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Papers: 31 Oct 2020 - 6 Nov 2020

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A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.

The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.

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Parallel ascending spinal pathways for affective touch and pain.

The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that  express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.

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Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling.

Complex regional pain syndrome (CRPS) results in chronic and excruciating pain in patients. Conventional therapies lack effectiveness, rendering it one of the most difficult to treat neurological conditions.. Electroacupuncture (EA) is an effective alternative therapy for pain relief. Here, we investigated whether EA exerts analgesic effect on a rat model of CRPS type-I (CRPS-I) and related mechanisms. The rat chronic postischemic pain (CPIP) model was established to mimic CRPS-I. 100Hz EA exerted robust and persistent antiallodynic effect on CPIP model compared with 2 Hz EA or sham EA. EA markedly suppressed the overexpression of CXCL12/CXCR4 in spinal cord dorsal horn (SCDH) of CPIP model, leading to substantial decrease in neuronal and glial cell activities in SCDH. Pharmacological blocking CXCR4 mimicked EA-induced antiallodynic effect and related cellular events in SCDH, whereas exogenous CXCL12 abolished EA's effect. CXCR4 signaling resulted in ERK activation in SCDH, contributing to mechanical allodynia of CPIP model rats, whereas EA markedly reduced ERK activation. Therefore, we demonstrated that EA interferes with CXCL12/CXCR4 signaling in SCDH and downstream ERK pathway to exert robust antiallodynic effect on an animal model of CRPS-I. Our work suggests that EA may be a potential therapeutic option for CRPS-I in clinic. PERSPECTIVE: Our work identified that EA exerts robust antiallodynic effect on an animal model of CRPS-I, via mechanisms involving inhibition of CXCL12/CXCR4 signaling. EA further attenuates downstream neuronal and glial cell activation and ERK pathway in SCDH. This work suggests that EA may be a potential therapeutic option for CRPS-I management in clinic.

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An underrepresented majority: A systematic review utilizing allodynic criteria to examine the present scarcity of discrete animal models for episodic migraine.

Despite increasing evidence differentiating episodic and chronic migraine, little work has determined how currently utilized animal models of migraine best represent each distinct disease state.

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Molecular Genetics of Kappa Opioids in Pain and Itch Sensations.

The opioid peptides and their receptors have been linked to multiple key biological processes in the nervous system. Here we review the functions of the kappa opioid receptor (KOR) and its endogenous agonists dynorphins (Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L, Proc Natl Acad Sci U S A 76:6666-6670, 1979) in modulating itch and pain (nociception). Specifically, we discuss their roles relative to recent findings that tell us more about the cells and circuits which are impacted by this opioid and its receptor and present reanalysis of single-cell sequencing data showing the expression profiles of these molecules. Since the KOR is relatively specifically activated by peptides derived from the prodynorphin gene and other opioid peptides that show lower affinities, this will be the only interactions we consider (Chavkin C, Goldstein A, Nature 291:591-593, 1981; Chavkin C, James IF, Goldstein A, Science 215:413-415, 1982), although it was noted that at higher doses peptides other than dynorphins might stimulate KOR (Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F, Nat Neurosci 9:1534-1540, 2006). This review has been organized based on anatomy with each section describing the effect of the kappa opioid system in a specific location but let us not forget that most of these circuits are interconnected and are therefore interdependent.

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Biased Ligands at the Kappa Opioid Receptor: Fine-Tuning Receptor Pharmacology.

The kappa opioid receptor (KOR) is a G protein-coupled receptor (GPCR) that can signal through multiple signaling pathways. KOR agonists are known to relieve pain and itch, as well as induce dysphoria, sedation, hallucinations, and diuresis. As is the case with many other GPCRs, specific signaling pathways downstream of the KOR have been linked to certain physiological responses induced by the receptor. Those studies motivated the search and discovery of a number of KOR ligands that preferentially activate one signaling pathway over another. Such compounds are termed functionally selective or biased ligands, and may present a way of inducing desired receptor effects with reduced adverse reactions. In this chapter, I review the molecular intricacies of KOR signaling and discuss the studies that have used biased signaling through the KOR as a way to selectively modulate in vivo physiology.

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Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study.

Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US.

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Methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a systematic review.

Mechanism-based classification of pain has been advocated widely to aid tailoring of interventions for individuals experiencing persistent musculoskeletal pain. Three pain mechanism categories are defined by the International Association for the Study of Pain: nociceptive, neuropathic, and nociplastic pain. Discrimination between them remains challenging. This study aimed to: build on a framework developed to converge the diverse literature of pain mechanism categories to systematically review methods purported to discriminate between them; synthesise and thematically analyse these methods to identify convergence and divergence of opinion; and report validation, psychometric properties and strengths/weaknesses of these methods. The search strategy identified papers discussing methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system. Studies that assessed validity of methods to discriminate between categories were assessed for quality. Extraction and thematic analysis were undertaken on 184 papers. Data synthesis identified 200 methods in five themes: clinical examination, quantitative sensory testing, imaging, diagnostic and laboratory testing, and pain-type questionnaires. Few methods have been validated for discrimination between pain mechanism categories. There was general convergence but some disagreement regarding findings that discriminate between pain mechanism categories. A combination of features and methods, rather than a single method, was generally recommended to discriminate between pain mechanism categories. Two major limitations were identified: overlap of findings of methods between categories due to mixed presentations, and many methods considered discrimination between two pain mechanism categories but not others. The results of this review provide a foundation to refine methods to differentiate mechanisms for musculoskeletal pain.

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Stratification of patients based on the neuropathic pain symptom inventory (NPSI): development and validation of a new algorithm.

The personalization of neuropathic pain treatment could be improved by identifying specific sensory phenotypes (i.e. specific combinations of symptoms and signs) predictive of the response to different classes of drugs. A simple and reliable phenotyping method is required for such a strategy. We investigated the utility of an algorithm for stratifying patients into clusters corresponding to specific combinations of neuropathic symptoms assessed with the Neuropathic Pain Symptom Inventory (NPSI). Consistent with previous results, we first confirmed, in a cohort of 628 patients, the existence of a structure consisting of three clusters of patients characterized by higher NPSI scores for: pinpointed pain (cluster 1), evoked pain (cluster 2) or deep pain (cluster 3). From these analyses, we derived a specific algorithm for assigning each patient to one of these three clusters. We then assessed the clinical relevance of this algorithm for predicting treatment response, through post hoc analyses of two previous controlled trials of the effects of subcutaneous injections of botulinum toxin A (BTX-A). Each of the 97 patients with neuropathic pain included in these studies was individually allocated to one cluster, by applying the algorithm to their baseline NPSI responses. We found significant effects of BTX-A relative to placebo in clusters 2 and 3, but not in cluster 1, suggesting that this approach was, indeed, relevant. Finally, we developed and performed a preliminary validation of a web-based version of the NPSI and algorithm for the stratification of patients in both research and daily practice.

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Impaired short-term visual paired associative plasticity in patients with migraine between attacks.

A common experimental neurophysiological method to study synaptic plasticity is pairing activity of somatosensory afferents and motor cortical circuits, so-called paired associative stimulation (PAS). Dysfunctional inhibitory and excitatory PAS mechanisms within the sensorimotor system were described in patients with migraine without aura (MO) between attacks. We have recently observed that the same bidirectional PAS rules also apply to the visual system. Here, we have tested whether dysfunctioning associative plasticity might characterize the visual system of patients with MO. In 14 patients with MO between attacks and in 15 healthy volunteers, we performed a previously validated visual PAS (vPAS) protocol by coupling 90 black-and-white checkerboard reversals with low-frequency transcranial magnetic stimulation pulses over the occipital cortex at 2 interstimulus intervals of -25/+25 ms around the visual-evoked potential (VEP) P1 latency. We recorded VEPs (600 sweeps) before, immediately after, and 10 min after each vPAS session. We analysed VEP N1-P1 amplitude and delayed habituation. Although vPAS-25 significantly enhanced and vPAS + 25 reduced VEP amplitude habituation in healthy volunteers, the same protocols did not significantly change VEP amplitude habituation in MO between attacks. We provide evidence for lack of habituation enhancing and habituation suppressing visual PAS mechanisms within the visual system in interictal migraine. This finding, in combination with those previously obtained studying the sensorimotor system, leads us to argue that migraine disease-related dysrhythmic thalamocortical activity prevents the occurrence of physiological bidirectional synaptic plasticity induced by vPAS.

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Prior pain exposure and mere possession of a placebo analgesic predict placebo analgesia: Findings from a randomised, double-blinded, controlled trial.

A recent study found that merely possessing a placebo analgesic reduces pain. The current study tested for a possible moderator of this effect. Specifically, does the mere possession of a placebo analgesic affect pain for individuals with and without immediate prior experience with the pain task? Healthy participants (N=127) were randomized to prior pain (PP) condition or without prior pain (No-PP) condition. In the PP condition, participants first did a preliminary trial of a cold pressor test (CPT) to induce direct experience with this pain stimulus. Then they were randomized to possess an inert cream described as either an analgesic cream or an anti-itch cream (pain-irrelevant control object). Participants then completed the main CPT. In the No-PP condition, participants underwent identical procedures and randomization except that they did not do a preliminary CPT, thus having no immediate prior CPT pain experience. We found a significant prior pain experience and possession status interaction effect on placebo analgesia. Participants in the No-PP condition showed evidence of lower pain when they merely possessed an analgesic cream than an anti-itch cream. Such mere possession effect was not found in the PP condition. The impact of expectancy and emotion on the underlying process are discussed. PERSPECTIVE: This article presents a novel finding that prior pain exposure and mere possession of a placebo analgesic predicted placebo analgesia. It offers a novel perspective on the time course of placebo effect. It provides practical implications on potential pain intervention for clinicians and paradigm design for researchers of placebo study.

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Descending modulation of laryngeal vagal sensory processing in the brainstem orchestrated by the submedius thalamic nucleus.

The nodose and jugular vagal ganglia supply sensory innervation to the airways and lungs. Jugular vagal airway sensory neurons wire into a brainstem circuit with ascending projections into the submedius thalamic nucleus (SubM) and ventrolateral orbital cortex (VLO), regions known to regulate the endogenous analgesia system. Here we investigate whether the SubM-VLO circuit exerts descending regulation over airway vagal reflexes in male and female rats using a range of neuroanatomical tracing, reflex physiology and chemogenetic techniques. Anterograde and retrograde neuroanatomical tracing confirmed connectivity of the SubM and VLO. Laryngeal stimulation in anesthetized rats reduced respiration, a reflex that was potently inhibited by activation of SubM. Conversely, inhibition of SubM potentiated laryngeal reflex responses, while prior lesions of VLO abolished the effects of SubM stimulation. In conscious rats, selective chemogenetic activation of SubM neurons specifically projecting to VLO significantly inhibited respiratory responses evoked by inhalation of the nociceptor stimulant capsaicin. Jugular vagal inputs to SubM via the medullary paratrigeminal nucleus were confirmed using anterograde transsynaptic conditional herpes viral tracing. Respiratory responses evoked by microinjections of capsaicin into the paratrigeminal nucleus were significantly attenuated by SubM stimulation, whereas those evoked via the nucleus of the solitary tract were unaltered. These data suggest jugular vagal sensory pathways input to a nociceptive thalamocortical circuit capable of regulating jugular sensory processing in the medulla. This circuit organization suggests an intersection between vagal sensory pathways and the endogenous analgesia system, potentially important for understanding vagal sensory processing in health and mechanisms of hypersensitivity in disease.Jugular vagal sensory pathways are increasingly recognized for their important role in defensive respiratory responses evoked from the airways. Jugular ganglia neurons wire into a central circuit that is notable for overlapping with somatosensory processing networks in the brain rather than the viscerosensory circuits in receipt of inputs from the nodose vagal ganglia. Here we demonstrate a novel and functionally relevant example of intersection between vagal and somatosensory processing in the brain. The findings of the study offer new insights into interactions between vagal and spinal sensory processing, including the medullary targets of the endogenous analgesia system, and offer new insights into the central processes involved in airway defense in health and disease.

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The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels.

TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by µ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels.

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Association between COVID-19 and headache: What evidence and history tell us.

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Headache associated with COVID-19: Frequency, characteristics and association with anosmia and ageusia.

To assess the frequency and characteristics of headache in patients with COVID-19 and whether there is an association between headache and anosmia and ageusia.

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Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine.

Acute medication overuse is prevalent in patients with migraine.

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Characterization and preclinical evaluation of a protease activated receptor 2 (PAR2) monoclonal antibody as a preventive therapy for migraine.

Migraine pain is thought to result from activation of meningeal nociceptors that might involve dural mast cell degranulation and release of proteases and pronociceptive mediators. Tryptase, the most abundant dural mast cell protease, has been demonstrated to stimulate dural mast cells, as well as trigeminal nociceptors by activating the protease activated receptor 2. Mast cell or neuronal protease activated receptors 2 may therefore represent a novel target for migraine treatment. In this study, we characterized and evaluated a novel protease activated receptor 2 monoclonal antibody as a preventive anti-migraine pain therapy in preclinical models.

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Characteristics of headache attributed to COVID-19 infection and predictors of its frequency and intensity: A cross sectional study.

To study the characteristics of headache attributed to COVID-19 infection and predictors of its severity.

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Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.

To define headache characteristics and evolution in relation to COVID-19 and its inflammatory response.

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The cool things to know about TRPM8!

Transient receptor potential melastatin 8 (TRPM8) channels play a central role in the detection of environmental cold temperatures in the somatosensory system. TRPM8 is found in a subset of unmyelinated (C-type) afferents located in the dorsal root (DRG) and trigeminal ganglion (TG). Cold hypersensitivity is a common symptom of neuropathic pain conditions caused by cancer therapy, spinal cord injury, viral infection, multiple sclerosis, diabetes, or withdrawal symptoms associated with chronic morphine treatment. Therefore, TRPM8 has received great attention as a therapeutic target. However, as the activity of TRPM8 is unique in sensing cool temperature as well as warming, it is critical to understand the signaling transduction pathways that control modality-specific activity of TRPM8 in healthy versus pathological settings. This review summarizes recent advances in our understanding of the mechanisms involved in the regulation of the TRPM8 activity.

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I stay at home with headache. A survey to investigate how the lockdown for COVID-19 impacted on headache in Italian children.

The present Italian multicenter study aimed at investigating whether the course of primary headache disorders in children and adolescents was changed during the lockdown necessary to contain the COVID-19 emergency in Italy.

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Phenotypic characterization of acute headache attributed to SARS-CoV-2: An ICHD-3 validation study on 106 hospitalized patients.

Headache is a common symptom of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we aimed to characterize the phenotype of headache attributed to SARS-CoV-2 infection and to test the International Classification of Headache Disorders (ICHD-3) phenotypic criteria for migraine and tension-type headache.

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Daily persistent headache after a viral illness during a worldwide pandemic may not be a new occurrence: Lessons from the 1890 Russian/Asiatic flu.

New daily persistent headache was first documented in the medical literature in the 1980s. The leading trigger is a viral illness. As we navigate our way thru the current SARS-CoV-2 pandemic, looking back at past viral epidemics may help guide us for what to expect in the near future in regard to headaches as a persistent manifestation of the SARS-CoV-2 infection. The 1890 viral pandemic known as the "Russian or Asiatic flu", has extensive documentation about the neurologic sequelae that presented months to years after the pandemic ended. One of the complications was daily persistent headache. There are actually many similarities between the viral presentation of the 1890 pandemic and the current SARS-CoV-2 pandemic, which may then suggest that not only will NDPH be part of the neurological sequelae but a possible key consequence of the SARS-CoV-2 infection.

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Comparative effectiveness of physical exercise interventions for chronic non-specific neck pain: a systematic review with network meta-analysis of 40 randomised controlled trials.

To compare the effectiveness of different physical exercise interventions for chronic non-specific neck pain.

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Outcome in young adults who were diagnosed with complex regional pain syndrome in childhood and adolescence.

Complex regional pain syndrome (CRPS) is a neuropathic pain condition of unknown etiology. Little is known of long-term outcomes of young adults who were diagnosed with CRPS as children.

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Improving outcomes and decreasing costs for neurological diseases: mind the gap.

Neurological disorders are the leading cause of disability-adjusted life years (DALYs) and the second leading cause of deaths. The four large contributors of neurological DALYs are stroke, migraine, dementia and meningitis [1]. Global and regional actions to decrease this burden are urgently needed. To appropriately set priorities and allocate resources for such actions, political leaders need to be informed by epidemiological and health economic studies.

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The early influence of COVID-19 pandemic-associated restrictions on pain, mood, and everyday life of patients with painful polyneuropathy.

The SARS-Cov-2 pandemic requires special attention on its psychological effects and the impact on patients with chronic pain.

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NMDA receptors in axons: there’s no coincidence.

In the textbook view, N-methyl-D-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident.

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Effect of Pain Education and Exercise on Pain and Function in Chronic Achilles Tendinopathy: Protocol for a Double-Blind, Placebo-Controlled Randomized Trial.

Achilles tendinopathy (AT) rehabilitation traditionally includes progressive tendon loading exercises. Recent evidence suggests a biopsychosocial approach that incorporates patient education on psychosocial factors and mechanisms of pain can reduce pain and disability in individuals with chronic pain. This is yet to be examined in individuals with AT.

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The Source of Hemisensory Disturbances in Complex Regional Pain Syndrome.

In complex regional pain syndrome (CRPS), sensory deficits and/or hyperalgesia often extend beyond the affected limb to encompass other sites on the ipsilateral side of the body. The aim of this study was to determine whether hyperalgesia in the ipsilateral forehead reflects disinhibition and/or sensitization of trigeminal afferent or second-order neurons on the CRPS-affected side.

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Cognitive behavioral therapy (CBT) and pain education for people with chronic pain: Tests of treatment mechanisms.

The goals of the study were to determine to what degree changes in pain-related cognition during cognitive behavioral treatment (CBT) and pain education (EDU) represented treatment mechanisms and whether these cognitive changes worked to a larger extent to produce favorable outcomes in CBT than in EDU.

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Adverse childhood experiences in parents of youth with chronic pain: prevalence and comparison with a community-based sample.

Adverse childhood experiences (ACEs) are common occurrences that are related to poor health outcomes, including chronic pain, in youth and adults. Research suggests that children of parents exposed to ACEs are also at risk of poor outcomes. However, little is known about the risk that ACEs confer for chronic pain across generations. Parent ACEs may play an important role in pediatric chronic pain, given their association with key parent factors (eg, mental and physical health).

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Nonopioid drug combinations for cancer pain: protocol for a systematic review.

Pain related to cancer, and its treatment, is common, may severely impair quality of life, and imposes a burden on patients, their families and caregivers, and society. Cancer-related pain is often challenging to manage, with limitations of analgesic drugs including incomplete efficacy and dose-related adverse effects.

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Inpatient postoperative undesirable side effects of analgesics management: a pediatric patients and parental perspective.

The use of analgesics for the treatment of post-operative pain is common, however, such medications are known to have potential side effects. These undesirable secondary effects can have an important impact on patients and impede their recovery.

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Greater mechanical temporal summation of pain in Latinx-Americans and the role of adverse life experiences.

Adverse life experiences disproportionately impact Latinx-Americans and are related to greater chronic pain rates. However, little is known about how adversities interact with central pain mechanisms for the development of later pain among Latinx-Americans.

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Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery.

In recent months, with the emergence of the COVID-19 pandemic, the American College of Surgeons and the U.S. Centers for Disease Control and Prevention officially recommended the delay of nonemergency procedures until the public health crisis is resolved. Deferring elective joint replacement surgeries for an unknown period is likely to decrease the incidence of infection with SARS-CoV-2 but is likely to have detrimental effects in individuals suffering from chronic knee pain. These detrimental effects extend beyond the discomfort of osteoarthritis (OA) and the inconvenience of rescheduling surgery. Disabling pain is a driving factor for individuals to seek medical intervention, including pharmacological palliative treatment and surgical procedures. The need for surgical intervention due to chronic pain as for knee and hip replacement is now put on hold indefinitely because access to surgical care has been limited. Although a moderate delay in surgical intervention may not produce a significant progression of OA within the knee, it could lead to muscle wasting due to immobility and exacerbate comorbidities, making rehabilitation more challenging. Importantly, it will have an impact on comorbidities driven by OA severity, notably decreased quality of life and depression. These patients with unremitting pain become increasingly susceptible to substance use disorders including opioids, alcohol, as well as prescription and illegal drugs. Appreciation of this downstream crisis created by delayed surgical correction requires aggressive consideration of nonsurgical, nonopiate supported interventions to reduce the morbidity associated with these delays brought upon by the currently restricted access to joint repair.

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Pain in Endometriosis.

Endometriosis is a chronic and debilitating condition affecting ∼10% of women. Endometriosis is characterized by infertility and chronic pelvic pain, yet treatment options remain limited. In many respects this is related to an underlying lack of knowledge of the etiology and mechanisms contributing to endometriosis-induced pain. Whilst many studies focus on retrograde menstruation, and the formation and development of lesions in the pathogenesis of endometriosis, the mechanisms underlying the associated pain remain poorly described. Here we review the recent clinical and experimental evidence of the mechanisms contributing to chronic pain in endometriosis. This includes the roles of inflammation, neurogenic inflammation, neuroangiogenesis, peripheral sensitization and central sensitization. As endometriosis patients are also known to have co-morbidities such as irritable bowel syndrome and overactive bladder syndrome, we highlight how common nerve pathways innervating the colon, bladder and female reproductive tract can contribute to co-morbidity via cross-organ sensitization.

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Will that hurt? A contingency learning task to assess pain-expectancy judgments for low back postures.

Contingency learning, i.e. learning that a cue predicts the presence (or absence) of an event, is central to the formation of beliefs regarding painfulness of body postures. Such beliefs may spread to safe cues due to compromised learning (e.g., excessive generalization, impaired safety learning), prompting avoidance and leading to disability. Despite its importance, compromised learning about low back pain is underinvestigated. We propose a low back pain scenario contingency learning task for the investigation of back pain-related learning.

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Proposal of a clinical care pathway for quality and safe management of headache patients: a consensus study report.

Headache is one of the most prevalent and disabling conditions. Its optimal management requires a coordinated and comprehensive response by health systems, but there is still a wide variability that compromises the quality and safety of the care process.

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A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain.

More than a quarter of veterans of the 1990-1991 Persian Gulf War suffer from Gulf War Illness (GWI), a chronic, multi-symptom illness that commonly includes musculoskeletal pain. Exposure to a range of toxic chemicals, including sarin nerve agent, are a suspected root cause of GWI. Moreover, such chemical exposures induce a neuroinflammatory response in rodents, which has been linked to several GWI symptoms in rodents and veterans with GWI. To date, a neuroinflammatory basis for pain associated with GWI has not been investigated. Here, we evaluated development of nociceptive hypersensitivity in a model of GWI. Male Sprague Dawley rats were treated with corticosterone in the drinking water for 7 days, to mimic high physiological stress, followed by a single injection of the sarin nerve agent surrogate, diisopropyl fluorophosphate. These exposures alone were insufficient to induce allodynia. However, an additional sub-threshold challenge (a single intramuscular injection of pH 4 saline) induced long-lasting, bilateral allodynia. Such allodynia was associated with elevation of markers for activated microglia/macrophages (CD11b) and astrocytes/satellite glia (GFAP) in the lumbar dorsal spinal cord and dorsal root ganglia (DRG). Additionally, Toll-like receptor 4 (TLR4) mRNA was elevated in the lumbar dorsal spinal cord, while IL-1β and IL-6 were elevated in the lumbar dorsal spinal cord, DRG, and gastrocnemius muscle. Demonstrating a casual role for such neuroinflammatory signaling, allodynia was reversed by treatment with either minocycline, the TLR4 inhibitor (+)-naltrexone, or IL-10 plasmid DNA. Together, these results point to a role for neuroinflammation in male rats in the model of musculoskeletal pain related to GWI. Therapies that alleviate persistent immune dysregulation may be a strategy to treat pain and other symptoms of GWI.

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Investigation of light-induced lacrimation and pupillary responses in episodic migraine.

The purpose of this pilot study was to investigate the light-induced pupillary and lacrimation responses mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) in migraine. Ten participants with episodic migraine and normal tear production, as well as eleven visually normal controls participated in this study. Following an initial baseline trial (no light flash), participants received seven incremental and alternating red and blue light flashes. Pupillometry recording of the left eye and a 1-min anesthetized Schirmer's test of the right eye (using 0.5% proparacaine) were performed simultaneously. Intrinsic and extrinsic ipRGC photoactivities did not differ between migraine participants and controls across all intensities and wavelengths. Migraine participants, however, had significantly lower lacrimation than controls following the highest blue intensity. A positive correlation was found between melanopsin-driven post-illumination pupillary responses and lacrimation following blue stimulation in both groups. Our results show that participants with self-reported photophobia have normal ipRGC-driven responses, suggesting that photophobia and pupillary function may be mediated by distinct ipRGC circuits. The positive correlation between melanopsin-driven pupillary responses and light-induced lacrimation suggests the afferent arm of the light-induced lacrimation reflex is melanopsin-mediated and functions normally in migraine. Lastly, the reduced melanopsin-mediated lacrimation at the highest stimulus suggests the efferent arm of the lacrimation reflex is attenuated under certain conditions, which may be a harbinger of dry eye in migraine.

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A low pKa ligand inhibits cancer-associated pain in mice by activating peripheral mu-opioid receptors.

The newly designed fentanyl derivative [( ±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide] (NFEPP) was recently shown to produce analgesia selectively via peripheral mu-opioid receptors (MOR) at acidic pH in rat inflamed tissues. Here, we examined the pH-dependency of NFEPP binding to brain MOR and its effects on bone cancer-induced pain in mice. The IC of NFEPP to displace bound [H]-DAMGO was significantly higher compared to fentanyl at pH 7.4, but no differences were observed at pH 5.5 or 6.5. Intravenous NFEPP (30-100 nmol/kg) or fentanyl (17-30 nmol/kg) inhibited heat hyperalgesia in mice inoculated with B16-F10 melanoma cells. The peripherally-restricted opioid receptor antagonist naloxone-methiodide reversed the effect of NFEPP (100 nmol/kg), but not of fentanyl (30 nmol/kg). The antihyperalgesic effect of NFEPP was abolished by a selective MOR- (cyprodime), but not delta- (naltrindole) or kappa- (nor-binaltorphimine) receptor antagonists. Ten-fold higher doses of NFEPP than fentanyl induced maximal antinociception in mice without tumors, which was reversed by the non-restricted antagonist naloxone, but not by naloxone-methiodide. NFEPP also reduced heat hyperalgesia produced by fibrosarcoma- (NCTC 2472) or prostate cancer-derived (RM1) cells. These data demonstrate the increased affinity of NFEPP for murine MOR at low pH, and its ability to inhibit bone cancer-induced hyperalgesia through peripheral MOR. In mice, central opioid receptors may be activated by ten-fold higher doses of NFEPP.

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Patient acceptable symptom state for patient-reported outcomes in people with non-specific chronic low back pain.

The patient acceptable symptom state (PASS) is a treatment-response criterion developed to determine the clinical relevance of a treatment effect. Its estimates for some patient-reported outcomes (PROs) in non-specific chronic low back pain (cLBP) are lacking and the stability of PRO estimates between independent cLBP populations is unknown. We hypothesized that these PRO estimates will be stable.

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Perceptual amplification following sustained attention: implications for hypervigilance.

It is known that attending to a cutaneous stimulus briefly increases its subjective intensity. The purpose of the present study was to determine whether an extended period of attention would produce a longer-lasting perceptual amplification. Eighty subjects were assigned alternately to experimental and control groups. Members of the two groups received identical series of tactile stimuli (near-threshold von Frey filaments applied to the forearm), but those in the experimental group carried out a two-interval forced-choice detection task that required attention to the filaments, while subjects in the control group attended instead to a video game. After this initial phase, all subjects gave magnitude estimates of the intensity of a wide range of von Frey filaments. The experimental group gave estimates 42% greater than those of the control group, both for filaments used in the initial phase, and others not presented previously; the perceptual amplification did not, however, transfer to a different type of pressure stimulus, a 5 mm-diameter rod applied to the skin. The aftereffect of sustained attention lasted for at least 15 min. This phenomenon, demonstrated in normal subjects, may have implications for the hypervigilance of some chronic pain patients, which is characterized by both heightened attention to pain and long-lasting perceptual amplification of noxious stimuli.

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Chronic Pain and High-impact Chronic Pain Among U.S. Adults, 2019.

Chronic pain (1) and chronic pain that frequently limits life or work activities, referred to in this report as high-impact chronic pain (2), are among the most common reasons adults seek medical care (3) and are associated with decreased quality of life, opioid dependence, and poor mental health (1,4,5). This report examines chronic pain and high-impact chronic pain in the past 3 months among U.S. adults aged 18 and over by selected demographic characteristics and urbanization level.

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Treatment patterns and medication adherence among newly diagnosed patients with migraine: a drug utilisation study.

Prophylactic drugs currently used for migraine treatment are not specific. Furthermore, few studies in existing literature describe drugs utilisation patterns and adherence to migraine prophylactic treatment. This study is aimed to describe utilisation patterns of migraine drugs, evaluate adherence to prophylactic medications and investigate drug-related costs.

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Analgesic medicines for adults with low back pain: protocol for a systematic review and network meta-analysis.

There is limited evidence for the comparative effectiveness of analgesic medicines for adults with low back pain. This systematic review and network meta-analysis aims to determine the analgesic effect, safety, acceptability, effect on function, and relative rank according to analgesic effect, safety, acceptability, and effect on function of a single course of [an] analgesic medicine(s) or combination of these medicines for people with low back pain.

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Safety of Low-Dose Tanezumab in the Treatment of Hip or Knee Osteoarthritis: A Systemic Review and Meta-analysis of Randomized Phase III Clinical Trials.

To evaluate the safety of low-dose tanezumab in the treatment of knee or hip osteoarthritis (OA).

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Wearable Respiratory Monitoring and Feedback for Chronic Pain in Adult Survivors of Childhood Cancer: A Feasibility Randomized Controlled Trial From the Childhood Cancer Survivor Study.

Approximately 40% of childhood cancer survivors experience chronic pain, with many also reporting pain-related disability. Given associations established in the general population among respiration, anxiety, and pain, continuous tracking and feedback of respiration may help survivors manage pain.

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Isolated intracranial hypertension associated with COVID-19.

Headache is a frequent complaint in COVID-19 patients. However, no detailed information on headache characteristics is provided in these reports. Our objective is to describe the characteristics of headache and the cerebrospinal fluid (CSF) profile in COVID-19 patients, highlighting the cases of isolated intracranial hypertension.

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Implementation and Policy Recommendations from the VHA State-of-the-Art Conference on Strategies to Improve Opioid Safety.

Evidence-based treatment of opioid use disorder, the prevention of opioid overdose and other opioid-related harms, and safe and effective pain management are priorities for the Veterans Health Administration (VHA). The VHA Office of Health Services Research and Development hosted a State-of-the-Art Conference on "Effective Management of Pain and Addiction: Strategies to Improve Opioid Safety" on September 10-11, 2019. This conference convened a multidisciplinary group to discuss and achieve consensus on a research agenda and on implementation and policy recommendations to improve opioid safety for Veterans. Participants were organized into three workgroups: (1) managing opioid use disorder; (2) Long-term opioid therapy and opioid tapering; (3) managing co-occurring pain and substance use disorder. Here we summarize the implementation and policy recommendations of each workgroup and highlight important cross-cutting issues related to telehealth, care coordination, and stepped care model implementation.

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Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine.

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia – an animal model of migraine – and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways.

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Equity of African American Men in Headache in the United States: A Perspective From African American Headache Medicine Specialists (Part 2).

In part 1 of this opinion piece, we described inherent and potential challenges of the equity of African American (AA) men in headache medicine including headache disparities, mistrust, understudied/lack of representation in research, cultural differences, implicit/explicit bias, and the diversity tax. We shared personal experiences related to headache medicine likely faced due to the color of our skin. In part 2, we offer possible solutions to achieve equity for AA men in headache including: (1) addressing head and facial pain disparities and mistrust in AA men; (2) professionalism and inclusion; (3) organizational/departmental leadership buy-in for racial diversity; (4) implicit/explicit and other bias training; (5) diversity panels with open discussion; (6) addressing diversity tax; (7) senior mentorship; (8) increased opportunities for noteworthy and important roles; (9) forming and building alliances and partnerships; (10) diversity leadership training programs; (11) headache awareness, education, and literacy with a focus to underrepresented in medicine trainees and institutions; and (12) focused and supported the recruitment of AA men into headache medicine.

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Localised neuropathic pain in the primary care setting: a cross-sectional study of prevalence, clinical characteristics, treatment patterns, quality of life and sleep performance.

Localised Neuropathic Pain (LNP) is challenging to diagnose and manage in primary care. To describe clinical characteristics, treatment patterns, quality of life and sleep performance of patients with LNP and estimate its prevalence in primary care. Cross-sectional study in 4 European countries. Patients were identified using a screening tool for LNP. Patients completed the EQ-5D VAS score and Chronic Pain Sleep Inventory (CPSI). There were 1030 LNP patients for analysis. They presented a median pain intensity of 6.0 (IQR 4.0-7.0) with a median duration of 30.9 months (IQR 12.0 – 75.3), despite 97% receiving pain treatment. Main sites affected were the limbs (62% upper/58% lower) and spine (41%). Main aetiologies were neuropathic low back pain (47%), post-surgical neuropathic pain (17%), and diabetic poly-neuropathy (12%). Thirty percent received a single analgesic (2% topical), while combinations comprised 43% systemic-systemic, 24% topical-systemic, 1% topical-topical. Medications included NSAIDs (45%), anticonvulsants (38%), WHO step 2 opioids (35%), and topical analgesics (27%). In the previous 6 months, 40% had switched treatment. The mean (SD) EQ-5D VAS score was 58 (22.3) and the mean (SD) EQ-5D summary score (UK tariff) was 0.62 (0.25). Patients had a CPSI mean index of 41/100, and sleeping pills were used by 33% of patients. The standardised prevalence of LNP by age and sex was 2.01% in the general population and 43.3% among chronic pain patients. Many LNP patients reported pain intensities of six on a ten-point scale in average for durations longer than 2.5 years, with quality of life and sleep performance affected, with frequent treatment combinations and switches, suggesting suboptimal pain management.

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Equity of African American Men in Headache in the United States: A Perspective From African American Headache Medicine Specialists (Part 1).

Migraine and severe headache affect approximately 1 in 6 U.S. adults and migraine is one of the most disabling disorders worldwide. Approximately 903,000 to 1.5 million African American (AA) men are affected by migraine in the United States. Racial disparities in headache medicine exist. In addition, there are limited headache studies that attest to the inclusion of or have robust data on AA men in headache medicine in the United States. Racial concordance between provider and patient may ameliorate some aspects of care disparities. Moreover, it has been demonstrated that diversity and inclusion particularly in leadership of organizations has consistently produced positive change, increased innovation, and long-term success. Most national headache organizations strive to improve the care and lives of people living with headache disorders yet only ~0.5% of their physician members are AA men. Herein, we provide an observation of equity issues from the perspective of AA men in the headache medicine subspecialty. Part 1 of this manuscript explores inherent and potential challenges of the equity of AA men in headache medicine including headache disparities, mistrust, understudied/lack of representation in research, cultural differences, implicit/explicit bias, and the diversity tax. Part 2 of this work offers possible solutions to achieve equity for AA men in headache including: (1) addressing head and facial pain disparities and mistrust in AA men; (2) professionalism and inclusion; (3) organizational/departmental leadership buy-in for racial diversity; (4) implicit/explicit and other bias training; (5) diversity panels with open discussion; (6) addressing diversity tax; (7) senior mentorship; (8) increased opportunities for noteworthy and important roles; (9) forming and building alliances and partnerships; (10) diversity leadership training programs; (11) headache awareness, education, and literacy with focus to underrepresented in medicine trainees and institutions; and (12) focused and supported the recruitment of AA men into headache medicine. More work is needed for equity of AA men in headache medicine.

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Microglia-Astrocyte Cross Talk through IL-18/IL-18R Signaling Modulates Migraine-like Behavior in Experimental Models of Migraine.

Interleukin-18 (IL-18) is an important regulator of innate and immune responses, and is involved in the pain process, including neuropathic and cancer pain. The current study demonstrated that inflammatory soup (IS) dural infusions elicited the activation of microglia and astrocytes. In comparison, IS dural infusions induced the upregulation of IL-18 and IL-18R in microglia and astrocytes, respectively. Blocking the IL-18 signaling pathway attenuated nociceptive behavior. In comparison, blocking IL-18 signaling also suppressed the activation of astrocytes and nuclear factor-kappa B (NF-κB). IL-18 dural infusions induced nociceptive behavior and glia activation. IL-18 is a product of the activation of microglial toll-like receptor 4 (TLR4), and it acted on IL-18R expressed in astrocytes. Subsequently, it stimulated the activation of nuclear factor-kappa B (NF-κB), leading to the activation of astrocytes. In conclusion, IL-18-mediated microglia/astrocyte interactions in the medullary dorsal horn likely contribute to the development of hyperpathia or allodynia induced by migraines.

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Functional Alterations in the Posterior Insula and Cerebellum in Migraine Without Aura: A Resting-State MRI Study.

: Hypothesis-driven functional connectivity (FC) analyses have revealed abnormal functional interaction of regions or networks involved in pain processing in episodic migraine patients. We aimed to investigate the resting-state FC patterns in episodic migraine by combining data-driven voxel-wise degree centrality (DC) calculation and seed-based FC analysis. : Thirty-nine patients suffering from episodic migraine without aura and 35 healthy controls underwent clinical assessment and functional MRI. DC was analyzed voxel-wise and compared between groups, and FC of regions with DC differences were further examined using a seed-based approach. : Compared with the control group, the migraine group showed increased and decreased DC in the right posterior insula and left crus I, respectively. Seed-based FC analyses revealed that migraine patients demonstrated increased right posterior insula connections with the postcentral gyrus, supplementary motor area/paracentral lobule, fusiform gyrus and temporal pole. The left crus I showed decreased FC with regions of the default mode network (DMN), including the medial prefrontal cortex (mPFC), angular gyrus, medial and lateral temporal cortex in patients with migraine. Furthermore, pain intensity positively correlated with DC in the right amygdala/parahippocampal gyrus, and migraine frequency negatively correlated with FC between the left crus I and mPFC. : Patients with episodic migraine without aura have increased FC with the right posterior insula and decreased FC within the DMN, which may underlie disturbed sensory integration and cognitive processing of pain. The left crus I-mPFC connectivity may be a useful biomarker for assessing migraine frequency.

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Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo.

Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene-related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.

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SIRT3 alleviates neuropathic pain by deacetylating FoxO3a in the spinal dorsal horn of diabetic model rats.

The underlying mechanisms of neuropathic pain remain unclear. This work aimed to investigate the role of Sirtuin3 (SIRT3), an nicotinamide adenosine dinucleotide+-dependent histone deacetylase, in the development of neuropathic pain induced by type 2 diabetes mellitus (T2DM) and to explore the associated mechanisms.

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Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants.

Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes-, , and -have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for , , and mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the , , , , , , and genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.

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The Context Matters: A Retrospective Analysis of Life Stage at Chronic Pain Onset in Relation to Pain Characteristics and Psychosocial Outcomes.

Developmental life stage at chronic pain onset differs among chronic pain patients. Although pain affects multiple life domains, it is unknown whether the timing of chronic pain onset relates to pain characteristics and psychosocial outcomes. The purpose of this retrospective study was to investigate differences in pain characteristics and psychosocial outcomes in patients at different developmental life stages at chronic pain onset.

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Optimal treatment strategy of fremanezumab in migraine prevention: a systematic review with network meta-analysis of randomized clinical trials.

Identifying the optimal fremanezumab treatment strategy is crucial in treating patients with migraines. The optimal strategy was investigated by assessing the cumulative 50% reduction rate (50%CRR), cumulative 75% reduction rate (75%CRR), reduction in the number of migraine days, treatment-related adverse events, and serious adverse events in patients treated with fremanezumab 225 mg monthly (225 mg), 675 mg monthly (675 mg), 900 mg monthly (900 mg), a single high dose of 675 mg (S675mg), 675 mg at baseline with 225 mg monthly (675/225 mg), and placebo. Biomedical databases were searched for randomized controlled trials on this topic, and data were individually extracted. Risk ratios and mean differences were used to present the pooled results. The surface under the cumulative ranking curve (SUCRA) was used to determine the effects of the medication strategies of fremanezumab. Five trials (n = 3404) were used to form a six-node network meta-analysis. All fremanezumab medication strategies displayed significantly higher cumulative 50% reduction rates than the placebo. The SUCRA revealed that treatment with 675 mg yielded the highest 50%CRR value (mean rank = 2.5). S675 mg was the only treatment with significantly higher 75%CRR reduction rate than placebo, whereas the SUCRA for 225 mg displayed the highest mean rank (2.2). Moreover, 225 mg (mean rank = 2.2) and S675 mg (mean rank = 2.2) presented lower probabilities of serious adverse events. Collectively, S675mg and 225 mg exhibited the optimal balance between efficacy and safety within three months. Long-term efficacy and safety remain unclear, and future studies should further evaluate the long-term outcomes.

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Neocortical in vivo focal and spreading potassium responses and the influence of astrocytic gap junctional coupling.

Raised extracellular potassium ion (K) concentration is associated with several disorders including migraine, stroke, neurotrauma and epilepsy. K spatial buffering is a well-known mechanism for extracellular K regulation/distribution. Astrocytic gap junction-mediated buffering is a controversial candidate for K spatial buffering. To further investigate the existence of a K spatial buffering and to assess the involvement of astrocytic gap junctional coupling in K redistribution, we hypothesized that neocortical K and concomitant spreading depolarization (SD)-like responses are controlled by powerful local K buffering mechanisms and that K buffering/redistribution occurs partially through gap junctional coupling. Herein, we show, in vivo, that a threshold amount of focally applied KCl is required to trigger local and/or distal K responses, accompanied by a SD-like response. This observation indicates the presence of powerful local K buffering which mediates a rapid return of extracellular K to the baseline. Application of gap junctional blockers, carbenoxolone and Gap27, partially modulated the amplitude and shape of the K response and noticeably decreased the velocity of the spreading K and SD-like responses. Opening of gap junctions by trimethylamine, slightly decreased the amplitude of the K response and markedly increased the velocity of redistribution of K and SD-like events. We conclude that spreading K responses reflect powerful local K buffering mechanisms which are partially modulated by gap junctional communication. Gap junctional coupling mainly affected the velocity of the K and SD-like responses.

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Central sensitization in migraine is related to restless legs syndrome.

We hypothesized that, in migraine patients, central sensitization (CS) could be associated with comorbid restless legs syndrome (RLS).

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Synergistic interaction between haloperidol and gabapentin in a model of neuropathic nociception in rat.

Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.

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Development of Diphenethylamines as Selective Kappa Opioid Receptor Ligands and Their Pharmacological Activities.

Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, the knowledge that activation of the KOR, opposite to the mu opioid receptor (MOR), does not produce euphoria or leads to respiratory depression or overdose, has stimulated the interest in discovering ligands targeting the KOR as novel pharmacotherapeutics. However, the KOR mediates the negative side effects of dysphoria/aversion, sedation, and psychotomimesis, with the therapeutic promise of biased agonism (i.e., selective activation of beneficial over deleterious signaling pathways) for designing safer KOR therapeutics without the liabilities of conventional KOR agonists. In this review, the development of new KOR ligands from the class of diphenethylamines is presented. Specifically, we describe the design strategies, synthesis, and pharmacological activities of differently substituted diphenethylamines, where structure-activity relationships have been extensively studied. Ligands with distinct profiles as potent and selective agonists, G protein-biased agonists, and selective antagonists, and their potential use as therapeutic agents (i.e., pain treatment) and research tools are described.

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Diagnosis and Treatment of Chronic Neuropathic and Mixed Pain in Children and Adolescents: Results of a Survey Study amongst Practitioners.

Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children.

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Rates of Vascular Events in Patients With Migraine: A MarketScan Database Retrospective Cohort Study.

To estimate the baseline rates of vascular events among people with migraine.

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Sex-dependent effects of an Hnrnph1 mutation on fentanyl addiction-relevant behaviors but not antinociception in mice.

Opioid Use Disorder (OUD) and opioid-related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identified Hnrnph1 as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work demonstrates that hnRNP H1, the RNA-binding protein encoded by Hnrnph1, post-transcriptionally regulates Oprm1 (mu opioid receptor gene) – the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis that Hnrnph1 mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl. Hnrnph1 mutants showed reduced sensitivity to fentanyl-induced locomotor activity, along with a female-specific reduction in, and a male-specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.). Hnrnph1 mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference. Male Hnrnph1 mutants showed reduced fentanyl reinforcement. Hnrnph1 mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl-induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest that Hnrnph1 dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.

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Association Between Opioid Dose Reduction Against Patients’ Wishes and Change in Pain Severity.

There is inadequate evidence of long-term benefit from opioid medications for chronic pain and substantial evidence of potential harms. For patients, dose reduction may be beneficial when implemented voluntarily and supported by a multidisciplinary team but experts have advised against involuntary opioid reduction.

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Benefits and Harms of Long-term Opioid Dose Reduction or Discontinuation in Patients with Chronic Pain: a Rapid Review.

Many clinicians are reevaluating the use of long-term opioid therapy (LTOT) for chronic pain in response to the opioid crisis and calls from organizations including the Centers for Disease Control & Prevention to limit prescribing of high-dose opioids. However, this practice change is occurring largely in the absence of data regarding patient outcomes. A 2017 systematic review found inconclusive evidence on the impact of LTOT dose reduction and discontinuation on pain severity and function, quality of life, withdrawal symptoms, substance abuse, and adverse effects. This rapid systematic review provides an updated evidence synthesis of patient outcomes following LTOT dose reduction including serious harms such as overdose and suicide.

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Single center observational study on the role of demoralization and meaning in life in influencing suicidal ideation among patients affected by chronic pain (DEMiL study): A study protocol.

Chronic pain is a significant risk factor for suicidal ideation (SI) and suicidal behavior (SB), including a 20-40% prevalence rate of SI, a prevalence between 5-14% of suicidal attempts (SA), and a doubled risk of death by suicide in patients with chronic pain compared to controls. In most studies, associations between chronic pain and suicidality are robust even after adjusting for the effect of socio-demographics and psychiatric comorbidity, and particularly for depressive conditions. A number of specific conditions that can modulate suicidality risk in patients with chronic pain have been investigated, but there is a need for their more specific characterization. Numerous recent studies have shown that demoralization and Meaning in Life (MiL) constructs affect suicidality, as risk and protective factors, respectively. These constructs have been mainly investigated in patients with somatic illness and in community-dwelling individuals who may present with SI or SB independently of a psychiatric diagnosis of depression. However, a paucity of studies investigated them in suicidal patients affected by chronic pain.

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Blockade of IL-33 signalling attenuates osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis characterised by cartilage degradation, synovitis and pain. Disease modifying treatments for OA are not available. The critical unmet need is to find therapeutic targets to reduce both disease progression and pain. The cytokine IL-33 and its receptor ST2 have been shown to play a role in immune and inflammatory diseases, but their role in osteoarthritis is unknown.

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Associations between Childhood Abuse and Chronic Pain in Adults with Substance Use Disorders.

Both childhood abuse and chronic pain are common in people with substance use disorders (SUDs). Studies have found that exposure to childhood abuse is associated with chronic pain in adulthood; however, few studies have examined this association in people with SUDs. This study aimed to characterize the association between childhood abuse and chronic pain presence and severity in adults with SUDs. Data were obtained from 672 treatment-seeking participants with SUDs on an inpatient detoxification unit. Regression models evaluated whether childhood physical or sexual abuse was associated with the likelihood of chronic pain and severity of several pain-related characteristics: pain catastrophizing, pain severity, and pain interference. Childhood physical and sexual abuse were significantly associated with a greater likelihood of chronic pain in adulthood. In the adjusted analyses, childhood physical abuse was associated with worse pain severity, whereas childhood sexual abuse was associated with greater pain catastrophizing and worse pain interference. Childhood physical and sexual abuse were associated with a greater likelihood of chronic pain in adults with SUDs. Among those with chronic pain, exposure to childhood abuse was associated with a more severe symptom profile, characterized by greater pain severity, more catastrophic interpretations of pain, and more pain-related interference with daily life. People with SUDs and a history of childhood abuse may benefit from screening for pain and interventions to reduce pain catastrophizing. These findings highlight the importance of longitudinal research to understand mechanisms linking childhood abuse exposure to later pain and substance misuse.

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Effects of Procedural Discomfort and Expectation of Benefit on Therapy Continuation in Chronic Migraine Patients Treated With OnabotulinumtoxinA.

OnabotulinumtoxinA (BTX) has become a mainstream treatment for chronic migraine (CM). Patients often have varied expectations for treatment success but little is known about how these initial impressions influence continuation of therapy.

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Basics and recent advances in the pathophysiology of atopic dermatitis.

Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.

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Controlling the “Opioid Epidemic”: A Novel Chemical Entity (NCE) to Reduce or Supplant Opiate Use for Chronic Pain.

We report on the ongoing project "A Novel Therapeutic to Ameliorate Chronic Pain and Reduce Opiate Use." Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world's population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an "epidemic" of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a novel chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. In our initial preclinical studies, we demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain in five animal models. The overall goal of the project is to complete the investigational new drug (IND)-enabling preclinical studies of Kindolor, and once IND approval is gained, we will proceed to the clinical Phase Ia and 1b safety studies and a Phase 2a efficacy study. The work is in its second year, and the present report describes progress toward our overall goal of bringing our compound to a full Phase 2 ready stage.

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Upregulation of μ-Opioid Receptor in the Rat Spinal Cord Contributes to the α2-Adrenoceptor Agonist Dexmedetomidine-Induced Attenuation of Chronic Morphine Tolerance in Cancer Pain.

Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats.

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Diminished corticomotor excitability in Gulf War Illness related chronic pain symptoms; evidence from TMS study.

Chronic diffuse body pain is unequivocally highly prevalent in Veterans who served in the 1990-91 Persian Gulf War and diagnosed with Gulf War Illness (GWI). Diminished motor cortical excitability, as a measurement of increased resting motor threshold (RMT) with transcranial magnetic stimulation (TMS), is known to be associated with chronic pain conditions. This study compared RMT in Veterans with GWI related diffuse body pain including headache, muscle and joint pain with their military counterparts without GWI related diffuse body pain. Single pulse TMS was administered over the left motor cortex, using anatomical scans of each subject to guide the TMS coil, starting at 25% of maximum stimulator output (MSO) and increasing in steps of 2% until a motor response with a 50 µV peak to peak amplitude, defined as the RMT, was evoked at the contralateral flexor pollicis brevis muscle. RMT was then analyzed using Repeated Measures Analysis of Variance (RM-ANOVA). Veterans with GWI related chronic headaches and body pain (N = 20, all males) had a significantly (P < 0.001) higher average RMT (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state. The impact of this observed supraspinal functional impairment on other GWI related symptoms and the potential use of TMS in rectifying this abnormality and providing relief for pain and co-morbid symptoms requires further investigation.Trial registration: This study was registered on January 25, 2017, on ClinicalTrials.gov with the identifier: NCT03030794. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03030794 .

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Habitual sleep disturbances and migraine: a Mendelian randomization study.

Sleep disturbances are associated with increased risk of migraine, however the extent of shared underlying biology and the direction of causal relationships between these traits is unclear. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights and inform subsequent intervention studies. Here, we used genetic approaches to test for shared genetic influences between sleep patterns and migraine, and to test whether habitual sleep patterns may be causal risk factors for migraine and vice versa.

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High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer.

Advanced head and neck cancer (HNC) can invade facial bone and cause bone pain, thus posing a significant challenge to the quality of life of patients presenting with advanced HNC. The present study was designed to investigate HNC bone pain (HNC‑BP) in an intratibial mouse xenograft model that utilized an HNC cell line (SAS cells). These mice develop HNC‑BP that is associated with an expression of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in dorsal root ganglia (DRG) sensory neurons. Our experiments demonstrated that the inhibition of high mobility group box 1 (HMGB1) by short hairpin (shRNA) transduction, HMGB1 neutralizing antibody, and HMGB1 receptor antagonist suppressed the HNC‑BP and the pERK1/2 expression in DRG. It was also observed that HNC‑derived HMGB1 increased the expression of the acid‑sensing nociceptor, transient receptor potential vanilloid 1 (TRPV1), which is a major cause of osteoclastic HNC‑BP in DRG. Collectively, our results demonstrated that HMGB1 originating in HNC evokes HNC‑BP via direct HMGB1 signaling and hypersensitization for the acid environment in sensory neurons.

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Single-cell multi-omics analysis presents the landscape of peripheral blood T-cell subsets in human chronic prostatitis/chronic pelvic pain syndrome.

Cumulative evidence suggests that abnormal differentiation of T lymphocytes influences the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Thus, understanding the immune activation landscape of CP/CPPS would be helpful for improving therapeutic strategies. Here, we utilized BD™ AbSeq to digitally quantify both the protein and mRNA expression levels in single peripheral blood T cells from two CP/CPPS patients and two healthy controls. We utilized an integrated strategy based on canonical correlation analysis of 10 000+ AbSeq profiles and identified fifteen unique T-cell subpopulations. Notably, we found that the proportion of cluster 0 in the CP/CPPS group (30.35%) was significantly increased compared with the proportion in the healthy control group (9.38%); cluster 0 was defined as effector T cells based on differentially expressed genes/proteins. Flow cytometry assays confirmed that the proportions of effector T-cell subpopulations, particularly central memory T cells, T helper (Th)1, Th17 and Th22 cells, in the peripheral blood mononuclear cell populations of patients with CP/CPPS were significantly increased compared with those of healthy controls (P < 0.05), further confirming that aberration of effector T cells possibly leads to or intensifies CP/CPPS. Our results provide novel insights into the underlying mechanisms of CP/CPPS, which will be beneficial for its treatment.

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