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Fibromyalgia syndrome (FMS) is characterized by widespread pain and tenderness, and patients typically experience fatigue and emotional distress. The etiology and pathophysiology of fibromyalgia are not fully explained and there are no effective drug treatments. Here we show that IgG from FMS patients produced sensory hypersensitivity by sensitizing nociceptive neurons. Mice treated with IgG from FMS patients displayed increased sensitivity to noxious mechanical and cold stimulation, and nociceptive fibers in skin-nerve preparations from mice treated with FMS IgG displayed an increased responsiveness to cold and mechanical stimulation. These mice also displayed reduced locomotor activity, reduced paw grip strength, and a loss of intraepidermal innervation. In contrast, transfer of IgG-depleted serum from FMS patients or IgG from healthy control subjects had no effect. Patient IgG did not activate naive sensory neurons directly. IgG from FMS patients labeled satellite glial cells and neurons in vivo and in vitro, as well as myelinated fiber tracts and a small number of macrophages and endothelial cells in mouse dorsal root ganglia (DRG), but no cells in the spinal cord. Furthermore, FMS IgG bound to human DRG. Our results demonstrate that IgG from FMS patients produces painful sensory hypersensitivities by sensitizing peripheral nociceptive afferents and suggest that therapies reducing patient IgG titers may be effective for fibromyalgia.
Learn More >Pain is a complex perceptual phenomenon. Coordinated activity among local and distant brain networks is a central element of the neural underpinnings of pain. Brain oscillatory rhythms across diverse frequency ranges provide a functional substrate for coordinating activity across local neuronal ensembles and anatomically distant brain areas in pain networks. This review addresses parallels between insights from human and rodent analyses of oscillatory rhythms in acute and chronic pain and discusses recent rodent-based studies that have shed light on mechanistic underpinnings of brain oscillatory dynamics in pain-related behaviors. We highlight the potential for therapeutic modulation of oscillatory rhythms, and identify outstanding questions and challenges to be addressed in future research.
Learn More >Projection neurons in the spinal dorsal horn relay sensory information to higher brain centres. The activation of these populations is shaped by afferent input from the periphery, descending input from the brain, and input from local interneuron circuits. Much of our recent understanding of dorsal horn circuitry comes from studies in transgenic mice; however, information on projection neurons is still based largely on studies in monkey, cat, and rat. We used viral labelling to identify and record from mouse parabrachial nucleus (PBN) projecting neurons located in the dorsal horn of spinal cord slices. Overall, mouse lamina I spinoparabrachial projection neurons (SPBNs) exhibit many electrophysiological and morphological features that overlap with rat. Unbiased cluster analysis distinguished 4 distinct subpopulations of lamina I SPBNs, based on their electrophysiological properties that may underlie different sensory signalling features in each group. We also provide novel information on SPBNs in the deeper lamina (III-V), which have not been previously studied by patch clamp analysis. These neurons exhibited higher action potential discharge frequencies and received weaker excitatory synaptic input than lamina I SPBNs, suggesting this deeper population produces different sensory codes destined for the PBN. Mouse SPBNs from both regions (laminae I and III-V) were often seen to give off local axon collaterals, and we provide neuroanatomical evidence they contribute to excitatory input to dorsal horn circuits. These data provide novel information to implicate excitatory input from parabrachial projection neuron in dorsal horn circuit activity during processing of nociceptive information, as well as defining deep dorsal horn projection neurons that provide an alternative route by which sensory information can reach the PBN.
Learn More >To identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways.
Learn More >Fibromyalgia syndrome (FMS) is a highly prevalent, debilitating disease with heterogeneous symptoms of widespread pain and tenderness, fatigue, sleep disturbance, and impaired cognition. The cause of FMS is unknown, but the clinical constellation of symptoms and abnormalities in the neuroendocrine system, autonomic nervous system, and sleep implicate the nervous system in its pathogenesis. In this issue of the JCI, Goebel, Krock, et al. identified antibodies from patients with FMS that produce FMS in mice by binding to satellite glial cells (SGCs), which envelope sensory neurons. Because antibodies harvested from patients with FMS, but not controls, stimulated SGCs to an activated state known to mediate chronic pain by augmenting neuronal activity, these findings reveal a pivotal role for autoreactive IgG in the pathophysiology of FMS. These important findings pave a pathway to study mechanism-based experimental therapeutics targeting IgG titers or antibody binding to SGCs underlying the neuroimmune dysfunction of FMS.
Learn More >Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We did a randomised double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned in a 1:1 ratio to M1 or DLPFC-rTMS and re-randomised in a 2:1 ratio to active or sham rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary endpoint was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (group by time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory (BPI), using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified ITT population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self reported pain intensity and fatigue (patients diary), patient and clinician global impression of change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomised and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for group x session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; p = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI:-0.04 to 0.03, p = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimenson of pain, self reported pain intensity and fatigue, PGIC and CGIC. There were no effect on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups respectively (p = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.
Learn More >Identifying common genetic variants that confer genetic risk for cluster headache.
Learn More >Chronic pain is a leading cause of disability worldwide and its prevalence is likely to increase over the next decades. Treatment for chronic pain remains insufficient and therapeutical advances have not made comparable progress with that for many chronic disorders, thus amplifying the concern on the future burden of the disease. At the same time, and even after decades of intense research, the underlying pathophysiology of chronic pain remains minimally understood. We believe advancing our current understanding of chronic pain requires mechanistically explicit, hypothesis-driven, and clinically focused models. In this review we highlight some of the main findings over the last decades that have contributed to the present knowledge of brain mechanisms of chronic pain, and how such advances were possible due to a reverse translational research approach. We argue that this approach is essential in the chronic pain field, in order to generate new scientific hypotheses, probe physiological mechanisms, develop therapeutic strategies and translate findings back into promising human clinical trials.
Learn More >Postoperative pain management is still insufficient, leading to major deficits, including patient suffering, impaired surgical recovery, long-term opioid intake, and post-surgical chronic pain. Yet, identifying the best treatment options refers to a heterogeneous outcome assessment in clinical trials, not reflecting relevant pain-related aspects after surgery, and therefore hamper evidence synthesis. Establishing a core outcome set for perioperative pain management of acute pain after surgery may overcome such limitations. An international, stepwise consensus process on outcome domains ("what to measure") for pain management after surgery, e.g., after total knee arthroplasty, sternotomy, breast surgery, and surgery related to endometriosis, was performed. The process, guided by a steering committee, involved 9 international stakeholder groups and patient representatives. The face-to-face meeting was prepared by systematic literature searches identifying common outcome domains for each of the 4 surgical procedures and included break-out group sessions, world-café formats, plenary panel discussions, and final voting. The panel finally suggested an overall core outcome set for perioperative pain management with 5 core outcome domains: physical function (in terms of a condition-specific measurement), pain intensity at rest, pain intensity during activity, adverse events, and self-efficacy. Innovative aspects of this work were inclusion of the psychological domain self-efficacy, as well as the specific assessment of pain intensity during activity and physical function recommended to be assessed in a condition-specific manner. The IMI-PROMPT COS seeks to improve assessing efficacy and effectiveness of perioperative pain management in any clinical and observational studies as well as in clinical practice.
Learn More >Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally directed, dendrites, and ventrally directed axons. As under resting conditions, CGRP interneurons are under tonic inhibitory control, neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive Aβ primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. On the other hand, chemogenetic activation of the neurons produced a mechanical hypersensitivity in response to von Frey stimulation, whereas their caspase-mediated ablation led to mechanical hyposensitivity. Finally, after partial peripheral nerve injury, innocuous stimulation (brush) induced significant Fos expression in the CGRP interneurons. These findings suggest that CGRP interneurons become hyperexcitable and contribute either to ascending circuits originating in deep dorsal horn or to the reflex circuits in baseline conditions, but not in the setting of nerve injury.
Learn More >Gabapentin (Neurontin) is prescribed widely for conditions for which it has not been approved by regulators, including certain neuropathic pain conditions. There is limited evidence that gabapentin is safe and effective for the treatment of neuropathic pain. Published trial reports, and systematic reviews based on published trial reports, mislead patients and providers because information about gabapentin's harms has been published only partly. We confirmed that trials conducted by the drug developer have been abandoned, and we plan to conduct a restoration with support from the Restoring Invisible and Abandoned Trials Support Centre (https://restoringtrials.org/).
Learn More >Youth with functional abdominal pain (FAP) experience significant pain-related distress and functional impairment. Although quantitative sensory testing protocols have identified alterations in pain modulatory systems that distinguish youth with FAP from healthy controls, the extent to which evoked pain responses predict subsequent trajectories of pain symptoms and disability over and above established psychosocial risk factors is unclear.
Learn More >The purpose of this study was to evaluate changes in pain intensity among Veterans transitioning from long-term opioid therapy (LTOT) to either intermittent therapy or discontinuation compared to continued LTOT. Pain intensity was assessed using the Numeric Rating Scale in 90-day increments starting in the 90-day period prior to potential opioid transitions and the two ensuing 90-day periods after transition. Primary analyses used a 1:1 greedy propensity matched sample. A total of 29,293 Veterans switching to intermittent opioids and 5,972 discontinuing opioids were matched to Veterans continuing LTOT. Covariates were well balanced after matching except minor differences in baseline mean pain scores. Pain scores were lower in the follow up periods for those switching to intermittent opioids and discontinuing opioids compared to those continuing LTOT (0-90 days: Intermittent: 3.79, 95%CI: 3.76, 3.82; LTOT: 4.09, 95%CI: 4.06, 4.12, p<0.0001; Discontinuation: 3.06, 95%CI: 2.99, 3.13; LTOT: 3.86, 95%CI: 3.79, 3.94, p=<0.0001; 91-180 days: Intermittent: 3.76, 95%CI: 3.73, 3.79; LTOT: 3.99, 95%CI: 3.96, 4.02, p<0.0001; Discontinuation: 3.01, 95%CI: 2.94, 3.09; LTOT: 3.80, 95%CI: 3.73, 3.87, p=<0.0001). Sensitivity analyses found similar results. Discontinuing opioid therapy or switching to intermittent opioid therapy was not associated with increased pain intensity. Perspective: This article evaluates the association of switching to intermittent opioid therapy or discontinuing opioids with pain intensity after using opioids long-term. Pain intensity decreased after switching to intermittent therapy or discontinuing opioids, but remained relatively stable for those continuing long-term opioid therapy. Switching to intermittent opioids or discontinuing opioids was not associated with increased pain intensity.
Learn More >Recently, the FDA approved ubrogepant and rimegepant as oral drugs to treat migraines by targeting the calcitonin-gene related peptide receptor (CGRPR). Unfortunately, there is no high-resolution complex structure with these two drugs; thus the detailed interaction between drugs and the receptor remains elusive. This study uses molecular docking and molecular dynamics simulation to model the drug-receptor complex and analyze their binding interactions at a molecular level. The complex crystal structure (3N7R) of the gepant drugs' predecessor, olcegepant, was used for our molecular docking of the two drugs and served as a control system. The three systems, with ubrogepant, rimegepant, and crystal olcegepant, were subject to 3 × 1000 ns molecular dynamics simulations and followed by the simulation interaction diagram (SID), structural clustering, and MM-GBSA binding energy analyses. Our MD data revealed that olcegepant binds most strongly to the CGRPR, followed by ubrogepant and then rimegepant, largely due to changes in hydrophobic and electrostatic interactions. The order of our MM-GBSA binding energies of these three compounds is consistent with their experimental IC values. SID analysis revealed the pharmacophore of the gepant class to be the dihydroquinazolinone group derivative. Subtle differences in interaction profile have been noted, including interactions with the W74 and W72 residues. The ubrogepant and rimegepant both contact A70 and M42 of the receptor, while olcegepant does not. The results of this study elucidate the interactions in the binding pocket of CGRP receptor and can assist in further development for orally available antagonists of the CGRP receptor.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a somatosensory small fiber axonopathy in cancer patients receiving any of a variety of widely-use antitumor agents. CIPN can lead to long-lasting neuropathic pain that limits the dose or length otherwise life-saving cancer therapy. Accumulating evidence over the last two decade indicates that many chemotherapeutic agents cause mitochondrial injury in the peripheral sensory nerves by disrupting mitochondrial structure and bioenergetics, increasing nitro-oxidative stress and altering mitochondrial transport, fission, fusion and mitophagy. The accumulation of abnormal and dysfunctional mitochondria in sensory neurons are linked axonal growth defects resulting in loss of intraepidermal nerve fibers in the hands and feet, increased spontaneous discharge and the sensitization of peripheral sensory neurons that provoke and promote changes in the central nervous system that establish chronic neuropathic pain. This has led to the propose mitotoxicity theory of CIPN. Strategies that improve mitochondrial function have shown success in preventing and reversing CIPN in pre-clinical animal models and have begun to show some progress toward translation to the clinic. In this review, we will review the evidence for, the causes and effects of and current strategies to target mitochondrial dysfunction in CIPN.
Learn More >Peak alpha frequency (PAF) reduces during cutaneous pain, but no studies have investigated PAF during movement-related muscle pain. Whether high-pain sensitive (HPS) individuals exhibit a more pronounced PAF response to pain than low-pain sensitive (LPS) individuals is unclear. As a pain model, twenty-four participants received nerve growth factor injections into a wrist extensor muscle at Day0, Day2, and Day4. At Day4, a subgroup of twelve participants also undertook eccentric wrist exercise to induce additional pain. Pain numerical rating scale (NRS) scores and electroencephalography were recorded at Day0 (before injection), Day4, and Day6 for 3 minutes (eyes closed) with wrist at rest (Resting-state) and extension (Contraction-state). The average pain NRS scores in contraction-state across Days were used to divide participants into HPS (NRS-scores≥2) and LPS groups. PAF was calculated by frequency decomposition of electroencephalographic recordings. Compared with Day0, contraction NRS-scores only increased in HPS-group at Day4 and Day6 (P<0.001). PAF in Contraction-state decreased in both groups at Day6 compared with Day0 (P=0.011). Across days, HPS-group showed faster PAF than LPS-group during Resting-state and Contraction-state (P<0.04). Average pain NRS-scores across days during Contraction-states correlated with PAF at Day0 (P=0.012). Pain NRS-scores were associated with PAF during Contraction-state at Day4 and Day6 (P<0.05). Perspective: PAF was slowed during long-lasting movement-related pain in both groups, suggesting a widespread change in cortical excitability independent of the pain sensitivity. Moreover, HPS individuals showed faster PAF than LPS individuals during muscle pain, which may reflect a different cognitive, emotional, or attentional response to muscle pain among individuals.
Learn More >While mast cells (MCs) are previously well-known as a pathological indicator of pain, their role in alleviating pain is recently emerged in acupuncture research. Thus, this study systematically reviews the role of MC in acupuncture analgesia. Animal studies on MC changes associated with the acupuncture analgesia were searched in PubMed and EMBASE. The MC number, degranulation ratio and pain threshold changes were collected as outcome measures for meta-analyses. Twenty studies were included with 13 suitable for meta-analysis, most with a moderate risk of bias. A significant MC degranulation after acupuncture was indicated in the normal and was significantly higher in the pain model. In the subgroup analysis by acupuncture type, manual (MA) and electrical (EA, each p < .00001) but not sham acupuncture had significant MC degranulation. Meta-regression revealed the linear proportionality between MC degranulation and acupuncture-induced analgesia (p < .001), which was found essential in MA (p < .00001), but not in EA (p = .45). MC mediators, such as adenosine and histamine, are involved in its mechanism. Taken together, skin MC is an essential factor for acupuncture-induced analgesia, which reveals a new aspect of MC as a pain alleviator. However, its molecular mechanism requires further study. PERSPECTIVE: This systematic review synthesizes data from studies that examined the contribution of skin MC in acupuncture analgesia. Current reports suggest a new role for skin MC and its mediators in pain alleviation and explain a peripheral mechanism of acupuncture analgesia, with suggesting the need of further studies to confirm these findings.
Learn More >Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n=56) and compared them with a pool of age-and sex-matched controls (n=22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (e.g. migraine 4.89 IU ± 0.62 versus controls 4.62 IU ± 0.38; p=0.02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. PERSPECTIVE: This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.
Learn More >Peripheral nerve injury induces a myriad of immune-derived symptoms that negatively impacts pain, depression, and overall quality of life. Neuroimmune differences underlie sexual dimorphisms in various pain states. The innate immune system is a source of these sex differences, which promotes inflammation and pro-nociception through bidirectional signaling with the nervous system. Spatiotemporal interactions between leukocytes and sensory neurons could hold the key to explain ascribed differences between sexes. To date, studies have found it difficult to display these interactions. We are poised to answer important questions regarding the recruitment of peripheral leukocytes to key tissues of the pain system, the dorsal root ganglia (DRG) and sciatic nerve after nerve injury. We optically clear whole DRGs and sciatic nerves and concomitantly use multi-photon microscopy and transgenic reporter lines, to visualize leukocyte dynamics involved in neuropathic pain development following nerve injury. We observed robust sexual dimorphisms in leukocyte recruitment to the lumbar DRGs after nerve injury. We also assessed immune cell size and morphology to understand activation states in the context of nervous tissue inflammation. The altered mechanisms by which the male and female immune systems respond to nerve injury are still topics of further research, however; the continued use of next-generation imaging with advanced whole tissue image analysis remains an important tool in understanding the reciprocal interactions between neuronal and non-neuronal cells.
Learn More >Isolated injuries to the lateral cutaneous nerve (LCNC) branch of the common peroneal nerve can cause obscure chronic posterolateral knee and upper calf pain and sensory symptoms. Routine examination and electrodiagnostic testing do not detect them because the LCNC has no motor distribution and it is not interrogated by typical peroneal nerve conduction study. There are only about 10 prior cases-thus scant physician awareness-so most LCNC injuries remain misdiagnosed or undiagnosed, hindering care.
Learn More >The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl-trinitrate (GTN)-induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level-dependent (BOLD) response to oral glucose ingestion with 3T-functional MRI in 33 women, 16 with migraine without aura and 11 controls group-matched for age and BMI, on one day without prior GTN-administration, and on a second day after GTN-administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN-triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between- and within-group effects. Without prior GTN-infusion, the BOLD-response to glucose was similar in migraine participants and controls (P = 0.41). After prior GTN-infusion, recovery occurred steeper and faster in migraineurs (versus day 1; P < 0.0001) and in those who developed an attack versus those who did not (P < 0.0001). Prior GTN-infusion did not alter the glucose-induced response in controls (versus baseline; P = 0.71). Just before spontaneous attacks, the BOLD-response recovery was also faster (P < 0.0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN-provoked and spontaneous migraine attacks.
Learn More >The calcitonin gene-related peptide (CGRP) system has emerged as a key pharmacological target for the treatment of migraine. However, some individuals who suffer from migraine have low or no response to anti-CGRP or other treatments, suggesting the need for additional clinical targets. CGRP belongs to the calcitonin family of peptides, including calcitonin, amylin, adrenomedullin and adrenomedullin 2. These peptides display a range of pro- and anti-nociceptive actions, including in primary headache conditions such as migraine. Calcitonin family peptides also show expression at sites relevant to migraine and pain. This suggests that calcitonin family peptides and their receptors, beyond CGRP, may be therapeutically useful in the treatment of migraine and other pain disorders. This review considers the localisation of the calcitonin family in peripheral pain pathways and discusses how they may contribute to migraine and pain.
Learn More >Chronic overlapping pain conditions (COPCs) represent a co-aggregation of widespread pain disorders. We characterized differences in physical and psychosocial functioning in patients with chronic migraine (CM) and those with CM and COPCs.
Learn More >Activation of spinal cord microglia contributes to the development of peripheral nerve injury-induced neuropathic pain. However, the molecular mechanisms underlying microglial function in neuropathic pain are not fully understood. We identified that the voltage-gated proton channel Hv1, which is functionally expressed in spinal microglia, was significantly increased after spinal nerve transection (SNT). Hv1 mediated voltage-gated proton currents in spinal microglia and mice lacking Hv1 (Hv1 KO) display attenuated pain hypersensitivities after SNT compared with wildtype (WT) mice. In addition, microglial production of reactive oxygen species (ROS) and subsequent astrocyte activation in the spinal cord was reduced in Hv1 KO mice after SNT. Cytokine screening and immunostaining further revealed that IFN-γ expression was compromised in spinal astrocytes in Hv1 KO mice. These results demonstrate that Hv1 proton channel contributes to microglial ROS production, astrocyte activation, IFN-γ upregulation, and subsequent pain hypersensitivities after SNT. This study suggests Hv1-dependent microglia-astrocyte communication in pain hypersensitivities and identifies Hv1 as a novel therapeutic target for alleviating neuropathic pain.
Learn More >Neuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we described and validated F11 cells as a model of DRG (dorsal root ganglia) neurons. In the current work, we employed F11 cells to identify regulators of antiretroviral-induced neuropathic pain combining functional and transcriptomic analysis. The antiretroviral zalcitabine (ddC) increased the excitability of differentiated F11 cells associated with calcium signaling without morphological changes in the neuronal phenotype, mimicking the observed increase of painful signaling in patients suffering from antiretroviral-induced neuropathic pain. Employing RNA sequencing, we observed that zalcitabine treatment upregulated genes related with oxidative stress and calcium homeostasis. The functional impact of the transcriptomic changes was explored, finding that the exposure to zalcitabine significantly increased intracellular oxidative stress and reduced store-operated calcium entry (SOCE). Because the functional and transcriptomic evidence points toward fundamental changes in calcium signaling and oxidative stress upon zalcitabine exposure, we identified that NAD(P)H quinone dehydrogenase and the sarcoplasmic/endoplasmic reticulum calcium ATPase 3 were involved in zalcitabine-induced hyperexcitability of F11 cells. Overexpression of those genes increases the calcium-elicited hyperexcitability response and reduces SOCE, as well as increases intracellular ROS levels. These data do not only mimic the effects of zalcitabine but also highlight the relevance of oxidative stress and of calcium-mediated signaling in antiretroviral-induced hyperexcitability of sensory neurons, shedding light on new therapeutic targets for antiviral-induced neuropathic pain.
Learn More >Evidence suggests that Δ-tetrahydrocannabinol (Δ-THC), the intoxicating component of cannabis, may cause enduring changes in the structure and function of adolescent brain circuits implicated in nociceptive responding. Yet, whether such changes might persistently disrupt nociceptive behaviors remains unknown. In the present study, we subjected C57BL6/J mice of both sexes to once-daily injections of Δ-THC (5 mg-kg, intraperitoneal) or vehicle throughout adolescence (PND 30-43) and, when the animals had reached adulthood (PND 70), assessed nociceptive behavior using the formalin and chronic constriction injury (CCI) tests. We also investigated, using the tail immersion test, the antinociceptive effects of morphine and the development of tolerance to such effects. The results show that adolescent Δ-THC exposure does not significantly impair nociceptive responding or morphine-related antinociception and tolerance. The findings suggest that frequent exposure to a moderate dose of Δ-THC during adolescence does not permanently alter nociceptive circuits in male or female mice. The endocannabinoid system serves critical functions in the central and peripheral nervous systems, including regulation of pain, and can be modified by prolonged exposure to the intoxicating constituent of cannabis, Δ-tetrahydrocannabinol (Δ-THC). This raises the possibility that regular use of Δ-THC-containing cannabis during adolescence might cause changes in nociception that persist into adulthood. We found that frequent early-life exposure to a moderate dose of Δ-THC does not permanently alter nociceptive function in male or female mice.
Learn More >Human immunodeficiency virus (HIV) infection and antiretroviral therapy can independently induce HIV-associated neuropathic pain (HIV-NP). There is a dearth of drugs or therapeutic modalities that can alleviate HIV-NP. Smoked cannabis has been reported to improve pain measures in patients with neuropathic pain. Cannabis, phytocannabinoids, and the endocannabinoids such N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), produce some of their effects via cannabinoid receptors (CBRs). Endocannabinoids are degraded by various enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase. We searched PubMed, Google Scholar, clinicaltrials.gov and clinicaltrialsregister.eu using various key words and their combinations for published papers that studied HIV-NP and cannabis, cannabinoids, or endocannabinoids up to 27th December 2020. All original research articles that evaluated the efficacy of molecules that modulate the endocannabinoid system (ECS) for the prevention and/or treatment of pain in HIV-NP animal models and patients with HIV-NP were included. The PubMed search produced a total of 117 articles, whereas the Google Scholar search produced a total of 9467 articles. Amongst the 13 articles that fulfilled the inclusion criteria 11 articles were found in both searches whereas 2 articles were found in Google Scholar only. The clinicaltrials.gov and clinicaltrialsregister.eu searches produced five registered trials of which three were completed and with results. Ten preclinical studies found that the endocannabinoids (2-AG and AEA), synthetic mixed CB1R/CB2R agonist WIN 55,212-2, a CB2R-selective phytocannabinoid β-caryophyllene, synthetic CB2R-selective agonists (AM1710, JWH015, JWH133 and Gp1a, but not HU308); FAAH inhibitors (palmitoylallylamide, URB597 and PF-3845) and a drug combination of indomethacin plus minocycline, which produces its effects in a CBR-dependent manner, either prevented the development of and/or attenuated established HIV-NP. Two clinical trials demonstrated greater efficacy of smoked cannabis over placebo in alleviating HIV-NP, whereas another clinical trial demonstrated that cannabidivarin, a cannabinoid that does not activate CBRs, did not reduce HIV-NP. The available preclinical results suggest that targeting the ECS for prevention and treatment of HIV-NP is a plausible therapeutic option. Clinical evidence shows that smoked cannabis alleviates HIV-NP. Further research is needed to find out if non-psychoactive drugs that target the ECS and are delivered by other routes than smoking could be useful as treatment options for HIV-NP.
Learn More >Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved.
Learn More >Circadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases.
Learn More >Interdisciplinary treatment (IDT) is an internationally recommended intervention for chronic pain, despite inconclusive evidence of its effects on sickness absence.
Learn More >To investigate the current headache medicine education paradigm in allopathic and osteopathic medical schools in the United States and Canada.
Learn More >This systematic review synthesized evidence about the relationship between childhood bullying victimization and chronic pain, with a focus on the temporal nature of the relationship and moderating factors, such as the type and intensity of victimization.
Learn More >Opioid doctor shopping has not yet been investigated in patients followed in tertiary care settings. This study aimed at assessing the prevalence of opioid doctor shopping among patients with chronic non-cancer pain (CNCP) (ie, pain lasting ≥3 months) attending multidisciplinary pain clinics in Quebec, Canada.
Learn More >Legalization of cannabidiol (CBD) products has ignited interest in clinical practice and research. One desired indication includes possible pain-relieving effects of CBD. The purposes of the current article are to (1) clarify terminology relevant to cannabinoids; (2) explain and understand the pharmacotherapeutics of CBD; (3) examine research of the current use of CBD by older adults for treating pain; (4) discuss safety considerations with using CBD products; and (5) provide best practice recommendations for clinicians as they advise their older adult patients. A review of the literature demonstrated mixed results on the efficacy of CBD in relieving pain in older adults. There is inconsistency in the labeling of over-the-counter CBD products that can result in safety issues and will require more federal quality control. Likewise, gaps in knowledge regarding safety and efficacy of CBD use in older adults are vast and require further research. [(7), 6-15.].
Learn More >The involvement of intervertebral disc (IVD) tissues, whole blood (WB) cytokines, and chemokines in pain in patients with lumbar degenerative disc disease (LDD) is unknown. We investigated the relationships between inflammatory cytokines and chemokines in human IVD tissues and WB samples and their association with pain. Expression levels of chemokines and cytokine gene expression were measured in samples from 20 patients with LDD and compared between IVD tissues and WB samples. The associations between WB chemokine and cytokine gene expression levels and pain intensity (numeric rating scale) were also analyzed. The mRNA of CCL20, CCR6, IL-6, IL-1β, IL-17, and TNF-α was expressed in degenerated IVD tissues. Pearson's product-moment correlation analysis produced positive correlations between CCR6 and IL-6 expression levels in IVD tissues (r = 0.845, P < .001) and WB samples (r = 0.963, P < .001). WB IL-6 and CCR6 mRNA expression levels correlated significantly with present pain, maximum pain, and average pain. By contrast, low back pain did not correlate with serum chemokine/cytokine expression. This is the first study to report correlations between chemokine and inflammatory cytokine gene expression levels in IVD tissues and WB samples in patients with LDD in relation to pain intensity. WB CCR6 and IL-6 gene expression levels correlated significantly with present pain, maximum pain, and average pain, but not with LBP. These data provide a new understanding of the role of chemokines and inflammatory cytokines in patients with LDD and may lead to new treatment strategies for pain. This article is protected by copyright. All rights reserved.
Learn More >: Chronic pain affects one in five persons and is a leading contributor to years lived with disability and high health care costs. In 2016, the government of Ontario increased public funding for pediatric and adult hospital-based interprofessional chronic pain clinics (HICPCs) in Ontario, Canada, expanding the role of physiotherapy in chronic pain management in the province. This role has yet to be described in the literature. : The aim of this study was to explore physiotherapy practice within HICPCs in Ontario. : We conducted an interpretive description qualitative study based on semistructured interviews with physiotherapists employed in pediatric and adult HICPCs in Ontario. Interviews were audio recorded, transcribed verbatim, and reviewed for accuracy. We analyzed interview data using thematic analysis. : Ten physiotherapists who practiced in pediatric and adult HICPCs ( = 4 pediatric; = 6 adult) in Ontario were interviewed between February and April 2020. We constructed five themes related to physiotherapy practice in this setting. Themes included (1) contributing a functional lens to care; (2) empowering through pain education; (3) facilitating participation in physical activity and exercise; (4) supporting engagement in self-management strategies; and (5) implementing a collaborative approach to whole-person care. : Our results illuminate how physiotherapy practice within HICPCs in Ontario focuses on providing a collaborative and whole-person approach to care, with an emphasis on supporting patients to increase their functional capacity by promoting engagement in active chronic pain management strategies.
Learn More >Musculoskeletal pain is a significant contributor to the global disease burden. Management of musculoskeletal pain where a neuropathic component is present can be challenging. This study evaluated the internal structure of the PROMIS® pain quality scales, explored the prevalence of neuropathic and nociceptive pain, and identified health demographics and behaviours related to musculoskeletal pain presentations.
Learn More >: The opioid overdose epidemic has led health care providers to increased vigilance for opioid-related risks in the treatment of chronic non-cancer pain (CNCP). Media have conveyed stigmatizing representations of opioid analgesics. This study aimed to understand how the opioid overdose epidemic has impacted health care experiences among people living with CNCP in two Canadian provinces (British Columbia, Quebec). This qualitative study proceeded through 22 semi-structured interviews conducted in 2019. Participants were recruited from a cross-sectional survey examining the effects of the opioid overdose epidemic on individuals with CNCP. We collected in-depth narratives that we analyzed using a thematic framework. The sample included 12 women and 10 men aged 20 to 70 years, with 11 from each province. Several participants described increased difficulty in accessing medical services for pain since the onset of the opioid overdose epidemic. They reported that some physicians urged them to taper opioids regardless of their pain severity and functional limitations. Some participants reported facing discrimination and care denials as they were labeled "drug-seeking," especially in hospital. Depending on their educational resources, they were unequally able to counter providers' stigmatizing behaviors. However, participants described empathetic relationships with providers with whom they had a long-term relationship. Some participants drew distinctions between themselves and the stigmatized status of "addict" in ways that reinforced stigma toward people who are dependent on opioids. Health policies and provider education programs aimed at reducing opioid-related stigma are needed to counter detrimental consequences of the opioid overdose epidemic for people living with CNCP.
Learn More >Recent evidence suggests that pain dampens attentional processes. However, much of this work has been based on higher-order attentional tasks that involve only spatial attention. Other aspects of the process through which pain engages and holds attention are relatively understudied, in particular, temporal attention. The present set of studies explored how naturally occurring pain (i.e., acute headache) and pain-valenced stimuli affect ability to recall the second of two targets presented in rapid succession. Across both experiments participants were required to indicate the presence of a predefined probe (T2) and, in the dual task, identify a target (T1). The probe (T2) was placed in three different temporal proximities (ranging from 70ms to 1000ms) following presentation of the target (T1). In experiment 1, thirty-six participants completed a task that comprised a rapid stream of letters. Experiment 2 manipulated the threat value, and the complexity, of the stimuli by replacing letters with words. In the dual task condition, T1 was a word from one of four affect categories (neutral, positive, negative, pain). Being in acute pain reduced the accuracy of identification. This reduction in performance occurred regardless of the temporal positioning of the probe consistent with previous work that suggests pain has an overall dampening effect. Further, when the affect category of the word was pain-related, T2 accuracy performance was negatively affected. These findings add to the previous evidence that pain has a general dampening effect on attention and that pain-related stimuli are difficult to disengage from.
Learn More >Disruptions caused by the COVID-19 pandemic could disproportionately affect the health of vulnerable populations, including patients experiencing persistent health conditions (i.e., chronic pain), along with populations living within deprived, lower socioeconomic areas. The current cross-sectional study characterized relationships between neighborhood deprivation and perceived changes in pain-related experiences during the COVID-19 pandemic (early-September to mid-October 2020) for adult patients (N = 97) with nonspecific chronic low back pain.
Learn More >This study evaluated the association between pain outcomes and post-traumatic stress disorder (PTSD) symptom trajectories after combat-related injury, while adjusting for receipt of regional anesthesia (RA) soon after injury.
Learn More >This study sought to evaluate if actively informing new chronic pain patients about treatment options and setting realistic expectations for care, through the use of a pre-visit informational handout prior to the first clinic visit, improved patient satisfaction with subsequently proposed treatment plans.
Learn More >Alloknesis, an abnormal itch sensation induced by innocuous stimuli, is a key phenomenon in the vicious itch-scratch cycle in patients with atopic dermatitis. Dry skin and pruritus, including alloknesis, are major health problems in peri- and post-menopausal women. We recently reported permeability barrier dysfunction in ovariectomised (OVX) mice-a model of menopause-and found that the dysfunction was related to dry skin. However, the mechanism of the itch remains unknown. Therefore, we examined touch- and pruritogen-evoked alloknesis and epidermal innervation in OVX mice and acetone, diethyl ether, and water (AEW)-treated mice, for the experimental dry skin model. Both alloknesis and epidermal innervation were comparable in OVX and AEW mice. Neutralising antibodies against IL-4 and IL-13 inhibited alloknesis in both OVX and AEW mice as early as 30 min after intradermal administration. Comparable values close to the measurement limit of IL-4 were found in the skin of HRT and Sham mice as well as AEW and the control mice, but the levels of IL-4 were within the measurement limit in OVX mice. We could not detect mRNAs of IL-4 or IL-13 in any groups of mice. On the other hand, the number of eosinophils and basophils was increased in OVX and AEW mice. These results suggest that impaired barrier function in cooperation with type 2 cytokines derived from eosinophils and basophils in the skin or with endogenous type 2 cytokine may trigger the development of alloknesis, and thus, these cytokines could be a therapeutic target for sensitive skin.
Learn More >Peripheral neuropathic pain (pNeP) is prevalent, and current treatments, including drugs and motor cortex repetitive transcranial magnetic stimulation (rTMS) leave a substantial proportion of patients with suboptimal pain relief.
Learn More >In 2016, the Center for Disease Control and Prevention released an opioid prescribing guideline for primary care in response to opioid overdose deaths. Despite efforts to encourage safer prescribing practices, experts and federal agencies suspect prescribing guidelines may be misapplied in clinical practice, resulting in abrupt tapering from opioid therapy. Although state laws likely influence prescriber behavior, little is known about state tapering laws. Thus, we examined the scope and variation of state tapering laws compared with federal opioid guidelines.
Learn More >Multicentre cross-sectional study.
Learn More >A qualitative study of patients' experiences and the impacts of peer support groups that patients maintained after UK NHS group pain management programmes (PMPs).
Learn More >Baricitinib previously demonstrated improvements in itch and sleep disturbance versus placebo in adults with moderate-to-severe atopic dermatitis (AD).
Learn More >Itch, the most bothersome symptom in atopic dermatitis, is largely mediated by pruritogenic cytokines via Janus kinase 1 signaling in cutaneous sensory neurons.
Learn More >Obesity has been associated with increased chronic pain susceptibility but causes are unclear. In this review, we systematize and analyze pain outcomes in rodent models of obesity as these can be important tools for mechanistic studies. Studies were identified using MEDLINE/PubMed and Scopus databases using the following search query: (((pain) OR (nociception)) AND (obesity)) AND (rat OR (mouse) OR (rodent))). From each eligible record we extracted the following data: species, strain, sex, pain/obesity model and main behavioral readouts. Out of 695 records 33 were selected for inclusion. 27 studies assessed nociception/acute pain and 17 studies assessed subacute or chronic pain. Overall genetic and dietary models overlapped in pain-related outcomes. Most acute pain studies reported either decreased or unaltered responses to noxious painful stimuli. However, decreased thresholds to mechanical innocuous stimuli, i.e. allodynia, were frequently reported. In most studies using subacute and chronic pain models, namely of subcutaneous inflammation, arthritis and perineural inflammation, decreased thresholds and/or prolonged pain manifestations were reported in obesity models. Strain comparisons and longitudinal observations indicate that genetic factors and the time course of the pathology might account for some of the discrepancies observed across studies. Two studies reported increased pain in animals subjected to high fat diet in the absence of weight gain. Pain-related outcomes in experimental models and clinical obesity are aligned indicating that the rodent can be an useful tool to study the interplay between diet, obesity and pain. In both cases weight gain might represent only a minor contribution to abnormal pain manifestation.
Learn More >Data defining and subsequently guiding the use of psychotropic medications in children and adolescents is sparse. We conducted a meta-analysis of randomized control trials to examine the effectiveness of psychotropic medications in children and adolescents with chronic pain.
Learn More >It is known that chronic pain makes it difficult to lose weight, but it is unknown whether obese patients (body mass index ≥30 kg/m) who experience significant pain relief after interdisciplinary multimodal pain rehabilitation (IMMPR) lose weight.
Learn More >Migraine is often accompanied with chronic tinnitus that will affect the cerebral blood flow (CBF) and exacerbate the tinnitus distress. However, the potential relationship between migraine and tinnitus remains unclear. This study will investigate whether aberrant CBF patterns exist in migraine patients with tinnitus and examine the influence of migraine on CBF alterations in chronic tinnitus.
Learn More >Satellite glial cells (SGC) surrounding neurons in sensory ganglia can buffer extracellular potassium, regulating the excitability of injured neurons and possibly influencing a shift from acute to neuropathic pain. SGC apoptosis may be a key component in this process. This work evaluated induction or enhancement of apoptosis in cultured trigeminal SGC following changes in intracellular potassium [K]ic.
Learn More >Study of intraepidermal nerve fiber density (IENFD) by skin biopsy represents a promising tool in the evaluation of patients with ATTRv polyneuropathy (ATTRv-PN). Herein, we retrospectively analyze intraepidermal innervation and quantitative sensory test (QST) data from an Italian cohort of Italian ATTRv-PN patients and asymptomatic carriers aimed to provide insights into early nerve pathological and functional changes in this disease.
Learn More >: Much is known about the impact of pain in terms of medical costs and missed work. Less is known about its associations when individuals are present for work. This study examines "presenteeism" by analyzing the psychosocial costs of pain in the workplace, using the 2015 European Working Conditions Survey (EWCS). : We conducted cross-sectional analysis of 2384 individuals with chronic pain and 2263 individuals without pain (matched by age and sex) using data from the 2015 EWCS. We compared groups in terms of the following psychosocial factors: supervisor support, job responsibility, team cohesion, discrimination, threats/abuse, job competency, job reward, sexual harassment, stress, and job security. The groups were also compared in terms of days lost due to illness. : People with pain were 64% less likely to view their job as rewarding (odds ratio [OR] = 0.61; 95% confidence interval [CI], 0.57-0.65), 47% more likely to be subjected to threats/abuse in the workplace (OR = 0.68; 95% CI, 0.63-0.73), 30% more likely to report poor supervisor support (OR = 0.77; 95% CI, 0.73-0.82), and 28% more likely to perceive discrimination in the workplace (OR = 0.78; 95% CI, 0.71-0.85). People with pain missed approximately nine more days of work per year than respondents without pain. : Chronic pain was associated with lower vocational fulfillment and feelings of being ostracized in the workplace. These findings suggest that the presence of pain in the workplace goes well beyond lost productivity due to absenteeism.
Learn More >Given the national opioid crisis, post-operative analgesia at discharge must be thoughtfully prescribed. Data, specifically related to thoracic procedures, remains scarce. This study assesses adequacy of pain control with standardized and limited opioids after thoracic procedures.
Learn More >There is an unmet need for new efficacious, well-tolerated, acute treatments for migraine in adolescents. Remote electrical neuromodulation (REN) is a novel, non-pharmacological treatment, that provides significant symptom relief with good tolerability. The current post-hoc analysis compared the efficacy of REN to that of standard-care medications, for the acute treatment of migraine in adolescents.
Learn More >: This study explored the heterogeneity of Canadian Armed Forces veterans living with chronic pain to inform service needs planning and research using cluster analysis. : We used a national cross-sectional Statistics Canada population survey. : Participants included 2754 Canadian Armed Forces (CAF) Regular Force veterans released from service between 1998 and 2015 and surveyed in 2016. : We used cluster analysis of veterans with chronic pain based on pain severity, mental health, and activity limitation characteristics. We compared clusters for sociodemographic, health, and service utilization characteristics. : Of 2754 veterans, 1126 (41%) reported chronic pain. Veterans in cluster I (47%) rarely had severe pain (2%) or severe mental health problems (8%), and none had severe activity limitations. Veterans in cluster II (26%) more often than veterans in cluster I but less often than veterans in cluster III endorsed severe pain (27%) and severe mental health problems (22%) and were most likely to report severe activity limitation (91%). Veterans in cluster III (27%) were most likely to report severe pain (36%) and severe mental health problems (96%), and a majority reported severe activity limitations (72%). There was evidence of considerable heterogeneity among individuals in terms of socioeconomic characteristics, pain characteristics, mental and physical health status, activity limitations, social integration, and service utilization indicators. : About half of Canadian veterans living with chronic pain infrequently endorse severe pain or serious mental health issues without severe activity limitations. The other half had more complex characteristics. The heterogeneity of CAF veterans with chronic pain emphasizes the need for support systems that can address variability of needs.
Learn More >Transient receptor potential vanilloid type 3 (TRPV3) is a Ca permeable nonselective cation channel and expressed abundantly in skin keratinocytes. TRPV3 emerges as an attractive target for treatment of pruritic, inflammatory, pain and skin-related diseases. However, only a few reports of TRPV3 inhibitors exist at present besides some patents. Therefore, TRPV3 research has always been fraught with challenges. Through a combination of virtual screening and biological evaluation, compound P1 (10 μM) was identified as a top hit with 34.5% inhibitory effect on 2-APB (1 mM)-evoked currents of mTRPV3-WT. Further structural optimization provided the inhibitor PC5 with the best activity (IC = 2.63 ± 0.28 μM), and point mutation assays indicated that amino acids V629 and F633 are crucial for the binding of PC5 and TRPV3. In summary, these newly discovered inhibitors could serve as promising lead compounds for the development of TRPV3 inhibitors in the future.
Learn More >In spite of the relevance of daily function in individuals with chronic pain, few questionnaires have been designed to assess this domain in individuals with musculoskeletal pain. In addition, the Impairment and Functioning Inventory (IFI-R) is the only instrument that assesses perceived decreases in levels of daily activity after the onset of pain.
Learn More >Concomitant with expanded legalization, cannabis is increasingly used to treat chronic pain among persons with HIV (PWH), despite equivocal benefit in research limited by small sample sizes and short duration of follow-up. To address these limitations, among a sample of PWH with pain interference enrolled in the Veterans Aging Cohort Study, we performed a target trial emulation study to compare the impact of four cannabis use strategies on pain interference. Among those receiving long-term opioid therapy (LTOT), we also explored impact of these strategies on ≥ 25% LTOT dose reduction. Among the analytic sample ( = 1284), the majority were men with a mean age of 50. Approximately 31% used cannabis and 12% received LTOT at baseline. Adjusting for demographic and clinical factors, cannabis use in any of 4 longitudinal patterns was not associated with resolved pain interference over 12- to 24-month follow-up. Among 153 participants receiving LTOT at baseline, cannabis use at both baseline and follow-up was negatively associated with LTOT dose reduction compared to no use at both baseline and follow-up. These findings support other observational studies finding no association between cannabis use and improved chronic pain or LTOT reduction among PWH.
Learn More >The General Health Questionnaire 12 (GHQ-12) is a short easy-to-use scale to assess psychological distress. The GHQ-12 has not been validated for assessing psychological distress in patients with chronic low back pain (LBP).
Learn More >Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (K ) channels. Here, we investigated the effect of the K channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.
Learn More >: Irritable Bowel Syndrome (IBS) and Migraine are two diseases featuring high prevalence. Previous studies have suggested a relationship between IBS and migraine, although the causal association remains unclear. The authors sought to explore the causal association between IBS and migraine, and to show the importance of migraine prevention in IBS patients.
Learn More >Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.
Learn More >The misuse of opioids has led to an epidemic in recent times. The endothelin A receptor (ETAR) has recently attracted attention as a novel therapeutic target to enhance opioid analgesia. We hypothesized that endothelin A receptors may affect pain mechanisms by heterodimerization with μ opioid receptors. We examined the mechanisms of ETAR-mediated pain and the potential therapeutic effects of an ETAR antagonist, Compound-E, as an agent for analgesia.
Learn More >Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain or discomfort. Previous studies have illustrated that the gut microbiota might play a critical role in IBS, but the conclusions of these studies, based on various methods, were almost impossible to compare, and reproducible microorganism signatures were still in question. To cope with this problem, previously published 16S rRNA gene sequencing data from 439 fecal samples, including 253 IBS samples and 186 control samples, were collected and processed with a uniform bioinformatic pipeline. Although we found no significant differences in community structures between IBS and healthy controls at the amplicon sequence variants (ASV) level, machine learning (ML) approaches enabled us to discriminate IBS from healthy controls at genus level. Linear discriminant analysis effect size (LEfSe) analysis was subsequently used to seek out 97 biomarkers across all studies. Then, we quantified the standardized mean difference (SMDs) for all significant genera identified by LEfSe and ML approaches. Pooled results showed that the SMDs of nine genera had statistical significance, in which the abundance of , and in IBS were higher, while the dominant abundance genera of healthy controls were Ruminococcaceae , , , and . In summary, based on six published studies, this study identified nine new microbiome biomarkers of IBS, which might be a basis for understanding the key gut microbes associated with IBS, and could be used as potential targets for microbiome-based diagnostics and therapeutics.
Learn More >Neuropathic pain (NP) is a devastating chronic pain condition affecting roughly 80% of the spinal cord injury (SCI) patient population. Current treatment options are largely ineffective and neurophysiological mechanisms of NP are not well-understood. Recent studies in neuroimaging have suggested that NP patients have differential patterns of functional activity that are dependent upon the neurological condition causing NP. We conducted an exploratory pilot study to examine functional activation and connectivity in SCI patients with chronic NP compared to SCI patients without NP. We developed a novel somatosensory attention task to identify short term fluctuations in neural activity related to NP vs. non-painful somatosensation using functional magnetic resonance imaging (fMRI). We also collected high-resolution resting state fMRI to identify connectivity-based correlations over time between the two groups. We observed increased activation during focus on NP in brain regions associated with somatosensory integration and representational knowledge in pain subjects when compared with controls. Similarly, NP subjects showed increased connectivity at rest in many of the same areas of the brain, with positive correlations between somatomotor networks, the dorsal attention network, and regions associated with pain and specific areas of painful and non-painful sensation within our cohort. Although this pilot analysis did not identify statistically significant differences between groups after correction for multiple comparisons, the observed correlations between NP and functional activation and connectivity align with hypotheses regarding pain, and provide a well-controlled preliminary basis for future research in this severely understudied patient population. Altogether, this study presents a novel task, identifies regions of increased task-based activation associated with NP after SCI in the insula, prefrontal, and medial inferior parietal cortices, and identifies similar regions of increased functional connectivity associated with NP after SCI in sensorimotor, cingulate, prefrontal, and inferior medial parietal cortices. This, along with our complementary results from a structurally based analysis, provide multi-modal evidence for regions of the brain specific to the SCI cohort as novel areas for further study and potential therapeutic targeting to improve outcomes for NP patients.
Learn More >Bone cancer pain (BCP) was associated with microRNA dysregulation. In this study, we intended to clarify the potential role of miR-135-5p in a BCP mouse model, which was established by tumor cell implantation (TCI) in the medullary cavity of the mouse femur. The BCP-related behaviors were tested, including the paw withdrawal mechanical threshold (PWMT) and number of spontaneous flinches (NSF). The miRNA expression profiles in astrocytes of the sham and tumor groups were compared, and miRNA microarray and quantitative real-time PCR (qRT-PCR) assays confirmed that the amount of expression of miR-135-5p was significantly decreased in astrocytes of the tumor group. Gain- and loss-of-function studies showed that miR-135-5p could inhibit astrocyte activation and inflammation cytokine (TNF-α and IL-1β) expression. The relation between miR-135-5p and JAK2 was detected by bioinformatic analysis and dual luciferase reporter gene assay. By conducting in vitro experiments, it was shown that the miR-135-5P mimics lowered the level of JAK2/STAT3 proteins and inflammatory factors in astrocytes. Moreover, in vivo analysis on BCP mice model indicated that the miR-135-5p agonist could sufficiently increase PWMT and decrease NSF. Meanwhile, reduced activation of astrocytes in the spinal cord, as well as decreased expression of JAK2/STAT3 and inflammatory mediators, were found after miR-135-5p agonist treatment. Collectively, the results showed that miR-135-5p could potentially reduce BCP in mice through inhibiting astrocyte-mediated neuroinflammation and blocking of the JAK2/STAT3 signaling pathway, indicating that the upregulation of miR-135-5P could be a therapeutic focus in BCP treatment.
Learn More >Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σR), a unique Ca-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N-methyl-d-aspartate receptor (NMDAR) and cannabinoid 1 receptor (CBR). Overwhelming pharmacological and genetic evidence indicates that σR antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σRs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σR antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σR antagonism represents a promising avenue for the development of potent and safer analgesics.
Learn More >Drosophila Class IV neurons are polymodal nociceptors that detect noxious mechanical, thermal, optical and chemical stimuli. Escape behaviors in response to attacks by parasitoid wasps are dependent on Class IV cells, whose highly branched dendritic arbors form a fine meshwork that is thought to enable detection of the wasp's needle-like ovipositor barb. To understand how mechanical stimuli trigger cellular responses, we used a focused 405-nm laser to create highly local lesions to probe the precise position needed to evoke responses. By imaging calcium signals in dendrites, axons, and soma in response to stimuli of varying positions, intensities and spatial profiles, we discovered that there are two distinct nociceptive pathways. Direct stimulation to dendrites (the contact pathway) produces calcium responses in axons, dendrites and the cell body whereas stimulation adjacent to the dendrite (the non-contact pathway) produces calcium responses in the axons only. We interpret the non-contact pathway as damage to adjacent cells releasing diffusible molecules that act on the dendrites. Axonal responses have higher sensitivities and shorter latencies. In contrast, dendritic responses have lower sensitivities and longer latencies. Stimulation of finer, distal dendrites leads to smaller responses than stimulation of coarser, proximal dendrites, as expected if the contact response depends on the geometric overlap of the laser profile and the dendrite diameter. Because the axon signals to the CNS to trigger escape behaviors, we propose that the density of the dendritic meshwork is high not only to enable direct contact with the ovipositor, but also to enable neuronal activation via diffusing signals from damaged surrounding cells. Dendritic contact evokes responses throughout the dendritic arbor, even to regions distant and distal from the stimulus. These dendrite-wide calcium signals may facilitate hyperalgesia or cellular morphological changes following dendritic damage.
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