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Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis.
Learn More >Pain is a multi-dimensional experience of sensory-discriminative, cognitive, and affective processes; however, current basic research methods rely heavily on response to threshold stimuli, bypassing the supraspinal processing that ultimately gives rise to the pain experience. We developed the Operant Planter Thermal Assay (OPTA), which utilizes a novel, conflict-based operant task requiring evaluation and active decision making to obtain reward under thermally aversive conditions to quantify thermal pain tolerance. In baseline measures, male and female mice exhibited similar temperature preferences, however in the OPTA, female mice exhibited greater temperature-dependent tolerance, as defined by choice time spent in an adverse thermal condition to obtain reward. Increasing reward salience (4% vs 10% sucrose solution) led to increased thermal tolerance for males but not females. To determine whether neuropathic and inflammatory pain models alter thermal tolerance, animals with chronic constriction injury (CCI) or complete Freund's adjuvant (CFA), respectively, were tested in the OPTA. Surprisingly, neuropathic animals exhibited increased thermal tolerance, as shown by greater time spent in the reward zone in an adverse thermal condition, compared with sham animals. There was no effect of inflammation on thermal tolerance. Administration of clonidine in the CCI model led to increased thermal tolerance in both injured and sham animals. In contrast, the non-steroidal anti-inflammatory meloxicam was anti-hyperalgesic in the CFA model, but reduced thermal pain tolerance. These data support the feasibility of utilizing the OPTA to assess thermal pain tolerance to gain new insights into complex pain behaviors and to investigate novel aspects of analgesic efficacy. The translation of novel pain management techniques has been hindered, in part, by reliance on pre-clinical models that do not to measure the multi-dimensional experience of pain. Here we present a novel device and protocol to assess pain tolerance in the mouse. We show that pain tolerance is a dynamic behavior influenced by sex, that hypersensitivity does not necessarily predict pain tolerance, and that analgesics that reduce hypersensitivity may not enhance pain tolerance. This approach increases the capability to pursue new directions in basic pain research.
Learn More >Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABARs and by an α1-to-α2GABAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAR-subtypes and restoring Cl homeostasis.
Learn More >Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis are long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer induced bone pain (CIBP). Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activate CB1 and CB2 receptors inhibiting inflammation and pain. We demonstrate that administration of MJN110 significantly and dose-dependently alleviates spontaneous pain behavior during acute administration compared to vehicle control. In addition, the MJN110 maintains its efficacy in a chronic dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose dependent and significant decrease in cell viability of 66.1 breast adenocarcinoma cells and to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden evidenced by radiograph or histological analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer induced bone pain. SIGNIFICANCE STATEMENT: Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non-opioid based therapies is essential and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone.
Learn More >Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants.
Learn More >To evaluate the efficacy of ubrogepant on patient-reported functional disability, satisfaction with study medication, and global impression of change.
Learn More >Globally, it is estimated that one in five people suffer from chronic pain, with prevalence increasing with age. The pathophysiology of chronic pain encompasses complex sensory, immune, and inflammatory interactions within both the central and peripheral nervous systems. Microglia, the resident macrophages of the central nervous system (CNS), are critically involved in the initiation and persistence of chronic pain. Microglia respond to local signals from the CNS but are also modulated by signals from the gastrointestinal tract. Emerging data from preclinical and clinical studies suggest that communication between the gut microbiome, the community of bacteria residing within the gut, and microglia is involved in producing chronic pain. Targeted strategies that manipulate or restore the gut microbiome have been shown to reduce microglial activation and alleviate symptoms associated with inflammation. These data indicate that manipulations of the gut microbiome in chronic pain patients might be a viable strategy in improving pain outcomes. Herein, we discuss the evidence for a connection between microglia and the gut microbiome and explore the mechanisms by which commensal bacteria might influence microglial reactivity to drive chronic pain.
Learn More >The role of immune mediators, including pro-inflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel up-regulated IL-20 via dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.
Learn More >This clinical trial evaluated the independent and combined effects of a tricyclic antidepressant (desipramine) and cognitive behavioral therapy (CBT) for chronic back pain relative to an active placebo treatment. Participants (n=142) were patients experiencing daily chronic back pain at an intensity of ≥4/10 who were randomized to a single center, double blind, 12-week, four-arm, parallel groups controlled clinical trial of: 1) low concentration desipramine titrated to reach a serum concentration level of 15-65 ng/ml; 2) CBT and active placebo medication (benzotropine mesylate, 0.125mg); 3) low concentration desipramine and CBT; and 4) active benztropine placebo medication. Participants completed the Differential Description Scale and Roland-Morris Disability Questionnaires pre and post-treatment as validated measures of outcomes in back pain intensity and disability, respectively. Participants within each condition showed significant reductions from pre to post-treatment in pain intensity (mean changes ranged from = -2.58-3.87, Cohen's d's = 0.46-0.84) and improvements in pain disability (mean changes = -3.04-4.29, Cohen's d's = 0.54-0.88). However, intent-to-treat analyses at post-treatment showed no significant differences between any condition, with small effect sizes ranging from .06-.27. The results from this clinical trial did not support the hypothesis that desipramine, CBT, or their combination would be statistically superior to an active medicine placebo for reducing chronic back pain intensity or disability. Key limitations included recruiting 71% of the planned sample size and use of multiple inclusion/exclusion criteria that may limit generalizability to broader populations of patients with chronic back pain.
Learn More >Chronic musculoskeletal pain is a common problem globally. Current evidence suggests that maladapted central pain pathways are associated with pain chronicity following e.g. post-operative pain after knee replacement. Other factors such as low mood, anxiety and tendency to catastrophize are also important contributors. We aimed to investigate brain imaging features that underpin pain chronicity based on multivariate pattern analysis of cerebral blood flow (CBF), as a marker of maladaptive brain changes. This was achieved by identifying CBF patterns that discriminate chronic pain from pain-free conditions, and by exploring their explanatory power for factors thought to drive pain chronification. In 44 chronic knee pain patients and 29 pain-free controls, we acquired both CBF and T1-weighted data. Participants completed questionnaires related to affective processes, and pressure and cuff algometry to assess pain sensitization. Two factor scores were extracted from these scores representing negative affect and pain sensitization. A spatial covariance principal components analysis of CBF identified five components that significantly discriminated chronic pain patients from controls, with the unified network achieving 0.83 discriminatory accuracy (area under the curve). In chronic knee pain, significant patterns of relative hypoperfusion were evident in anterior default-mode and salience network hubs, while hyperperfusion was seen in posterior default-mode, thalamus, and sensory regions. One component correlated positively to the pain sensitization score (r=.43, p=.006), suggesting that this CBF pattern reflects neural activity changes encoding pain sensitization. Here, we report a distinct chronic knee pain-related representation of CBF, pointing toward a brain signature underpinning central aspects of pain sensitisation.
Learn More >It is consistently reported that in inflammatory arthritis (IA) pain may continue despite well controlled inflammation, most likely due to interactions between joint pathology and pain pathway alterations. Nervous system alterations have been described but much remains to be understood about neuronal and central non-neuronal changes in inflammatory arthritis.Using a rat model of IA induced by intra-articular CFA injection, this study includes a thorough characterization of joint pathology, and objectives to identify peripheral innervation changes and alterations in the spinal dorsal horn (DH) that could alter DH excitatory balancing. Male and female rats displayed long-lasting pain-related behavior but, in agreement with our previous studies, other pathological alterations emerged only at later times. Cartilage vascularization, thinning and decreased proteoglycan content were not detectable in the ipsilateral cartilage until 4 weeks post-CFA. Sympathetic and peptidergic nociceptive fibers invaded the ipsilateral cartilage alongside blood vessels, complex innervation changes were observed in the surrounding skin and ipsilateral NGF protein expression was increased. In the DH, we examined innervation by peptidergic and non-peptidergic nociceptors, inhibitory terminal density, the K-Cl co-transporter KCC2, microgliosis and astrocytosis. Here, we detected the presence of microgliosis and interestingly, an apparent loss of inhibitory terminals and decreased expression of KCC2.In conclusion, we found evidence of anatomical, inflammatory and neuronal alterations in the peripheral and central nervous systems in a model of inflammatory arthritis. Together these suggest that there may be a shift in the balance between incoming and outgoing excitation, and modulatory inhibitory tone in the DH.
Learn More >Chronic pain and mood disorders share common neuroanatomical substrates involving disruption of the reward system. Although increase in negative affect (NA) and decrease in positive affect (PA) are well-known factors complicating the clinical presentation of chronic pain patients, our understanding of the mechanisms underlying the interaction between pain and PA/NA remains limited. Here, we used a validated task probing behavioral and neural responses to monetary rewards and losses in conjunction with functional magnetic resonance imaging (fMRI) to test the hypothesis that dysfunction of the striatum, a key mesolimbic structure involved in the encoding of motivational salience, relates to mood alterations comorbid with chronic pain.
Learn More >Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the mouse orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. In this study we sought to address this problem using the Mouse Grimace Scale and a novel approach to the application of mechanical Von Frey hair stimuli. We use a dental pulp injury model that exposes the pulp to the outside environment, a procedure we have previously shown produces inflammation. Using RNAscope technology, we demonstrate an upregulation of genes that contribute to the pain state in the trigeminal ganglia of injured mice. We found that mice with dental pulp injury have greater Mouse Grimace Scores than sham within 24 hours of injury, suggestive of spontaneous pain. We developed a scoring system of mouse refusal to determine thresholds for mechanical stimulation of the face with Von Frey filaments. This method revealed that mice with a unilateral dental injury develop bilateral mechanical allodynia that is delayed relative to the onset of spontaneous pain. This work demonstrates that tooth pain can be quantified in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammatory pain and other forms of trigeminal pain.
Learn More >Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups.
Learn More >Conditioned pain modulation (CPM) is a task that involves measuring pain in response to a test stimulus before and during a painful conditioning stimulus (CS). The CS pain typically inhibits pain elicited by the test stimulus; thus, this task is used to assess endogenous pain inhibition. Moreover, less efficient CPM-related inhibition is associated with chronic pain risk. Pain catastrophizing is a cognitive-emotional process associated with negative pain sequelae, and some studies have found that catastrophizing reduces CPM efficiency.
Learn More >Chronic pain has been associated with alterations in brain structure and function that appear dependent on pain phenotype. Functional connectivity (FC) data on chronic back pain (CBP) is limited and based on heterogeneous pain populations. We hypothesize that failed back surgery syndrome (FBSS) patients being considered for spinal cord stimulation (SCS) therapy have altered resting state (RS) FC cross-network patterns that 1) specifically involve emotion and reward/aversion functions and 2) are related to pain scores.
Learn More >To explore the perspectives of general practitioners (GPs) concerning the risk of opioid misuse in people with cancer and pain and related clinical considerations.
Learn More >The five-repetition sit-to-stand (5R-STS) test was designed to capture objective functional impairment and thus provided an adjunctive dimension in patient assessment. The clinical interpretability and confounders of the 5R-STS remain poorly understood. In clinical use, it became apparent that 5R-STS performance may differ between patients with lumbar disk herniation (LDH), lumbar spinal stenosis (LSS) with or without low-grade spondylolisthesis, and chronic low back pain (CLBP). We seek to evaluate the extent of diagnostic information contained within 5R-STS testing.
Learn More >Neuropathic low back-related leg pain (LBLP) can be a challenge to healthcare providers to diagnose and treat. Accurate diagnosis of neuropathic pain is fundamental to ensure appropriate intervention is given. However, to date there is no gold standard to diagnose neuropathic LBLP. A Delphi study will therefore be conducted to obtain an expert-derived consensus list of clinical indicators to identify a neuropathic component to LBLP.
Learn More >To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain.
Learn More >Disability resulting from headache disorders is attributable in part to avoidant coping. Acceptance of pain connotes a willingness to experience pain in the service of life values, such that meaningful activities and goals are pursued despite pain. Acceptance facilitates positive health outcomes but has rarely been investigated in headache. Because headache disorders manifest differently than other forms of chronic pain, the present study sought to develop and validate a measure of acceptance of headache.
Learn More >Persistent pain in breast cancer survivors is common. Psychological and sleep-related factors modulate perception, interpretation and coping with pain and may contribute to the clinical phenotype. The present analysis pursued the hypothesis that breast cancer survivors form subgroups, based on psychological and sleep-related parameters that are relevant to the impact of pain on the patients' life.
Learn More >Modulation of pain perception by oxytocin (OXT) has attracted increased scientific and clinical interest. Neural mechanisms underlying these effects are poorly understood. In this study, we aimed to investigate the effects of intranasally applied OXT on intrinsic neural activity in patients with chronic low back pain (cLBP).
Learn More >Large (big)-conductance calcium-activated potassium (BK) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BK channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BK channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BK channels and ATP-sensitive potassium (K) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BK channel activation can provoke migraine in migraine patients, and whether the BK channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BK channel openers or blockers in migraine patients are needed.
Learn More >Synovitis is implicated in the severity and progression of pain and structural pathology of osteoarthritis (OA). Increases in inflammatory or immune cell subpopulations including macrophages and lymphocytes have been reported in OA synovium, but how the particular subpopulations influence symptomatic or structural OA disease progression is unclear. Two therapies, hyaluronan (HA) and mesenchymal stem cells (MSCs), have demonstrated efficacy in some clinical settings: HA acting as device to improve joint function and provide pain relief, while MSCs may have immunomodulatory and disease-modifying effects. We used these agents to investigate whether changes in pain sensitization or structural damage were linked to modulation of the synovial inflammatory response in post-traumatic OA.
Learn More >This review aims to identify perioperative patient-related factors that are associated with the development of persistent postoperative pain (PPP) in patients undergoing spine surgery.
Learn More >The purpose of the present investigation is to provide a comprehensive review of both patient and procedure specific predictors of acute postoperative pain.
Learn More >It is unclear if anxiety sensitivity may serve as mechanism underlying the relation between posttraumatic stress symptom severity and opioid misuse and dependence among trauma-exposed persons with chronic pain. Therefore, the current study evaluated the explanatory role of anxiety sensitivity in the relations between posttraumatic stress symptom severity and opioid misuse and dependence. Participants included 294 trauma-exposed adults with chronic pain (71.4% female, M = 37.79 years, SD = 10.85, M = 7.32/10) that reported current moderate to severe chronic pain and prescription opioid use. Participants were recruited via an online national survey in the United States of America. There were statistically significant indirect effects of posttraumatic stress symptom severity via anxiety sensitivity in relation to opioid misuse and dependence. The indirect effects of the reverse models for opioid misuse and dependence also were significant and suggest the potential for bi-directional relations; however, the magnitude of the effect was smaller in the tests of specificity than in the original models. The present findings provide initial empirical evidence that greater posttraumatic stress symptom severity is related to anxiety sensitivity, which in turn, is associated with increased opioid misuse and dependence among trauma-exposed individuals with chronic pain.
Learn More >To study lateral inhibition and habituation/sensitization in the somatosensory cortex of patients with chronic migraine (CM) and to identify correlations with clinical migraine features.
Learn More >Endometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS).
Learn More >To describe the 10-year evolution of a cohort of migraine patients, focusing on prognostic factors of improvement.
Learn More >To investigate the structural and functional connectivity changes of lateral geniculate nucleus (LGN) and their relationships with clinical characteristics in patients without aura.
Learn More >To investigate whether the self-treatment of migraine among neurologists and pain specialists corresponds to national medical guidelines and treatment of patients.
Learn More >Heterogeneity in chronic migraine (CM) presents significant challenge for diagnosis, management, and clinical trials. To explore naturally occurring clusters of CM, we utilized data reduction methods on migraine-related clinical dataset. Hierarchical agglomerative clustering and principal component analyses (PCA) were conducted to identify natural clusters in 100 CM patients using 14 migraine-related clinical variables. Three major clusters were identified. Cluster I (29 patients) – the severely impacted patient featured highest levels of depression and migraine-related disability. Cluster II (28 patients) – the minimally impacted patient exhibited highest levels of self-efficacy and exercise. Cluster III (43 patients) – the moderately impacted patient showed features ranging between Cluster I and II. The first 5 principal components (PC) of the PCA explained 65% of variability. The first PC (eigenvalue 4.2) showed one major pattern of clinical features positively loaded by migraine-related disability, depression, poor sleep quality, somatic symptoms, post-traumatic stress disorder, being overweight and negatively loaded by pain self-efficacy and exercise levels. CM patients can be classified into three naturally-occurring clusters. Patients with high self-efficacy and exercise levels had lower migraine-related disability, depression, sleep quality, and somatic symptoms. These results may ultimately inform different management strategies.
Learn More >: Neuropathic pain is a chronic condition that significantly affects the quality of life of millions of people globally. Most of the pharmacologic treatments currently in use demonstrate modest efficacy and over half of all patients do not respond to medical management. Hence, there is a need for new, efficacious drugs. Evidence points toward voltage-gated sodium channels as a key target for novel analgesics.: The role of voltage-gated sodium channels in pain pathophysiology is illuminated and the preclinical and clinical data for new sodium channel blockers and toxin-derived lead compounds are examined. The expansion of approved sodium channel blockers is discussed along with the limitations of current research, trends in drug development, and the potential of personalized medicine.: The transition from preclinical to clinical studies can be difficult because of the inherent inability of animal models to express the complexities of pain states. Pain pathways are notoriously intricate and may be pharmacologically modulated at a variety of targets; it is unlikely that action at a single target could completely abolish a pain response because pain is rarely unifactorial. Combination therapy may be necessary and this could further confound the discovery of novel agents.
Learn More >To investigate the number and characteristics of the Spanish population affected by headache disorders and the direct medical cost that these patients represent for the healthcare system.
Learn More >The anterior cingulate cortex (ACC) serves as a critical hub for the anxiety and pain perception. The large-conductance Ca-activated potassium channels, or BK channels, are ubiquitously expressed throughout the central nervous system including the cingulate cortex. However, what changes of cortical BK channels undergo in the ACC remains unknown in pain-related anxiety. In the present study, a significant upregulation of synaptic and non-synaptic BK channel accessory β4 subunits in the ACC was accompanied with pain-associated anxiety-like behaviors in the chronic compression of multiple dorsal root ganglia (mCCD) of the rat. NS1619, an opener of BK channels, significantly rescued the alteration of fAHP and AP duration of ACC pyramidal neurons in mCCD rats. The mRNA expression of BK β4 subunits was extremely upregulated in the ACC after mCCD with the increased amount of both synaptic and non-synaptic BK β4 subunit protein. Meanwhile, NS1619 reversed the enhanced AMPA receptor-mediated spontaneous excitatory postsynaptic current (sEPSC) frequency and the attenuated PPR of ACC neurons in mCCD rats. Local activation of BK channels in the ACC reversed mechanical allodynia and anxiety-like behaviors. These results suggest that the upregulation of postsynaptic and presynaptic BK β4 subunit may contribute to neuronal hyperexcitability and the enhanced synaptic transmission in the ACC in neuropathic pain state, and then may result in anxiety-like behavior induced by neuropathic pain.
Learn More >Cortical spreading depression (CSD) is a propagating wave of depolarization followed by depression of cortical activity. CSD triggers neuroinflammation via the pannexin-1 (Panx1) channel opening, which may eventually cause migraine headaches. However, the regulatory mechanism of Panx1 is unknown. This study investigates whether sarcoma family kinases (SFK) are involved in transmitting CSD-induced Panx1 activation, which is mediated by the NR2A-containing N-methyl-D-aspartate receptor. CSD was induced by topical application of K to cerebral cortices of rats and mouse brain slices. SFK inhibitor, PP2, or NR2A-receptor antagonist, NVP-AAM077, was perfused into contralateral cerebral ventricles (i.c.v.) of rats prior to CSD induction. Co-immunoprecipitation and Western blot were used for detecting protein interactions, and histofluorescence for addressing Panx1 activation. The results demonstrated that PP2 attenuated CSD-induced Panx1 activation in rat ipsilateral cortices. Cortical susceptibility to CSD was reduced by PP2 in rats and by TAT-Panx308 that disrupts SFK-Panx1 interaction in mouse brain slices. Furthermore, CSD promoted activated SFK coupling with Panx1 in rat ipsilateral cortices. Moreover, inhibition of NR2A by NVP-AAM077 reduced elevation of ipsilateral SFK-Panx1 interaction, Panx1 activation induced by CSD and cortical susceptibility to CSD in rats. These data suggest NR2A-regulated, SFK-dependent Panx1 activity plays an important role in migraine aura pathogenesis.
Learn More >Atopic dermatitis (AD), a chronic, highly pruritic skin disorder, impairs quality of life (QoL). Janus kinase inhibitors suppress inflammatory and pruritus-associated cytokine signaling in AD.
Learn More >The Illness Invalidation Inventory (3*I) was designed to assess individuals' perceived invalidation regarding chronic pain experiences. However, no study has yet investigated the psychometric properties of the 3*I among individuals with chronic low back pain (CLBP). Given the personal and societal impact of CLBP and the potential for invalidation associated with this condition, the current study sought to examine the psychometric properties of the 3*I among individuals with CLBP.
Learn More >Despite the worldwide increase in prevalence of chronic pain and the subsequent scientific interest, researchers studying the brain and brain mechanisms in pain patients have not yet clearly identified the exact underlying disease. Quantifying the neuronal interactions in electrophysiological data could help us gain insight into the complexity of chronic pain. Therefore, the aim of this study is to examine how different underlying pain states affect the processing of nociceptive information.
Learn More >: Most preventive migraine treatments modify the brain's excitation/inhibition balance and/or serotonin metabolism, which likely accounts for their unfavourable adverse effect profile. Novel biological therapies blocking CGRP transmission are effective and much better tolerated, but they are expensive and may not influence brain dysfunctions upstream in the pathophysiological cascade of migraine, including premonitory and aura symptoms. Biochemical and clinical studies suggest that there may be another complimentary treatment strategy, the one that targets the underestimated metabolic facet of migraine pathophysiology.: After a brief description of the metabolic abnormalities found in migraine patients, we will review and discuss published data on metabolic treatments of migraine. There is evidence that high dose riboflavin and co-enzyme Q10 are effective for the prevention of migraine and quasi devoid of adverse effects. Response rates are close to those of topiramate, propranolol, and CGRP/CGRPrec mAbs. The evidence is weaker for thioctic acid. Dietary and pharmacological strategies inducing ketosis are novel promising approaches for which preliminary trials with favourable outcomes have been published.: Metabolic treatments of migraine constitute an effective, well-tolerated, inexpensive, and evidence-supported therapeutic option for migraine prophylaxis, and may be considered as first treatment line in many patients, including in children and adolescents.
Learn More >The locus coeruleus (LC) is one of the brainstem nuclei that may be activated during migraine attack. As LC contains neuromelanin, a by-product of norepinephrine synthesis, it can be delineated in vivo using neuromelanin sensitive magnetic resonance imaging (MRI). The neuromelanin content in LC has been suggested to reflect previous LC activation. We investigated LC MRI contrast in patients with migraine with aura (MWA) and its correlation with migraine features.
Learn More >This cross-sectional study examined the association between adverse childhood experiences (ACEs) and history of frequent headaches (including migraine) among children 3-17 years old using data from the 2016 and 2017 U.S. National Survey of Children's Health (NSCH).
Learn More >Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical condition. However, the underlying mechanisms of CRPS-I have yet to be revealed. It is known that ischemia/reperfusion is one of the leading factors that causes CRPS-I. By means of prolonged ischemia and reperfusion of the hind limb, the rat chronic post-ischemia pain (CPIP) model has been established to mimic CRPS-I. The CPIP model has become a well-recognized animal model for studying the mechanisms of CRPS-I. This protocol describes the detailed procedures involved in the establishment of the rat model of CPIP, including anesthesia, followed by ischemia/reperfusion of the hind limb. Characteristics of the rat CPIP model are further evaluated by measuring the mechanical and thermal hypersensitivities of the hind limb as well as the nocifensive responses to acute capsaicin injection. The rat CPIP model exhibits several CRPS-I-like manifestations, including hind limb edema and hyperemia in the early stage after establishment, persistent thermal and mechanical hypersensitivities, and increased nocifensive responses to acute capsaicin injection. These characteristics render it a suitable animal model for further investigation of the mechanisms involved in CRPS-I.
Learn More >: Treatment for chronic pruritus ranges from use of topical formulations to newer biologic agents. Targeting treatment to the underlying etiology is key in reducing the burden of disease while avoiding systemic or adverse effects.: This review details the effective medical treatments used in various etiologies of chronic itch with a focus on the potential adverse effects and safety data available for each.: New drug developments in the areas of neural signaling and immune targeting show great promise for the future of chronic itch treatment. These new therapies broaden the available treatment options but also pose new considerations for safety and adverse effects.
Learn More >Fifth lumbar (L5) nerve injury in rats causes neuropathic pain manifested with thermal and mechanical hypersensitivity in the ipsilateral hind paw. This study aimed to determine whether the elimination of unmyelinated primary afferents of the adjacent uninjured nerves (L3 and L4) would alleviate peripheral neuropathic pain. Different concentrations of capsaicin or its analog, resiniferatoxin (RTX), were applied perineurally on either the left L4 or L3 and L4 nerves in Wistar rats whose left L5 nerves were ligated and cut. The application of both capsaicin and RTX on the L4 nerve significantly reduced both thermal and mechanical hypersensitivity. However, only the application of RTX on both L3 and L4 nerves completely alleviated all neuropathic manifestations. Interestingly, responses to thermal and mechanical stimuli were preserved, despite RTX application on uninjured L3, L4, and L5 nerves, which supply the plantar skin in rats. Perineural application of RTX caused downregulation of TRPV1, CGRP, and IB4 binding and upregulation of VIP in the corresponding DRG and the dorsal horn of the spinal cord. In comparison, VGLUT1 and NPY immunoreactivities were not altered. RTX application did not cause degenerative or ultrastructural changes in the treated nerves and corresponding DRGs. The results demonstrate that RTX induces neuroplasticity, rather than structural changes in primary afferents, that are responsible for alleviating hypersensitivity and chronic pain. Furthermore, this study suggests that treating uninjured adjacent spinal nerves may be used to manage chronic neuropathic pain following peripheral nerve injury. This article is protected by copyright. All rights reserved.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is one of the intractable long-term side effects of anticancer medications and results in pain and dysesthesia. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide effective relief for intractable neuropathic pain. The objective of this study was to investigate the effects of rTMS treatment on CIPN in cancer patients.
Learn More >Skeletal pathologies are often accompanied by bone pain, which has negative effects on the quality of life and functional status of patients. Bone pain can be caused by a wide variety of injuries and diseases including (poorly healed) fractures, bone cancer, osteoarthritis and also iatrogenic by skeletal interventions. Orthopedic interventions are considered to be the most painful surgical procedures overall. Two major groups of medication currently used to attenuate bone pain are NSAIDs and opioids. However, these systemic drugs frequently introduce adverse events, emphasizing the need for alternative therapies that are directed at the pathophysiological mechanisms underlying bone pain. The periosteum, cortical bone and bone marrow are mainly innervated by sensory A-delta fibers and C-fibers. These fibers are mostly present in the periosteum rendering this structure most sensitive to nociceptive stimuli. A-delta fibers and C-fibers can be activated upon mechanical distortion, acidic environment and increased intramedullary pressure. After activation, these fibers can be sensitized by inflammatory mediators, phosphorylation of acid-sensing ion channels and cytokine receptors, or by upregulation of transcription factors. This can result in a change of pain perception such that normally non-noxious stimuli are now perceived as noxious. Pathological conditions in the bone can produce neurotrophic factors that bind to receptors on A-delta fibers and C-fibers. These fibers then start to sprout and increase the innervation density of the bone, making it more sensitive to nociceptive stimuli. In addition, repetitive painful stimuli cause neurochemical and electrophysiological alterations in afferent sensory neurons in the spinal cord, which leads to central sensitization, and can contribute to chronic bone pain. Understanding the pathophysiological mechanisms underlying bone pain in different skeletal injuries and diseases is important for the development of alternative, targeted pain treatments. These pain mechanism-based alternatives have the potential to improve the quality of life of patients suffering from bone pain without introducing undesirable systemic effects.
Learn More >There are adverse effects associated with long-term opioid therapy (LTOT) for chronic pain and clinicians infrequently adhere to opioid treatment guideline recommendations for reducing risk and mitigating opioid-related harms. The primary goal of the Improving the Safety of Opioid Therapy (ISOT) intervention is to reduce harms related to prescription opioids. Secondary aims focus on enhancing the clinician-patient relationship and not having a negative impact on pain-related outcomes (to be examined through a non-inferiority analysis). The study is a cluster-randomized trial and the 44 primary care providers (PCPs) who enrolled were randomized to receive either (1) a two-hour educational workshop about a patient-centered approach to opioid therapy or (2) the educational workshop plus a collaborative care intervention delivered by a nurse care manager (NCM). Patients were assigned to the same condition as their treating PCP. ISOT was based on the chronic care model and include patient and provider activation, outcomes monitoring, and feedback to the PCP over 12 months. The NCM conducted a baseline assessment with intervention patients, tracked opioid-related behaviors and outcomes, and provided decision support to the opioid-prescribing clinician about opioid safety. Between June 2016 and October 2018, 293 veterans who were prescribed LTOT for chronic pain were enrolled, completed a baseline assessment, and assigned to a treatment condition. Participants were enrolled for 12 months. Masked assessments were conducted with participants at baseline, 6-months, and 12-months. This manuscript describes study rationale, research methods, and baseline findings.
Learn More >Cancer-induced pain (CIP) is a kind of chronic pain that occurs during cancer progression over time. However, the mechanisms are largely unknown, and clinical treatment remains challenging. LncRNAs have been reported to play critical roles in various biological processes, including chronic pain. The aim of our study was to investigate whether lncRNAs participate in the development of CIP by regulating the expression levels of some molecules related to pain modulation. The CIP model was established by injecting Walker 256 mammary gland tumor cells into the tibial canal of rats. In this study, we found that lncRNA-NONRATT021203.2 was increased in the CIP rats and that lncRNA-NONRATT021203.2-siRNA could relieve hyperalgesia in these rats. For elucidation of the underlying mechanism, we showed that lncRNA-NONRATT021203.2 could target C-X-C motif chemokine ligand 9 (CXCL9), which was increased in the CIP rats, and that CXCL9-siRNA could relieve hyperalgesia. At the same time, silencing lncRNA-NONRATT021203.2 expression decreased the mRNA and protein levels of CXCL9. Immunofluorescence analysis showed that CXCL9 was mainly expressed in the CGRP-positive and IB4-positive DRG neurons. Further research showed that lncRNA-NONRATT021203.2 and CXCL9 were colocalized in the DRG neurons. Our data suggested that lncRNA-NONRATT021203.2 participated in the CIP in rats and likely mediates the upregulation of CXCL9. The present study provided us with a new potential target for the clinical treatment of cancer-induced pain.
Learn More >People with migraine have localised (i.e., cephalic) mechanical sensitivity. There is uncertainty regarding widespread (i.e., extra-cephalic) mechanical sensitivity and variations in mechanical sensitivity throughout the migraine cycle. Therefore, this study aimed (1) to comprehensively assess mechanical sensitivity in both cephalic and extra-cephalic regions during the preictal, ictal, postictal and interictal phases; and (2) to compare these findings with mechanical sensitivity at corresponding time-points and locations in healthy participants.
Learn More >: Migraine is a chronic neurovascular disorder characterized by recurrent headache attacks associated with neurological and autonomic symptoms. The pathophysiological mechanisms of the disease are extremely complex, involving hypothalamic and trigeminovascular activation, cortical spreading depression, release of pro-inflammatory peptides, peripheral and central sensitization. The underlying cellular and molecular mechanisms have been scarcely investigated. Recently, genetic studies have suggested that different metabolic pathways could be involved in the pathogenesis of migraine.: This review focuses on cellular and molecular mechanisms involved in migraine, suggesting a role for circadian clocks, ion channels, synaptic plasticity, vascular factors, ion metal homeostasis, and impaired glucose metabolism in the pathogenesis of the disease. Accordingly, the article proposes new therapeutic targets that may be of particular relevance for disease prevention.: Several complex molecular mechanisms are involved in setting the genetic threshold for migraine and the pathogenesis of headache attacks. Most promising new therapeutic targets are the modulation of hypothalamic activity and ion channels involved in pain transmission. Further studies in animals and humans are necessary to enhance the elucidation of the molecular mechanisms of migraine and open new avenues for disease prevention.
Learn More >Although many patients with cluster headaches (CH) are disabled by their condition, few studies have examined this in detail. This cross-sectional, multicenter observational study prospectively collected demographic and clinical questionnaire data from 224 consecutive patients with CH. We assessed headache impact using the six-item Headache Impact Test (HIT-6) and evaluated the factors associated with the impact of CH. Participants with a HIT-6 score ≥ 60 were classified into a severe impact group. The majority (190, 84.8%) of the participants were classified into the severe impact group. These patients were characterized by younger age, earlier onset of CH, longer duration of each headache attack, higher pain intensity, more cranial autonomic symptoms, a higher proportion of depression or anxiety, higher score of stress, and lower score of quality of life. The anxiety (OR = 1.19, 95% CI: 1.08-1.31, p = 0.006), greater pain intensity (OR = 1.06, 95% CI: 1.02-1.10, p = 0.002), and age (OR = 0.99, 95% CI: 0.99-1.00, p = 0.008) were significant predictors for a severe impact of CH patients. According to the HIT-6 results, most of the CH patients were significantly affected by CH. As well as pain intensity, anxiety and age modulated CH's impact on their lives.
Learn More >: Document headache presence, intensity, and interference after concussion(s), as well as examine its association with cognition.: Participants 8-19 years of age were assessed on average 34 months ( = 21.5) after an orthopedic injury (OI, = 29), single concussion ( = 21), or multiple concussions ( = 15).: Headache intensity was rated using the Headache Rating Scale and headache interference was rated using the Post-Concussion Symptom Inventory (PCSI). Cognition was rated using the PCSI and measured using CNS Vital Signs.: Type of injury did not differ significantly in headache presence or intensity. However, there was a dose-response relationship found for children's ratings of headache interference, which was rated highest among children with multiple concussions, intermediate among those with single concussion, and lowest among children with OI. Both headache intensity and interference ratings correlated significantly with self and parent ratings of cognition on the PCSI, but not with cognitive test performance.: Youth with single or multiple concussions report greater headache interference – but not higher headache intensity – compared to youth without concussion. Although higher headache intensity and interference were associated with more self-reported cognitive symptoms, headaches did not correlate with cognitive test performance.
Learn More >The pivotal role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology was identified over 30 years ago, but the successful clinical development of targeted therapies has only recently been realized. This perspective traces the decades long evolution of medicinal chemistry required to advance small molecule CGRP receptor antagonists, also called gepants, including the current clinical agents: rimegepant, vazegepant, ubrogepant and atogepant. Providing clinically effective blockade of CGRP signaling required surmounting multiple challenging hurdles, including defeating a sizeable ligand with subnanomolar affinity for its receptor, designing antagonists with an extended confirmation and multiple pharmacophores while retaining solubility and oral bioavailability, and achieving circulating free plasma levels that provided near maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as are recent synthetic developments which have benefited from new structural biology data. The first oral gepant was recently approved and heralds a new era in the treatment of migraine.
Learn More >A variety of barriers ensures the protection of the peripheral nervous system from noxious blood-borne or surrounding stimuli. In this review, anatomy and functioning of the blood nerve barrier (BNB) and the blood DRG barrier (BDB) will be presented and key tight junction proteins described: ZO-1, claudin-1, -3, -5, -11, -12, -19, occludin, and tricellulin. Different diseases can lead to or be accompanied by nerve barrier disruption and impairment of nerve barriers worsens pathology. Peripheral nerve injury, diabetic neuropathy and inflammatory polyneuropathy cause an increased permeability of BNB and BDB. Knowledge and understanding of these mechanisms might ultimately lead to the invention of drugs to control barrier function to help ameliorating neurological diseases.
Learn More >The International Headache Society (IHS) has published four editions of in the past 28 years. This continuous update process has been driven by the increasing amount of scientific data in the field of migraine and by the need to continuously improve the quality of trials.
Learn More >Dipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole. These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue.
Learn More >Chronic musculoskeletal pain is a major health concern. The biopsychosocial approach is an evidence-based approach recommended for managing chronic musculoskeletal pain. However, the evidence for this approach is largely reported from high-income countries; therefore, it is important to ascertain how biopsychosocial approaches are operationalised in low- and middle-income countries to inform practice.
Learn More >Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes.
Learn More >Transient receptor potential vanilloid 1 (TRPV1) is a polymodal receptor channel, which plays an important role in pain transduction. It is important to understand the functional expression of this channel under neuropathic pain (NP) conditions. A novel method was used to investigate the dynamics of functional expression of this channel on regenerated neurons under NP conditions following trigeminal nerve injury using a combination of a permanently charged sodium channel blocker (QX-314) and a TRPV1 agonist (capsaicin; QX-CAP). The combination was originally introduced as a local anesthetic. Synchronization between the local anesthetic effect of QX-CAP and TRPV1 expression on regenerated neurons was observed following the nerve injury. QX-CAP had no local anesthetic effect under NP conditions 2 weeks after the injury when TRPV1 expression on regenerated neurons was low. However, this combination was effective under NP conditions 3 and 4 weeks following injury when TRPV1 expression in regenerated neurons was moderate to high. The current review, discusses the potential of QX-314 as a local anesthetic and a novel approach of using QX-CAP to reveal the dynamics of functional expression of TRPV1 on regenerated neurons following trigeminal nerve injury.
Learn More >Myofascial Pain Syndrome (MPS) is one of the most common conditions of chronic musculoskeletal pain, yet its mechanisms are still poorly understood. Delayed Onset Muscle Soreness (DOMS) is also a regional pain syndrome that has clinical similarities to MPS, but has been better investigated. Emerging research suggests that DOMS may be a valid experimental model for studying MPS; however, a comparison of the similarities and differences of these two conditions has previously not been performed. Herein, we aimed to identify the similarities and differences in the clinical features and biomarkers between DOMS and MPS in order to better define MPS and identify future areas of (DOMS-informed) MPS research.
Learn More >In this neurophysiological study, we aimed at verifying the nociceptive selectivity of the new, micropatterned electrode (150IDE), recently designed to generate an electric field limited to the intraepidermal free nerve endings.
Learn More >The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats. On day 3 after NPLA administration, the MHWT recovered considerably in IANX rats. Following L-arginine injection into the TG, the MHWT was significantly reduced within 15 min, and the mean number of TG cells encircled by glial fibrillary acidic protein (GFAP)-IR cells was substantially higher. The relative number of nNOS-IR cells encircled by GFAP-IR cells was significantly increased in IANX rats. In contrast, after NPLA injection into the TG, the relative number of GFAP-IR cells was considerably reduced in IANX rats. Fluorocitrate administration into the TG significantly reduced the number of GFAP-IR cells and prevented the MHWT reduction in IANX rats. The present findings suggest that following IANX, satellite glial cells are activated via nitric oxide (NO) signaling from TG neurons. The spreading satellite glial cell activation within the TG results in mechanical hypersensitivity of face regions not directly associated with the trigeminal nerve injury.
Learn More >Joint pain is common in subjects with IBD and is linked to several factors including SpA, drug therapy, concomitant OA or FM. The primary aim of this study was to estimate the prevalence of primary FM and concomitant FM and SpA in a cohort of patients with IBD utilizing clinical and US assessment.
Learn More >The aim of the study was to compare the International Classification of Diseases, 11th revision, (ICD-11) with current terminology of vulvodynia, approved by a broad-based consensus of the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS).
Learn More >The aim of this systematic review was to compile the latest evidence to assess the effectiveness of nonsteroidal anti-inflammatory drug(s) (NSAID) in patients with temporomandibular joint disorders (TMDs) in relieving pain. TMDs are a group of musculoskeletal disorders that affect the temporomandibular joint and/or masticatory muscles.
Learn More >Mounting studies pay attention to the functional roles of long non-coding RNAs (lncRNAs) in many human diseases including neuropathic pain. LncRNA MALAT1 has been indicated to serve as a critical mediator in neuropathic pain with unclear mechanisms. The present study aims to explore the functional roles of MALAT1 in neuropathic pain progression and the related mechanisms. Bilateral sciatic nerves were ligated to induce chronic constriction injury (CCI) in order to establish the neuropathic pain rat model followed by behavioral tests, RT-qPCR, Western blotting, and ELISA. Dual luciferase activity assay was performed to determine the binding effect between MALAT1 or HMGB1 and miR-129-5p. The mRNA levels of MALAT1 were significantly enhanced in CCI rats. MALAT1 inhibition repressed the development of neuropathic pain and neuroinflammation. Additionally, miR-129-5p was decreased and HMGB1 was increased, both of which could be rectified by MALAT1 inhibition. Meanwhile, MALAT1 targeted miR-129-5p/HMGB1 axis. Finally, miR-129-5p suppression attenuated the inhibitory effect of MALAT1 inhibition on neuropathic pain and neuroinflammation development in CCI rats. The present study demonstrates that MALAT1 might modulate neuropathic pain via targeting miR-129-5p/HMGB1 axis. These findings may lead to a promising and efficacious clinical approach for the treatment of neuropathic pain.
Learn More >AIMS The covalent linking of non-steroidal anti-inflammatory drugs (NSAIDs) to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increasing anti-inflammatory and analgesic potency. We have tested the hypothesis that a H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. RESULTS ATB-352 was significantly more potent as an analgesic than ketoprofen, and did not elicit GI damage. Pretreatment with a cannabinoid receptor-1 antagonist (AM251) significantly reduced the analgesic effects of ATB-352. The CB-1 antagonist exacerbated GI damage when co-administered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB-1 antagonist. ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. INNOVATION Ketoprofen is a potent analgesic, but its clinical use is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting the analgesic effectiveness.
Learn More >Migraine management is characterized by the poor use of preventive therapy and the overuse of acute medications. An analysis of current treatment patterns in migraineurs is needed to improve care in this patient population. The aim of this study was to describe treatment patterns and healthcare utilization of newly diagnosed migraine patients.
Learn More >Endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are endogenous lipids that activate cannabinoid receptors. Activation of these receptors produces anti-inflammatory and analgesic effects. Fatty acid amide hydrolase (FAAH) is a membrane enzyme that hydrolases endocannabinoids, thus inhibition of FAAH represents an attractive approach to develop new therapeutics for treating inflammation and pain. Previously, potent rat FAAH inhibitors containing 2-naphthyl- and 4-phenylthiazole scaffolds were identified, but up to the present time, very little structure-activity relationship (SAR) studies have been performed on these moieties. We designed and synthesized several analogs containing these structural motifs and evaluated their inhibition potencies against human FAAH enzyme. In addition, we built and validated a homology model of human FAAH enzyme and performed docking experiments. We identified several inhibitors in the low nanomolar range and calculated their ADME predicted values. These FAAH inhibitors represent promising drug candidates for future preclinical in vivo studies.
Learn More >In the pain matrix, the insular cortex (IC) is mainly involved in discriminative sensory and motivative emotion. Abnormal signal transmission from injury site causes neuropathic pain, which generates enhanced synaptic plasticity. The mammalian target of rapamycin (mTOR) complex is the key regulator of protein synthesis; it is involved in the modulation of synaptic plasticity. To date, there has been no report on the changes in optical signals in the IC under neuropathic condition after treatment with mTOR inhibitors, such as Torin1 and XL388. Therefore, we aimed to determine the pain-relieving effect of mTOR inhibitors (Torin1 and XL388) and observe the changes in optical signals in the IC after treatment. Mechanical threshold was measured in adult male Sprague-Dawley rats after neuropathic surgery, and therapeutic effect of inhibitors was assessed on post-operative day 7 following the microinjection of Torin1 or XL388 into the IC. Optical signals were acquired to observe the neuronal activity of the IC in response to peripheral stimulation before and after treatment with mTOR inhibitors. Consequently, the inhibitors showed the most effective alleviation 4 h after microinjection into the IC. In optical imaging, peak amplitudes of optical signals and areas of activated regions were reduced after treatment with Torin1 and XL388. However, there were no significant optical signal changes in the IC before and after vehicle application. These findings suggested that Torin1 and XL388 are associated with the alleviation of neuronal activity that is excessively manifested in the IC, and is assumed to diminish synaptic plasticity.
Learn More >A cognitive task, the n-back task, was used to interrogate the cognitive dimension of pain in patients with implanted dorsal root ganglion stimulators (DRGS). Magnetoencephalography (MEG) signals from thirteen patients with implanted DRGS were recorded at rest and while performing the n-back task at three increasing working memory loads with DRGS-OFF and the task repeated with DRGS-ON. MEG recordings were pre-processed, then power spectral analysis and source localization were conducted. DRGS resulted in a significant reduction in reported pain scores (mean 23%, = 0.001) and gamma oscillatory activity ( = 0.036) during task performance. DRGS-induced pain relief also resulted in a significantly reduced reaction time during high working memory load ( = 0.011). A significant increase in average gamma power was observed during task performance compared to the resting state. However, patients who reported exacerbations of pain demonstrated a significantly elevated gamma power (F(3,80) = 65.011612, < 0.001, adjusted -value = 0.01), compared to those who reported pain relief during the task. Our findings demonstrate that gamma oscillatory activity is differentially modulated by cognitive load in the presence of pain, and this activity is predominantly localized to the prefrontal and anterior cingulate cortices in a chronic pain cohort.
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