify evidence gaps. The Medline, EMBASE, Cumulative Index to Nursing and Allied Health Literature and Cochrane databases, as well as relevant websites, were searched for eligible records published from 2007 to 2018. Initiative characteristics and outcomes evaluated were extracted and synthesised. In all, 84 initiatives from 167 published and grey literature records were identified, including: (1) consumer initiatives that aimed to improve access to multidisciplinary care, health literacy and care navigation (n=56); (2) health professional capacity building initiatives that aimed to ensure health professionals are skilled and provide best-practice evidence-based care (n=21); and (3) quality improvement and health system support initiatives (n=7). Evidence gaps were found relating to initiatives addressing the secondary prevention of chronic pain, those targeting vulnerable and regional populations, health professional capacity building initiatives for all primary health care providers and quality improvement and system support initiatives. Addressing evidence gaps related to effectiveness, cost-effectiveness and implementation should be the focus for future chronic pain initiatives in primary care settings.

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All-cause mortality in patients with long-term opioid therapy compared with non-opioid analgesics for chronic non-cancer pain: a database study.

Hitherto only studies with selected populations have found an increased all-cause mortality of some selected opioids compared to selected non-opioids for chronic non-cancer pain (CNCP). We have examined the all-cause mortality for CNCP associated with all established opioids compared to non-opioid analgesic therapy (anticonvulsants, antidepressants, dipyrone, non-steroidal agents).

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Advances in Understanding the Initial Steps of Pruritoceptive Itch: How the Itch Hits the Switch.

Pruritoceptive (dermal) itch was long considered an accompanying symptom of diseases, a side effect of drug applications, or a temporary sensation induced by invading pruritogens, as produced by the stinging nettle. Due to extensive research in recent years, it was possible to provide detailed insights into the mechanism of itch mediation and modulation. Hence, it became apparent that pruritus is a complex symptom or disease in itself, which requires particular attention to improve patients' health. Here, we summarize recent findings in pruritoceptive itch, including how this sensation is triggered and modulated by diverse endogenous and exogenous pruritogens and their receptors. A differentiation between mediating pruritogen and modulating pruritogen seems to be of great advantage to understand and decipher the molecular mechanism of itch perception. Only a comprehensive view on itch sensation will provide a solid basis for targeting this long-neglected adverse sensation accompanying numerous diseases and many drug side effects. Finally, we identify critical aspects of itch perception that require future investigation.

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Study protocol for Long-Term Opioid Therapy in Spine Center Outpatients: The Spinal Pain Opioid Cohort (SPOC).

Spinal pain is the leading worldwide cause of patient-years lived with chronic pain and disability. While opioids are well documented as an effective short-term pain-relieving medication, more than a few weeks of treatment may result in a diminishing clinical effect as well as the development of addictive behavior. Even though opioid addiction in pain patients is a major problem commonly experienced in the clinic, no reference material exists on the scope of long-term problems in novel opioid users and the link to clinical outcomes.

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Which Chronic Low Back Pain Patients Respond Favorably to Yoga, Physical Therapy, and a Self-care Book? Responder Analyses from a Randomized Controlled Trial.

To identify baseline characteristics of adults with chronic low back pain (cLBP) that predict response (i.e., a clinically important improvement) and/or modify treatment effect across three nonpharmacologic interventions.

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Clinical effect modifiers of antibiotic treatment in patients with chronic low back pain and Modic changes – secondary analyses of a randomised, placebo-controlled trial (the AIM study).

Randomised trials on antibiotic treatment for patients with chronic low back pain and vertebral endplate changes visible on MRI (Modic changes) have shown mixed results. A possible explanation might be a real treatment effect in subgroups of the study populations. The purpose of the present study was to explore potential clinical effect modifiers of 3-months oral amoxicillin treatment in patients with chronic low back pain and type I or II Modic changes at the level of a previous lumbar disc herniation.

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Granulocyte Colony Stimulating Factor (GCSF) Can Attenuate Neuropathic Pain by Suppressing Monocyte Chemoattractant Protein-1 (MCP-1) Expression, through Upregulating the Early MicroRNA-122 Expression in the Dorsal Root Ganglia.

Our previous animal studies and several human clinical trials have shown that granulocyte-colony stimulating factor (GCSF) can attenuate neuropathic pain through various mechanisms. GCSF itself is also a multipotent cytokine that can modulate microribonucleic acid (microRNA) expression profiles in vitro. In this study, we used the NanoString nCounter analysis system to screen the expression of different rodent microRNAs at early stage after nerve injury and studied the expression of related cytokines/chemokines in the dorsal root ganglia (DRGs) of rats that underwent chronic constriction injury (CCI) to explore the underlying mechanisms of the analgesic effects of GCSF. We found that microRNA-122 expression was downregulated by CCI; in contrast, GCSF treatment significantly upregulated microRNA-122 expression in the DRGs of CCI rats on the 1st day after nerve injury. We further studied the expression of different cytokines/chemokines (IL-1β, IL-6, and monocyte chemoattractant protein-1 (MCP-1)) that were modulated by microRNA-122. MCP-1 has been reported to participate in neuropathic pain development, and its expression on the DRGs of vehicle-treated CCI rats was significantly higher than that on the DRGs of sham-operated rats; in contrast, GCSF-treated rats exhibited significantly lower MCP-1 expression in the DRG than vehicle-treated rats on the 7th day after nerve injury. An early GCSF treatment can suppress MCP-1 expressions, through upregulating microRNA-122 expressions in the DRGs of CCI rats at an earlier stage, thus indirectly attenuating neuropathic pain development.

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Visual snow syndrome: is it normal or a disorder – and what to do with patients?

Recently in the journal, epidemiological data are presented on visual snow syndrome (VSS) using a crowdsourcing online platform [1]. The authors applied criteria for VSS to a sample of people matched for age, sex, and ethnicity to United Kingdom census data. Further, they assessed frequent headache lasting longer than 4 hours, which was interpreted as migraine, and neurological symptoms during headache, interpreted as aura.

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Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany.

Chronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany.

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Cortical spreading depolarisation-induced facial hyperalgesia, photophobia and hypomotility are ameliorated by sumatriptan and olcegepant.

Cortical spreading depolarisation (CSD), the neural mechanism underlying migraine aura, may cause headache by sensitising the trigeminal system. Photophobia, the most bothersome accompanying symptom during migraine attacks, is more prevalent in migraine with aura than in migraine without aura. Whether CSD plays a role in developing photophobia remains unknown. Moreover, migraine-induced physical hypoactivity contributes to loss of productivity. We aimed to investigate the development of trigeminal sensitisation, photophobia and locomotive abnormality after KCl-induced CSD using 86 male C57BL/6 mice. Sham-operated mice were used as controls. We confirmed the presence of trigeminal sensitisation and photophobia at 24 h after CSD. CSD-subjected mice also exhibited significantly reduced locomotive activity in both light and dark zones. Hence, the CSD-induced hypomobility was likely to be independent of photophobia. The 5-HT agonist, sumatriptan, corrected all these CSD-induced abnormalities. Moreover, dose dependency was demonstrated in the ameliorating effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, olcegepant, on these abnormalities. Sumatriptan and olcegepant improved mouse locomotion with therapeutic lags ranging from 20 to 30 min. Collectively, CSD caused trigeminal sensitisation, photophobia and hypomobility that persisted for at least 24 h by a mechanism involving the 5-HT and CGRP activity.

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Tapentadol is effective in the management of moderate-to-severe cancer-related pain in opioid-naïve and opioid-tolerant patients: a retrospective study.

Tapentadol is a dual-acting mu-opioid receptor agonist and noradrenaline reuptake inhibitor with non-inferior analgesic efficacy to oxycodone and better gastrointestinal tolerability than full mu-opioid receptor agonists. Tapentadol is approved for cancer pain in Japan; however, real-world evidence on tapentadol's effectiveness and safety for cancer-related pain in Japan is limited.

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Triggers of Primary Headaches: Issues and Pathways Forward.

The triggers of primary headaches have considerable significance for our understanding and management of headache and migraine. Triggers explain the variance in headaches – why they occur when they do. Trigger management is generally viewed as an important component of a comprehensive treatment approach for headaches. Historically, however, triggers have not had a prominent place in the headache literature. This situation began to change 20 to 30 years ago, and the pace of change has increased exponentially in recent times. Nevertheless, the field is beset with issues that have held it back from achieving more. This review will focus on elaborating those issues with the goal of suggesting ways forward. The first issue considered will be the definition of a trigger, and how specific triggers are labeled. Consideration will then be given to a classification system for triggers. The review will discuss next the evidence relating to whether self-reported triggers can, indeed, precipitate headaches, and how the capacity to elicit headaches may be acquired or extinguished. Attention will be given to the very important clinical issue of trigger management. Finally, the pathways forward will be proposed. Perhaps the most useful thing to accomplish at this point in time would be agreement on a definition of headache triggers, a list of triggers, and a classification system for triggers. This would greatly assist in comparing research on triggers from different research groups as well as eliminating some of the issues identified in this review. An authoritative body such as the American Headache Society or the International Headache Society, could establish a multidisciplinary committee that would complete these tasks. Consideration should also be given to incorporating triggers into the International Classification of Headache Disorders as an axis or via the use of codes, as this would raise the profile of triggers in assessment and management.

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Is transcranial direct current stimulation (tDCS) effective for chronic low back pain? A systematic review and meta-analysis.

Transcranial direct current stimulation (tDCS) has been used to reduce pain in range of chronic pain states. The aim of this review is to evaluate the effectiveness of tDCS on pain reduction and related disability in patients with non-specific chronic low back pain (CLBP). A computer-based systematic literature search was performed in five databases according to PRISMA guidelines. Randomized controlled trials (RCTs) that assessed the effects of tDCS on pain and related disability in patients with non-specific CLBP were included. Modified Jadad scale and Cochrane's risk of bias assessment were used to determine the studies' quality and risk of bias. Meta-analyses were performed by calculating the standardized mean difference (SMD) at 95% confidence interval (CI). Nine RCTs (411 participants) were included in the systematic review according to inclusion criteria, while only five studies could be included in the meta-analysis. The primary motor cortex (M1) was the main stimulated target. The meta-analysis showed non-significant effect of multiple sessions of tDCS over M1 on pain reduction and disability post-treatment respectively, (SMD = 0.378; 95% CI = - 0.264-1.020; P = 0.249), (SMD = 0.143; 95% CI = - 0.214-0.499; P = 0.434). No significant adverse events were reported. The current results do not support the clinical use of tDCS for the reduction of pain and related disability in non-specific CLBP. However, the limited number of available evidence limits our conclusions on the effectiveness of these approaches.

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Triptan efficacy does not predict onabotulinumtoxinA efficacy but improves with onabotulinumtoxinA response in chronic migraine patients.

Chronic migraine (CM) is a highly disabling primary headache. Botulinum toxin (onabotulinumtoxinA) is effective for treatment of CM, with ~ 50% of patients responding after 24 weeks. A response predictor would prevent unnecessary treatments. Inhibiting calcitonin gene related peptide (CGRP) release from trigeminal nociceptive fibres is one of the modes of acting discussed for onabotulinumtoxinA in CM. Therefore, we hypothesized that the response to triptans might predict response to onabotulinumtoxinA. Contrariwise, onabotulinumtoxinA treatment might affect triptan efficacy. 49 CM patients scheduled for their first onabotulinumtoxinA treatment were included. Before (T0) and three months after (T1) onabotulinumtoxinA treatment, patients rated triptan efficacy and indicated number of headache days/month. At T1, patients additionally rated onabotulinumtoxinA efficacy. Headache days/month were on average reduced by 7.1 ± 7.0 days from T0 to T1 (p < 0.001). Triptan efficacy ratings at T0 did not predict onabotulinumtoxinA efficacy ratings at T1 (p = 0.19) or reduction of headache days (p = 0.37). However, triptan efficacy significantly improved from T0 to T1 in onabotulinumtoxinA responders (p < 0.001) but not in non-responders (p = 1.00). Triptan efficacy did not predict response to onabotulinumtoxinA in CM. However, triptan efficacy increased after successful onabotulinumtoxinA treatment. This supports the hypothesis that efficacy of acute migraine treatment with triptans improves with effective migraine prophylaxis.

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