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Prolonged endoplasmic reticulum stress has been identified in various diseases. Inflammatory mediators, which have been shown to induce endoplasmic reticulum stress in several studies, have been suggested to serve as the important modulators in pain development. In this study, the authors hypothesized that the endoplasmic reticulum stress triggered by inflammatory mediators contributed to pain development.
Learn More >Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.
Learn More >More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.
Learn More >Pain sensation and aversive behaviors entail the activation of nociceptor neurons, whose function is largely conserved across animals. The functional heterogeneity of nociceptors and ethical concerns are challenges for their study in mammalian models. Here, we investigate the function of a single type of genetically identified C. elegans thermonociceptor named FLP. Using calcium imaging in vivo, we demonstrate that FLP encodes thermal information in a tonic and graded manner over a wide thermal range spanning from noxious cold to noxious heat (8°C-36°C). This tonic-signaling mode allows FLP to trigger sustained behavioral changes necessary for escape behavior. Furthermore, we identify specific transient receptor potential, voltage-gated calcium, and sodium "leak" channels controlling sensory gain, thermal sensitivity, and signal kinetics, respectively, and show that the ryanodine receptor is required for long-lasting activation. Our work elucidates the task distribution among specific ion channels to achieve remarkable sensory properties in a tonic thermonociceptor in vivo.
Learn More >Race disparities in pain care are well-documented. Given that the majority of Black patients are treated by White providers, patient-provider racial discordance is one hypothesized contributor to these disparities. Research and theory suggest that providers' trait-level intergroup anxiety impacts their state-level comfort while treating patients, which, in turn, impacts their pain treatment decisions. To test these hypothesized relationships, we conducted a planned secondary analysis of data from a randomized controlled trial of a perspective-taking intervention to reduce pain treatment disparities. Mediation analyses were conducted on treatment decision data from White providers for Black virtual patients with chronic pain. Results indicated that White providers with higher trait-level intergroup anxiety reported lower state-level comfort treating Black patients and were thereby more likely to recommend opioid (indirect effect=0.76, 95% confidence interval [CI]: 0.21,1.51) and pain specialty (indirect effect=0.91, 95% CI: 0.26,1.78) treatments and less likely to recommend non-opioid analgesics (indirect effect=-0.45, 95% CI: -0.94,-0.12). Neither trait-level intergroup anxiety nor state-level comfort significantly influenced provider decisions for physical therapy. This study provides important new information about intra- and inter-personal contributors to race disparities in chronic pain care. These findings suggest that intergroup anxiety and the resulting situational discomfort encroach on the clinical decision-making process by influencing White providers' decisions about which pain treatments to recommend to Black patients. Should these findings be replicated in future studies, they would support interventions to help providers become more aware of their trait-level intergroup anxiety and manage their state-level reactions to patients who are racially/ethnically different from themselves.
Learn More >Research into acupuncture and acupressure and their application for cancer pain has been growing, but the findings have been inconsistent.
Learn More >To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.
Learn More >Understanding molecular alterations associated with peripheral inflammation is a critical factor in selectively controlling acute and persistent pain. The present report employs in situ hybridization of the two opioid precursor mRNAs coupled with quantitative measurements of two peptides derived from the prodynorphin and proenkephalin precursor proteins: dynorphin A 1-8 and [Met]-enkephalin-Arg-Gly-Leu (MERGL). In dorsal spinal cord ipsilateral to the inflammation, dynorphin A 1-8 was elevated after inflammation, and persisted as long as the inflammation was sustained. Qualitative identification by HPLC and gel permeation chromatography revealed the major immunoreactive species in control and inflamed extracts to be dynorphin A 1-8. In situ hybridization in spinal cord after administration of the inflammatory agent, carrageenan, showed increased expression of prodynorphin (Pdyn) mRNA somatotopically in medial superficial dorsal horn neurons. The fold increase in preproenkephalin mRNA (Penk) was comparatively lower, although the basal expression is substantially higher than Pdyn. While Pdyn is not expressed in the dorsal root ganglion (DRG) in basal conditions, it can be induced by nerve injury, but not by inflammation alone. A bioinformatic meta-analysis of multiple nerve injury datasets confirmed Pdyn upregulation in DRG across different nerve injury models. These data support the idea that activation of endogenous opioids, notably dynorphin, is a dynamic indicator of persistent pain states in spinal cord and of nerve injury in DRG. [218/200] PERSPECTIVE: This is a systematic, quantitative assessment of dynorphin and enkephalin peptides and mRNA in dorsal spinal cord and dorsal root ganglia neurons in response to peripheral inflammation and axotomy. These studies form the foundational framework for understanding how endogenous spinal opioid peptides are involved in nociceptive circuit modulation. (48/50).
Learn More >Trigeminal neuralgia is defined by its clinical characteristics of paroxysmal unilateral facial pain in a well-defined territory. Distribution of the pain may be in one or several of the cutaneous and/or mucous territories of the three divisions with V2 pain being the most frequent territory followed by V3 and V1. Factors determining the distribution of pain have not yet been systematically investigated. It is now well recognized that vascular compression factor is a predominant aetiology of classical trigeminal neuralgia. In this study we aimed to find whether there is a relation between the location of the vascular compression and the peripheral distribution of the pain. Patients with classical trigeminal neuralgia in whom microvascular decompression was performed were included. Data recorded pertained to the nature of the conflict, its degree and, most importantly, location around the root: supero-median, supero-lateral or inferior. Equally, clinical data for the distribution of pain were recorded. Most of the patients 318 (89.3%) had the compression coming from above, i.e. 220 (61.7%) had compression from a supero-medial direction and 98 (27.5%) from a supero-lateral direction; inferior compression was present in 38 patients (10.7%). Distribution of the pain was significantly different according to the location of the conflict (P = 0.0005, Fisher Exact test). Odds ratios were computed for each location of compression and painful territory involved. According to the overall distribution of pain, patients with supero-medial compression had an odds ratio of 2.7 [95% confidence interval (CI) 1.66-4.41] of manifesting with V1 pain. Conversely V3 pain was less likely to occur with supero-median compression than the other types of pain (odds ratio 0.53, 95% CI 0.34-0.83). Inferior compression on the other hand was more likely to manifest with V3 pain with an odds ratio of 2.56 (95% CI 1.21-5.45). Overall V2 pain had an odds ratio close to 1 regardless of the type of compression. These findings suggest an association between the location of the neurovascular conflict with its resulting insult and the distribution of pain supporting a somatotopic view of the organization of the trigeminal root and a role of the conflict in the clinical manifestation of trigeminal neuralgia.
Learn More >Alleviating chronic pain is challenging, due to lack of drugs that effectively inhibit nociceptors without off target effects on motor or central neurons. Dorsal root ganglia (DRG) contain nociceptive and non-nociceptive neurons. Drug screening on cultured DRG neurons, rather than cell lines, allows the identification of drugs most potent on nociceptors with no effects on non-nociceptors (as a proxy for unwanted side effects on CNS and motor neurons). However, screening using DRG neurons is currently a low-throughput process and there is a need for assays to speed this process for analgesic drug discovery. We previously showed that veratridine elicits distinct response profiles in sensory neurons. Here we show evidence that a veratridine-based calcium assay allows an unbiased and efficient assessment of a drug effect on nociceptors (targeted neurons) and non-nociceptors (non-targeted neurons). We confirmed the link between the oscillatory profile and nociceptors; and the slow-decay profile and non-nociceptors using three transgenic mouse lines of known pain phenotypes. We used the assay to show that blockers for Nav1.7 and Nav1.8 channels, which are validated targets for analgesics, affect non-nociceptors at concentrations needed to effectively inhibit nociceptors. However, a combination of low doses of both blockers had an additive effect on nociceptors without a significant effect on non-nociceptors, indicating that the assay can also be used to screen for combinations of existing or novel drugs for the greatest selective inhibition of nociceptors.
Learn More >This cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients.
Learn More >Migraine is defined by attacks of headache with a specific length and associated symptoms such as photophobia, phonophobia and nausea. It is long recognized that migraine is more than just the attacks and that migraine should be understood as a cycling brain disorder with at least 4 phases: interictal, preictal, ictal and postictal. However, unlike the pain phase, the other phases are less well defined, which renders studies focusing on these phases susceptible to bias. We herewith review the available clinical, electrophysiological, and neuroimaging data and propose that the preictal phase should be defined as up to 48 hours before the headache attack and the postictal phase as up to 24 hours following the ictal phase. This would allow future studies to specifically investigate these migraine phases and to make study results more comparable.
Learn More >Increasing numbers survive cancers in childhood and adolescence. Long-term survivors of cancers in adulthood have increased prevalence of pain and consumption of analgesics. It is not established whether long-term survivors of cancers in childhood and adolescence also have an increased use of analgesics. However, based on increased use of antidepressants and anxiolytics in long-term survivors of cancers in childhood and adolescence, we hypothesized that this group also had increased use of analgesics. Based on data from the two nationwide registers the Cancer Registry of Norway and the Norwegian Prescription Database a cohort of 5585 (52% males) long-term survivors of cancers in childhood, adolescence and early adult life was established. Age and gender adjusted comparisons were made to the general population. The age adjusted one-year periodic prevalence of receiving prescriptions of opioids, benzodiazepines and benzodiazepine-related hypnotics in the study population was increased by 20-50% and the one-year periodic prevalence of receiving prescriptions of gabapentinoids was approximately increased two-fold compared to the general population. For paracetamol and NSAIDs no difference was found. For those survivors, who were persistent or high-dose users of opioids, co-medication with high doses of benzodiazepines and/or benzodiazepine-related hypnotics was far more common than among persistent and high-dose opioid users in the general population. The high prevalence of gabapentinoids may indicate increased prevalence of neuropathic pain in this group. The high degree of co-medication with benzodiazepines and/or benzodiazepine-related hypnotics in survivors on persistent and high-dose opioids might be an indication of problematic opioid use or addiction.
Learn More >Inconsistent findings from migraine neuroimaging studies have limited attempts to localize migraine symptomatology. Novel brain network mapping techniques offer a new approach for linking neuroimaging findings to a common neuroanatomical substrate and localizing therapeutic targets. In this study, we attempted to determine whether neuroanatomically heterogeneous neuroimaging findings of migraine localize to a common brain network. We used meta-analytic coordinates of decreased grey matter volume in migraineurs as seed regions to generate resting state functional connectivity network maps from a normative connectome (n = 1000). Network maps were overlapped to identify common regions of connectivity across all coordinates. Specificity of our findings was evaluated using a whole-brain Bayesian spatial generalized linear mixed model and a region of interest analysis with comparison groups of chronic pain and a neurologic control (Alzheimer's disease). We found that all migraine coordinates (11/11, 100%) were negatively connected (t ≥ ±7, P < 10-6 family-wise error corrected for multiple comparisons) to a single location in left extrastriate visual cortex overlying dorsal V3 and V3A subregions. More than 90% of coordinates (10/11) were also positively connected with bilateral insula and negatively connected with the hypothalamus. Bayesian spatial generalized linear mixed model whole-brain analysis identified left V3/V3A as the area with the most specific connectivity to migraine coordinates compared to control coordinates (voxel-wise probability of ≥90%). Post hoc region of interest analyses further supported the specificity of this finding (ANOVA P = 0.02; pairwise t-tests P = 0.03 and P = 0.003, respectively). In conclusion, using coordinate-based network mapping, we show that regions of grey matter volume loss in migraineurs localize to a common brain network defined by connectivity to visual cortex V3/V3A, a region previously implicated in mechanisms of cortical spreading depression in migraine. Our findings help unify migraine neuroimaging literature and offer a migraine-specific target for neuromodulatory treatment.
Learn More >To describe morphological changes associated with degeneration and regeneration of large fibers in the skin using a model of chronic compression of the median nerve.
Learn More >: Migraine is the second leading cause of disability worldwide, yet many patients are unable to tolerate, benefit from, or afford pharmacological treatment options. Non-pharmacological migraine therapies exist, especially to reduce opioid use, which represents a significant unmet need. Mindfulness-based interventions (MBI) have potential as a non-pharmacological treatment for migraine, primarily through the development of flexible attentional capacity across sensory, cognitive, and emotional experiences.: The authors review efficacy and potential mechanisms of MBIs for migraine, including mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT).: While most mindfulness research studies for migraine to date have been pilot trials, which are small and/or lacked rigor, initial evidence suggests there may be improvements in overall headache-related disability and psychological well-being. Many research questions remain to help target the treatment to patients most likely to benefit, including the ideal dosage, duration, delivery method, responder characteristics, and potential mechanisms and biomarkers. A realistic understanding of these factors is important for patients, providers, and the media. Mindfulness will not "cure" migraine; however, mindfulness may be an important tool as part of a comprehensive treatment approach to help patients "mindfully" engage in valued life activities.
Learn More >Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 μg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.
Learn More >Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment. Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development. Here we evaluate the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis. In this model, female mice develop mechanical hypersensitivity in the caudal abdomen, mild anxiety-like behavior and substantial memory deficits associated with the presence of extrauterine endometrial cysts. Interestingly, daily treatments with THC (2 mg/kg) alleviate mechanical hypersensitivity and pain unpleasantness, modify uterine innervation and restore cognitive function without altering the anxiogenic phenotype. Strikingly, THC also inhibits the development of endometrial cysts. These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.
Learn More >The attrition of novel analgesic drugs in the clinic can be attributed in the main to two factors: failure of preclinical research findings translating into human pain conditions, and a drop-off of efficacy between proof-of-concept (i.e., Phase II trials) and pivotal, confirmatory (Phase III trials) testing. In order to enhance the efficiency of the clinical drug evaluation process and determine rapidly whether a potential therapeutic candidate gives pain relief, by modulating central pain neurobiology, we propose a 'pre-proof-of-concept' approach, in which an efficacy assessment is performed in a single individual (N-of-1) using subjective clinical pain assessments supported by objective validated functional neuroimaging measures. Using an N-of-1 + i methodology, clinical- and neuroimaging-based metrics can be quantified under conditions of drug versus placebo or drug versus current standard of care conditions.
Learn More >Chronic pain afflicts as much as 50% of the population at any given time but our methods to address pain remain limited, ineffective and addictive. In order to develop new therapies an understanding of the mechanisms of painful sensitization is essential. We discuss here recent progress in the understanding of mechanisms underlying pain, and how these mechanisms are being targeted to produce modern, specific therapies for pain. Finally, we make recommendations for the next generation of targeted, effective, and safe pain therapies.
Learn More >Monoamines are involved in regulating the endogenous pain system and indeed, peripheral and central monoaminergic dysfunction has been demonstrated in certain types of pain, particularly in neuropathic pain. Accordingly, drugs that modulate the monaminergic system and that were originally designed to treat depression are now considered to be first line treatments for certain types of neuropathic pain (e.g., serotonin and noradrenaline (and also dopamine) reuptake inhibitors). The analgesia induced by these drugs seems to be mediated by inhibiting the reuptake of these monoamines, thereby reinforcing the descending inhibitory pain pathways. Hence, it is of particular interest to study the monoaminergic mechanisms involved in the development and maintenance of chronic pain. Other analgesic drugs may also be used in combination with monoamines to facilitate descending pain inhibition (e.g., gabapentinoids and opioids) and such combinations are often also used to alleviate certain types of chronic pain. By contrast, while NSAIDs are thought to influence the monoaminergic system, they just produce consistent analgesia in inflammatory pain. Thus, in this review we will provide preclinical and clinical evidence of the role of monoamines in the modulation of chronic pain, reviewing how this system is implicated in the analgesic mechanism of action of antidepressants, gabapentinoids, atypical opioids, NSAIDs and histaminergic drugs.
Learn More >We have developed an experimental fibromyalgia (FM)-like mouse model using intermittent cold stress (ICS), where chronic pain is generalized, female-predominant and abolished in type 1 lysophosphatidic acid receptor-KO (LPA1-/-) mice, but is not reversed by systemic or brain treatment with morphine. In the present study, we investigated two issues whether both chronic pain mechanisms and lack of brain morphine analgesia are associated to each other in the ICS model, and what mechanisms are involved in the lack of morphine analgesia. The hyperalgesia was not affected in μ-opioid receptor-KO (MOPr-/-) mice, while the lack of brain morphine analgesia remained unchanged in LPA1-/- mice, which completely abolish the hyperalgesia in the ICS model. On the other hand, the lack of morphine analgesia was abolished in NR2A-NMDA receptor-KO (NR2A-/-) mice, and blocked by intracerebroventricular (i.c,v,) injection of (R)-CPP, an NR2A antagonist or by microinjection of siRNA for NR2A into PAG region, while no change was observed with Ro 04-5595, an NR2B antagonist (i.c.v.). The lack of morphine analgesia was also reversed by the concomitant treatment with 1 mg/kg (i.p.) of dextromethorphan possessing NMDA receptor antagonist activity, which has no analgesic activity. Finally, the hyperalgesia was completely reversed by methadone possessing MOPr agonist and NMDA receptor antagonist activity. Indeed, the methadone analgesia was abolished in MOPr-/- mice. All these results suggest that chronic pain status and lack of morphine analgesia are independent to each other, and the lack of morphine analgesia is mediated by an activation of NR2A-NMDA receptor system. SIGNIFICANCE STATEMENT: This study describes that a type of stress-induced wide-spread pain has chronic pain independent of endogenous opioid-mediated pain inhibitory system and lack of morphine analgesia independent of chronic pain status. This study describes that the lack of morphine analgesia is possibly mediated by endogenous opioid-induced analgesic tolerance and thereby reversed by anti-opioid NMDA receptor system. The latter view is evidenced by the findings that NMDA receptor blockades recover the morphine analgesia.
Learn More >To describe and compare phenotypic features of posttraumatic headaches (PTH) and headaches unrelated to concussion.
Learn More >Methadone is a long-acting opioid that has been reported to reduce postoperative pain scores and analgesic requirements and may attenuate development of chronic postsurgical pain. The aim of this secondary analysis of two previous trials was to follow up with patients who had received a single intraoperative dose of either methadone or traditional opioids for complex spine or cardiac surgical procedures.
Learn More >Endocannabinoids are showing great promise as effective mediators for controlling joint inflammation and pain. One strategy that could be harnessed to promote endogenous cannabinoid function is to inhibit the enzymatic break down of endocannabinoids locally in the joint. KML29 is an inhibitor of monoacylglycerol lipase (MAGL) activity which has been shown to promote increased 2-arachodonylglycerol (2-AG) levels in the circulation and in peripheral tissues. It is also known that 2-AG can be metabolised via the cyclo-oxygenase-2 (COX-2) pathway leading to the production of pro-inflammatory prostaglandins, which may counteract the effects of 2-AG. Therefore, this study examined the effect of KML29 alone as well as in combination with low-dose celecoxib (CXB) on joint pain and inflammation in the monoiodoacetate (MIA) model of osteoarthritis (OA) pain.
Learn More >The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in ( = 2.24 × 10), rs36098404 in ( = 2.24 × 10), and rs592026 in ( = 6.53 × 10). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism ( = 3.79 × 10) and fibroblast growth factor (FGF) signaling ( = 2.39 × 10). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.
Learn More >Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.
Learn More >The involvement of the visual network in migraine pathophysiology has been well-known for more than a century. Not only is the aura phenomenon linked to cortical alterations primarily localized in the visual cortex; but also migraine without aura has shown distinct dysfunction of visual processing in several studies in the past. Further, the study of photophobia, a hallmark migraine symptom, has allowed unraveling of distinct connections that link retinal pathways to the trigeminovascular system. Finally, visual snow, a recently recognized neurological disorder characterized by a continuous visual disturbance, is highly comorbid with migraine and possibly shares with it some common pathophysiological mechanisms. Here, we review the most relevant neuroimaging literature to date, considering studies that have either attempted to investigate the visual network or have indirectly shown visual processing dysfunctions in migraine. We do this by taking into account the broader spectrum of migrainous biology, thus analyzing migraine both with and without aura, focusing on light sensitivity as the most relevant visual symptom in migraine, and finally analyzing the visual snow syndrome. We also present possible hypotheses on the underlying pathophysiology of visual snow, for which very little is currently known.
Learn More >Consistent associations between the severity of neuropathic pain and cutaneous innervation have not been described. We collected demographic and clinical data, McGill Pain Questionnaires (MPQ) and skin biopsies processed for PGP9.5 and CGRP immunohistochemistry from patients with bortezomib-induced peripheral neuropathy (BiPN; n=22), painful diabetic neuropathy (PDN; n=16), chronic idiopathic axonal polyneuropathy (CIAP; n=16) and 17 age-matched healthy volunteers. Duration of neuropathic symptoms was significantly shorter in patients with BiPN in comparison with PDN and CIAP patients. BiPN was characterized by a significant increase in epidermal axonal swellings and upper dermis nerve fiber densities (UDNFD) and a decrease in subepidermal nerve fiber densities (SENFD) of PGP9.5-positive fibers and of PGP9.5 containing structures that did not show CGRP labeling, presumably non-peptidergic fibers. In PDN and CIAP patients, intraepidermal nerve fiber densities (IENFD) and SENFD of PGP9.5-positive and of non-peptidergic fibers were decreased in comparison with healthy volunteers. Significant unadjusted associations between IENFD and SENFD of CGRP-positive, i.e. peptidergic, fibers and the MPQ sensory-discriminative, as well as between UDNFD of PGP9.5-positive fibers and the MPQ evaluative/affective component of neuropathic pain, were found in BiPN and CIAP patients. No significant associations were found in PDN patients. Cutaneous innervation changes in BiPN confirm characteristic features of early, whereas those in CIAP and PDN are in line with late forms of neuropathic pathology. Our results allude to a distinct role for non-peptidergic nociceptors in BiPN and CIAP patients. The lack of significant associations in PDN may be caused by mixed ischemic and purely neuropathic pain pathology.
Learn More >Current pain therapeutics offer inadequate relief to patients with chronic pain. A growing literature supports that pro-inflammatory cytokine signaling between immune, glial, and neural cells is integral to the development of pathological pain. Modulation of these communications may hold the key to improved pain management. In this review we first offer an overview of the relationships between pro-inflammatory cytokine and chemokine signaling and pathological pain, with a focus on the actions of cytokines and chemokines in communication between glia (astrocytes and microglia), immune cells (macrophages and T cells), and neurons. These interactions will be discussed in relation to both peripheral and central nervous system locations. Several novel non-neuronal drug targets for controlling pain are emerging as highly promising, including non-viral IL-10 gene therapy, which offer the potential for substantial pain relief through localized modulation of targeted cytokine pathways. Preclinical investigation of the mechanisms underlying the success of IL-10 gene therapy revealed the unexpected discovery of the powerful anti-nociceptive anti-inflammatory properties of D-mannose, an adjuvant in the non-viral gene therapeutic formulation. This review will include gene therapeutic approaches showing the most promise in controlling pro-inflammatory signaling via increased expression of anti-inflammatory cytokines like interleukin-10 (IL-10) or IL-4, or by directly limiting the bioavailability of specific pro-inflammatory cytokines, as with tumor necrosis factor (TNF) by the TNF soluble receptor (TNFSR). Approaches that increase endogenous anti-inflammatory signaling may offer additional opportunities for pain therapeutic development in patients not candidates for gene therapy. Promising novel avenues discussed here include the disruption of lymphocyte function-associated antigen (LFA-1) activity, antagonism at the cannabinoid 2 receptor (CB2R), and toll-like receptor 4 (TLR4) antagonism. Given the partial efficacy of current drugs, new strategies to manipulate neuroimmune and cytokine interactions hold considerable promise.
Learn More >TRESK background K channel is expressed in sensory neurons and acts as a brake to reduce neuronal activation. Deletion of the channel enhances the excitability of nociceptors Skin nociceptive C-fibers show an enhanced activation by cold and mechanical stimulation in TRESK KO animals. Channel deletion selectively enhances mechanical and cold sensitivity in mice, without altering sensitivity to heat. These results indicate that the channel regulates the excitability of specific neuronal subpopulations involved in mechanosensitivity and cold-sensing.
Learn More >Sensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed-loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function.
Learn More >Systematic review with meta-analysis and meta-regression.
Learn More >For decades, antihistamines have been the mainstay of treatment for chronic pruritus, yet they often only work by making patients drowsy and forgetful of their itch. A new era of antipruritic drugs is quickly approaching, presenting more effective treatments for patients suffering from chronic itch. Several treatments have been developed targeting specific receptors in the nervous system, such as the transient receptor potential channels, sodium channels, neurokinin-1 receptors, opioid receptors, and many more. Additionally, antipruritic therapies developed to work on the immune system have become more targeted, leading to greater safety and efficacy measures. These include crisaborole, several interleukin antagonists, and janus kinase inhibitors. The promising results presented with these new antipruritic therapies allow physicians to be better equipped to treat their itchy patients.
Learn More >Chronic vulvar pain is a multidimensional condition with great variability in clinical presentation among affected women. In a companion article, part 1, we reviewed and recommended assessment and measurement tools for vulvar pain and related outcomes with a view toward improving consistency and comparison across studies. Yet methodological challenges to conducting research with this population remain and can further hinder conclusions regarding etiology and treatment.
Learn More >According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model.
Learn More >: Prurigo nodularis (PN) is an intensely pruritic skin condition of considerable morbidity. However, the pathogenesis of PN and its association with underlying neuropathy is unclear. : We sought to investigate the association between PN and etiologies of peripheral neuropathy. : A cross-sectional analysis of adult patients (≥18-year-old) with PN, AD, and Psoriasis at the Johns Hopkins Health System over a six-year period (January 2013-January 2019) was performed. The strength of association with etiologies of peripheral neuropathy were compared to a control cohort of individuals without PN, as well as those with AD or psoriasis. : A total of 1122 patients with PN were compared to 10,390 AD patients, 15,056 patients with psoriasis, and a control cohort of 4,949,017 individuals without PN, with respect to 25 comorbidities associated with peripheral neuropathies. : Comparisons between peripheral neuropathies and PN represent associations but are not causal relationships. : Prurigo nodularis is strongly associated with peripheral neuropathies, suggesting a role for neural dysregulation in pathogenesis.
Learn More >Vestibular migraine (VM), also known as migrainous vertigo or migraine-associated vertigo, is characterized by recurrent vestibular attacks often accompanied by migraine headaches and other migraine symptoms. It is one of the most common presenting complaints to physicians in primary care, otolaryngology, and neurology. Epidemiologic data suggest that VM may affect 1 to 3% of the general population and 10 to 30% of patients seeking treatment for dizziness. Attacks typically last minutes to hours and range from spontaneous and positional vertigo to extreme sensitivity to self and surround motion. As with headaches, nausea, and vomiting, phonophobia and photophobia are common accompanying symptoms. The clinical spectrum of VM and its underlying pathophysiological mechanisms are just being identified, with much debate about the causal relationship of vestibular symptoms and headache, no evidence-based guidelines for clinical management, limited characterization of its disease burden, and little information about its negative impact on health-related quality of life.
Learn More >Contemporary nonmalignant pain treatment algorithms commence with conservative non-invasive strategies, later progressing from minimally invasive interventions to invasive techniques or implantable devices. The most commonly used implantable devices are spinal cord stimulation (SCS) systems or targeted drug delivery (TDD) devices. Historically, SCS had been considered in advance of TDD, positioning TDD behind SCS failures. Following Institutional Review Board approval, data were extracted from electronic medical records of patients who underwent SCS trial in the Department of Pain Management at Cleveland Clinic from 1994 to 2013. The sample size was analyzed in two cohorts: those who succeeded with SCS and those who failed SCS and consequently proceeded to TDD. Univariate and multivariate analyses were performed and a predictive formula for successful outcomes was created. 945 patients were included in the cohort of which 119 (12.6%) subjects achieved adequate pain relief with TDD after failure of SCS. Gender, age, depression and primary pain diagnosis were significantly different in this subgroup. Males were 52% less likely to experience pain relief with SCS. The odds of SCS success decreased as age increased by 6% per year. Patients with comorbid depression, interestingly, were 63% more likely to succeed with SCS. A logistic model was created to predict SCS success which was used to create a predictive formula. Older male patients diagnosed with spine-related pain were more likely to benefit from TDD than SCS. This observation potentially identifies a subgroup in whom consideration for TDD in advance of SCS failure could prove more efficient and cost effective. These retrospective findings warrant prospective comparative studies to validate this derived predictive formula.
Learn More >Itch (pruritus), specifically chronic itch associated with disease conditions, significantly impairs the patient's quality of life. At present, the mechanisms underlying this aversive experience are still unclear, and the effective treatment of itch is largely unmet. Here, we report that intragastrical administration of bulleyaconitine A (BLA), which has been used for treating chronic pain for 30 years in China, inhibited itch-like behaviors induced by intradermal injection of histamine and chloroquine in mice and rats, dose-dependently. We found that a single application of the pruritic agents at the skin region innervated by the sural nerve induced long-term potentiation (LTP) of C-fiber field potentials evoked by the stimulation of the same nerve in the spinal dorsal horn of rats. The spinal LTP was remarkably reversed by the spinal application of either BLA or gastrin-releasing peptide receptor (GRPR) antagonist (PD176252). The effect of PD176252 was completely occluded by BLA, while the effect of BLA was only partially occluded by PD176252. Repetitive injection (daily, for four days) of either histamine or chloroquine in the back of the neck enhanced scratching behaviors progressively, and the itch sensitization persisted for at least one week after the discontinuation of the injections. The behavioral change was accompanied with the potentiation of C-fiber synaptic transmission in the dorsal horn. Both the itch sensitization and synaptic potentiation were substantially attenuated by intragastrical BLA. Together, BLA was effective in inhibiting histamine-dependent and histamine-independent itches, and the mechanisms underlying these effects were involved but not limited to the inhibition of GRP-GRPR signaling in the spinal dorsal horn.
Learn More >Acute pain is a common complication after injury of a peripheral nerve but the underlying mechanism is obscure. We established a model of acute neuropathic pain via pulling a pre-implanted suture loop to transect a peripheral nerve in awake rats. The tibial (both muscular and cutaneous), gastrocnemius-soleus (muscular only), and sural nerves (cutaneous only) were each transected. Transection of the tibial and gastrocnemius-soleus nerves, but not the sural nerve immediately evoked spontaneous pain and mechanical allodynia in the skin territories innervated by the adjacent intact nerves. Evans blue extravasation and cutaneous temperature of the intact skin territory were also significantly increased. In vivo electrophysiological recordings revealed that injury of a muscular nerve induced mechanical hypersensitivity and spontaneous activity in the nociceptive C-neurons in adjacent intact nerves. Our results indicate that injury of a muscular nerve, but not a cutaneous nerve, drives acute neuropathic pain.
Learn More >Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs.
Learn More >Given the unknown immediate impact of migraine on nighttime sleep, we prospectively examined whether migraine headaches were associated with subsequent shorter sleep duration, higher fragmentation and poorer quality in a cohort of 98 adults with episodic migraine.
Learn More >Major depressive disorders (MDD) and chronic pain (CP) affect significant portion of the world's population and have high comorbidity rate. Social defeat stress (SDS) model was standardized in mice and can trigger depressive-like behavior and chronic pain. Based especially on clinical trials showing an effective preventive and therapeutic effect of physical exercise on CP and symptoms associated with MDD, this study aimed to investigate if the voluntary running wheel exercise can exert these effects in mice submitted to the 10-day SDS protocol, using fluoxetine as positive control. For this, we ran two set of experiments: in the first set mice started performing voluntary running wheel exercise after submitted to SDS and, in the second set, mice performed voluntary running wheel exercise before and during SDS. Mechanical and chemical hyperalgesia was analyzed through electronic von Frey and capsaicin test, respectively. Depressive-like behavior was assessed through social interaction test. Our results showed that the voluntary running wheel exercise was more effective than fluoxetine reversing the SDS-induced persistent hyperalgesia and both, fluoxetine and voluntary running wheel exercise, was effective reversing SDS-induced social avoidance. Also, voluntary running wheel exercise is an effective tool preventing both hyperalgesia and social avoidance induced by SDS. To the best of our knowledge, this was the first study using physical exercise as a therapeutic and preventive tool for chronic pain and depressive-like behavior simultaneously induced by social stress.
Learn More >Children and adolescents with primary headache are at risk of persistent somatic symptoms and reduced quality of life (Qol) due to pain and pain-related behaviors, such as avoiding school and activities. Sleep is essential to health, and children and adolescents with primary headaches have more sleep complaints than do healthy controls. A treatment approach that addresses multifactorial causes is likely important. Nonpharmacological interventions seem promising. However, knowledge about effective strategies is limited. The objective of this review is to assess the effect of nonpharmacological interventions in randomized controlled trials (RCTs) among children and adolescents with primary headache in order to identify useful strategies.
Learn More >The activation of the AMP activated protein kinase (AMPK) exerts antinociceptive effects in acute and neuropathic pain models. Mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c), a mitochondrial-derived peptide, regulates many biological activities via activating AMPK. However, the role of MOTS-c in the formalin-induced inflammatory nociception remains unclear. In this study, we investigated the role of MOTS-c in the formalin-induced inflammatory nociception. The antinociceptive effect of MOTS-c was assessed by recording the time spent licking paw. The anti-inflammatory effect of MOTS-c was evaluated by detecting the inflammatory cytokine level changes in the mouse serum. Western blot was used to detect the changes of protein phosphorylation levels in the mouse spinal cord. Changes of c-fos expression in the spinal cord were assessed by immunohistochemistry. Our results showed that the intraperitoneal administration of MOTS-c reduced the time spent on licking in phase 2 in a dose-dependent manner in the formalin test. The antinociceptive effects of MOTS-c (50 mg/kg, i.p.) were attenuated by the AMPK antagonist compound C (10 mg/kg, i.p.). MOTS-c (50 mg/kg, i.p.) significantly reduced pro-inflammatory cytokine levels and elevated the level of anti-inflammatory cytokine in mouse serum. In addition, MOTS-c treatment significantly increased AMPKα phosphorylation level and suppressed formalin-induced extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK), and P38 activation and c-fos expression in the mouse spinal cord. These results suggest that systemic administration of MOTS-c exerts antinociceptive and anti-inflammatory effects, at least partially, through activating AMPK pathway and inhibiting MAP kinases-c-fos signaling pathway in the mouse formalin test.
Learn More >Sub-anesthetic ketamine is frequently used as an analgesic to reduce perioperative opioid consumption and has also been shown to have antidepressant effects. Side effects of ketamine include dizziness, diplopia, nystagmus, and psychomimetic effects. It is unclear what clinical factors may be associated with ketamine-related adverse drug events (ADEs).
Learn More >Chronic pain disproportionately affects older adults, severely impacting quality of life and independent living, with musculoskeletal pain most prevalent. Chronic musculoskeletal pain is associated with specific structural alterations in the brain and interindividual variability in brain structure is likely an important contributor to susceptibility for the development of chronic pain. However, understanding of age-related structural changes in the brain and their associations with chronic musculoskeletal pain is currently limited. Oxytocin (OT), a neuropeptide present in the periphery and central nervous system, has been implicated in pain attenuation. Variation of the endogenous OT system (e.g., OT receptor genotype, blood, saliva, and cerebrospinal fluid OT levels) is associated with morphology in brain regions involved in pain processing and modulation. Intranasal OT administration has been shown to attenuate pain. Yet, studies investigating the efficacy of OT for management of chronic musculoskeletal pain are lacking, including among older individuals who are particularly susceptible to the development of chronic musculoskeletal pain. The goal of this focused narrative review was to synthesize previously parallel lines of work on the relationships between chronic pain, brain morphology, and OT in the context of aging. Based on the existing evidence, we propose that research on the use of intranasal OT administration as an intervention for chronic pain in older adults is needed and constitutes a promising future direction for this field. The paper concludes with suggestions for future research in the emerging field, guided by our proposed
Learn More >Painful diabetic neuropathy (PDN), a debilitating and progressive chronic pain condition that significantly impacts quality of life, is one of the common complications seen with long-standing diabetes mellitus. Neither pharmacological treatments nor low-frequency spinal cord stimulation (SCS) has provided significant and long-term pain relief for patients with PDN. This study aims to document the value of 10-kHz SCS in addition to conventional medical management (CMM) compared with CMM alone in patients with refractory PDN.
Learn More >Background and aims A bio-psycho-social approach has been recommended in multidisciplinary pain clinics, and in Norway patients with severe chronic nonmalignant pain (CNMP, defined as pain that has persisted for more than 3 months) might be treated at a regional multidisciplinary pain center. The specific aims of this study were (1) to describe characteristics of a sample of outpatients referred and accepted for treatment/management to three regional multidisciplinary pain centers in Norway, (2) to examine patient differences between the centers and (3) to study associations between symptom scores (insomnia, fatigue, depression, anxiety) and patient characteristics. Methods Patients, aged 17 years or older with CNMP admitted to and given a date for first consultation at one of three tertiary, multidisciplinary pain centers: St. Olavs Hospital Trondheim University Hospital (STO), Haukeland University Hospital (HUS) and University Hospital of North Norway (UNN), were included in the study. Data on demographics, physical activity, characteristics of pain, previous traumatic events, social network, Insomnia Severity Index (ISI), Chalder Fatigue Questionnaire (CFQ), Hopkins Symptom Checklist-25 (HSCL-25) and SF-36v2® were retrieved from the local quality registry at each pain center. Results Data from 1563 patients [mean age 42 (SD 15) years and 63% females] were available for analyses. Average years with pain were 9.3 (SD 9.1). Primary education as highest level of education was reported by 20%, being actively working/student/military by 32%, and no physical activity by 31%. Further, 48% reported widespread pain, 61% reported being exposed to serious life event(s), and 77% reported having a close friend to talk to. Non-worker status, no physical activity, lack of social network, reports of being exposed to serious life event(s) and widespread pain were all characteristics repeatedly associated with clinically high symptom scores. No significant differences between the centers were found in the proportions of patients reporting fatigue nor mean levels of insomnia symptoms. However, the proportion of patients reporting symptoms of anxiety and depression was a little lower at UNN compared with STO and HUS. Conclusions Analyses of registry data from three tertiary multidisciplinary pain centers in Norway support previous findings from other registry studies regarding patient characterized: A large proportion being women, many years of pain, low employment rate, low physical activity rate, and a large proportion reporting previous traumatic event(s). Characteristics such as non-work participation, no physical activity, lack of social network, have been exposed to serious life event(s), and chronic widespread pain were all associated with high clinical score levels of insomnia, fatigue, and mental distress. Health related quality of life was low compared to what has been reported for a general population and a range of other patient groups. Implications The findings of this study indicate that physical activity and work participation might be two important factors to address in the rehabilitation of patients with chronic non-malignant pain. Future studies should also explore whether pre consultation self-reported data might give direction to rehabilitation modalities.
Learn More >To describe the protocol of a randomized controlled trial to evaluate the effectiveness and mechanisms of three behavioral interventions.
Learn More >Chronic pruritus is a frequent global condition. The pathophysiology, underlying aetiology, clinical manifestation, associated burden and response to therapy of chronic pruritus varies from patient to patient, making clinical research and management of this condition challenging. There are still several unmet needs, such as the need to standardize translational research protocols, diagnostic and therapeutic procedures and to enhance the knowledge of the humanistic and economic burden associated with chronic pruritus. Basic and clinical research is of the utmost importance to target these matters. Clinical research has the potential to identify new relevant mechanisms in affected patients, which may lead to identification of novel therapy targets. This article discusses in depth current shortcomings in the daily care of patients with chronic pruritus and the challenges clinical researchers and physicians treating chronic pruritus face in addressing these matters.
Learn More >To investigate the functional connectivity (FC) in nonacute sciatica and the neuronal correlation of acupuncture analgesia.
Learn More >Because abnormal activity of the autonomic nervous system is associated with chronification of pain, early detection of such dysfunction is important.
Learn More >Recent evidence has shown that many patients suffer from persistent pain and impaired function after primary or revision total knee arthroplasty (TKA). Post-surgical complications may in addition decrease physical performances and lead to more pain and impacted quality of life.The purpose of the study was to assess the changes in pain intensity and functional capacity among patients with post-surgical complications after TKA three weeks of intensive, personalized multimodal rehabilitation.
Learn More >For patients with nonspecific chronic low back pain CLBP, exercise therapy is stated to be the most effective intervention strategy but it is unclear which kind of exercise therapy is most beneficial.
Learn More >Racial and ethnic disparities in pain management are widely documented in the United States. The 2016 Centers for Disease Control and Prevention (CDC) guidelines for opioid prescribing have generated new imperatives for using complementary and alternative medicine approaches (CAM) to manage chronic pain, including cancer pain. This review's purpose was to explore the prevalence of CAM use for cancer-related pain among racial and ethnic minorities and to organize these findings according to the CAM modalities proposed by the National Center for Complementary and Integrative Health (NCCIH).
Learn More >Fibromyalgia (FM) is a chronic syndrome characterised by widespread musculoskeletal pain associated with other symptoms, including psychological distress. While negative mood (anxiety, depression, and anger) has been widely explored in FM, few studies have investigated emotional dysregulation. Our purpose was to evaluate problems in the processes of emotional regulation and to explore their influence on the severity of pain and disability.
Learn More >Pruritus is a major symptom of atopic dermatitis (AD) and is transmitted by a subpopulation of non-myelinated C-type free nerve endings in the epidermis and upper dermis. Stimulation of these nerve terminals is affected by histamine, neurotrophins and physical factors. Eosinophils of patients with AD are a source of neurotrophins, including brain-derived neurotrophic factor (BDNF), levels of which correlate with disease severity.
Learn More >Growing evidence suggests a critical role of astrocytes for pain regulation. The water channel protein aquaporin 4 (AQP4), a functional regulator of astrocytes, is involved in various neurological disorders. However, the pathophysiological roles of AQP4 in pain conditions remain unclear. In the present study, we investigated the effect of AQP4 gene knockout in central sensitization induced by complete Freund's adjuvant (CFA). The behavioral analysis revealed that mechanical allodynia and thermal hyperalgesia were more severe in AQP4 null mice than those of wild-type controls over the course of 11 days following CFA intraplantar injection. CFA caused activation of astrocytes with upregulated expression levels of AQP4 and glutamate transporter 1 (GLT1) in the dorsal horn of the spinal cord. AQP4 deficiency reduced GLT1 up-regulation, causing persistent expression of the neuronal activation marker Fos within superficial dorsal horn neurons, including glutamatergic neurons. However, AQP4 deletion did not affect CFA-evoked proinflammatory cytokine expression in the spinal cord. Together, these results have shown that AQP4 absence intensifies CFA-induced spinal central sensitization, which is associated with reduced compensatory up-regulation of GLT1, subsequently increasing glutamatergic overexcitation. Therefore, targeting spinal cord AQP4 may serve as a potential strategy for treatment of peripheral inflammation-evoked hyperalgesia.
Learn More >Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68 phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.
Learn More >To assess the efficacy and safety of S-8117, an oral, controlled-release formulation of oxycodone hydrochloride, in Japanese patients with chronic non-cancer pain (CNCP).
Learn More >Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100β, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.
Learn More >A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant upregulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as IL-1beta, IL-6, and IL-18. The obtained data provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.
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