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Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.
Learn More >Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC, LTD, and LTE, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC and its signaling through the CysLT receptor 2 (CysLTR) in itch. transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected in a broad population of human DRG neurons. Injection of leukotriene C (LTC) or its nonhydrolyzable form NMLTC, but neither LTD nor LTE, induced dose-dependent itch but not pain behaviors in mice. LTC-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC-induced itch was abrogated in mice deficient for or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for , , or mast cells (W mice). CysLTR played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or -induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC acts through CysLTR as its physiological receptor to induce itch, and CysLTR contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.
Learn More >Sex differences in pain severity, response, and pathological susceptibility are widely reported, but the neural mechanisms that contribute to these outcomes remain poorly understood. Here we show that dopamine (DA) neurons in the ventrolateral periaqueductal gray/dorsal raphe (vlPAG/DR) differentially regulate pain-related behaviors in male and female mice through projections to the bed nucleus of the stria terminalis (BNST). We find that activation of vlPAG/DR neurons or vlPAG/DR terminals in the BNST reduces nociceptive sensitivity during naive and inflammatory pain states in male mice, whereas activation of this pathway in female mice leads to increased locomotion in the presence of salient stimuli. We additionally use slice physiology and genetic editing approaches to demonstrate that vlPAG/DR projections to the BNST drive sex-specific responses to pain through DA signaling, providing evidence of a novel ascending circuit for pain relief in males and contextual locomotor response in females.
Learn More >Diabetic neuropathic pain (DNP) is a common complication of diabetes characterized by persistent pain. Emerging evidence links astrocytes to mechanical nociceptive processing, and the motor cortex (MCx) is a cerebral cortex region that is known to play a key role in pain regulation. However, the association between MCx astrocytes and DNP pathogenesis remains largely unexplored. Here, we studied this association using designer receptors exclusively activated by designer drugs (DREADDs) to specifically manipulate MCx astrocytes. We proved that the selective inhibition of MCx astrocytes reduced DNP in streptozocin (STZ)-induced DNP models and discovered a potential mechanism by which astrocytes release cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), to increase neuronal activation in the MCx, thereby regulating pain. Together, these results demonstrate a pivotal role for MCx astrocytes in DNP pathogenesis and provide new insight into DNP treatment strategies.Astrocytes are critical for maintaining CNS homeostasis. In recent years, astrocytes have been demonstrated to play roles in pain signaling modulation and neuropathic pain maintenance, with studies showing that they inhibit pain transmission at the spinal level. This work suggests that astrocytes also modulate pain at the supraspinal level. Indeed, we show that chemogenetically manipulated MCx astrocytes affect the mechanical withdrawal thresholds of rats and elucidate a potential mechanism by which astrocytes release inflammatory mediators to increase neuronal activation in the MCx, thereby regulating pain. Together, our data support that inhibition of astrocytes in the MCx region might have broad prospects for diabetic neuropathic pain treatment.
Learn More >Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female-specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges.
Learn More >Sustained neuropathic pain from injury or inflammation remains a major burden for society. Rodent pain models have informed some cellular mechanisms increasing neuronal excitability within the spinal cord and primary somatosensory cortex (S1), but how activity patterns within these circuits change during pain remains unclear. We have applied multiphoton in vivo imaging and holographic stimulation to examine single S1 neuron activity patterns and connectivity during sustained pain. Following pain induction, there is an increase in synchronized neuronal activity and connectivity within S1, indicating the formation of pain circuits. Artificially increasing neuronal activity and synchrony using DREADDs reduced pain thresholds. The expression of N-type voltage-dependent Ca channel subunits in S1 was increased after pain induction, and locally blocking these channels reduced both the synchrony and allodynia associated with inflammatory pain. Targeting these S1 pain circuits, via inhibiting N-type Ca channels or other approaches, may provide ways to reduce inflammatory pain.
Learn More >Despite emerging evidence of associations between dysmenorrhea, enhanced pain sensitivity, and functional neuroimaging patterns consistent with chronic pain, it is unknown whether dysmenorrhea is prospectively associated with chronic pain development. Gaining a better understanding of this relationship could inform efforts in prevention of chronic pain. Using data from the national Midlife in the United States cohort, we examined the prospective association between dysmenorrhea and chronic pain development during a 10-year follow-up (starting 10 years after dysmenorrhea was measured) among 874 community-dwelling women aged 25-74 at baseline (when dysmenorrhea was measured). We fit modified Poisson regression models adjusting for sociodemographic, lifestyle and psychosocial factors. Among women who were menstruating at baseline, self-reported dysmenorrhea was associated with a 41% greater (95% confidence interval [CI] = 6%-88%) risk of developing chronic pain. Women with dysmenorrhea also developed chronic pain in more body regions (≥ 3 regions vs 1-2 regions vs none, odds ratio [OR] = 1.77, 95% CI = 1.18-2.64) and experienced greater pain interference (high-interference vs low-interference vs none, OR = 1.73, 95% CI = 1.15-2.59). Among women who had stopped menstruation at baseline, we did not find evidence of an association between their history of dysmenorrhea and subsequent risk of chronic pain development. Results suggest dysmenorrhea may be a general risk factor for chronic pain development among menstruating women. PERSPECTIVE: This study supports the temporality of dysmenorrhea and chronic pain development in a national female sample. Dysmenorrhea was also associated with developing more widespread and disabling pain among women who were still menstruating. Early management of dysmenorrhea may reduce the development and severity of chronic pain in women, although further research is required to determine whether dysmenorrhea is a causal risk factor or a risk marker of chronic pain.
Learn More >As in other fields of medicine, development of new medications for management of neuropathic pain has been difficult since preclinical rodent models do not necessarily translate to the clinics. Aside from ongoing pain with burning or shock-like qualities, neuropathic pain is often characterized by pain hypersensitivity (hyperalgesia and allodynia), most often towards mechanical stimuli, reflecting sensitization of neural transmission.
Learn More >Pain is common in many different disorders and leads to a significant reduction in quality of life in the affected patients. Current treatment options are limited and often result in insufficient pain relief, partly due to the incomplete understanding of the underlying pathophysiological mechanisms. The identification of these pathomechanisms is therefore a central object of current research. There are also a number of rare pain diseases, that are generally little known and often undiagnosed, but whose correct diagnosis and examination can help to improve the management of pain disorders in general. In some of these unusual pain disorders like sodium-channelopathies or sensory modulation disorder the underlying pathophysiological mechanisms have only recently been unravelled. These mechanisms might serve as pharmacological targets that may also play a role in subgroups of other, more common pain diseases. In other unusual pain disorders, the identification of pathomechanisms has already led to the development of new drugs. A completely new therapeutic approach, the gene silencing, can even stop progression in hereditary transthyretin amyloidosis and porphyria, ie in pain diseases that would otherwise be rapidly fatal if left untreated. Thus, pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.
Learn More >Endometriosis is a painful inflammatory disorder affecting ~10% of women of reproductive age. Although chronic pelvic pain (CPP) remains the main symptom of endometriosis patients, adequate treatments for CPP are lacking. Animal models that recapitulate the features and symptoms experienced by women with endometriosis are essential for investigating the etiology of endometriosis, as well as developing new treatments. In this study, we used an autologous mouse model of endometriosis to examine a combination of disease features and symptoms including: a 10 week time course of endometriotic lesion development; the chronic inflammatory environment and development of neuroangiogenesis within lesions; sensory hypersensitivity and altered pain responses to vaginal, colon, bladder, and skin stimulation in conscious animals; and spontaneous animal behavior. We found significant increases in lesion size from week 6 posttransplant. Lesions displayed endometrial glands, stroma, and underwent neuroangiogenesis. Additionally, peritoneal fluid of mice with endometriosis contained known inflammatory mediators and angiogenic factors. Compared to Sham, mice with endometriosis displayed: enhanced sensitivity to pain evoked by (i) vaginal and (ii) colorectal distension, (iii) altered bladder function and increased sensitivity to cutaneous (iv) thermal and (v) mechanical stimuli. The development of endometriosis had no effect on spontaneous behavior. This study describes a comprehensive characterization of a mouse model of endometriosis, recapitulating the clinical features and symptoms experienced by women with endometriosis. Moreover, it delivers the groundwork to investigate the etiology of endometriosis and provides a platform for the development of therapeutical interventions to manage endometriosis-associated CPP.
Learn More >Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food.
Learn More >Guidelines recommend self-management for most people living with persistent musculoskeletal low back pain (PMLBP) when surgery is ruled out. Conveying this message to patients can be challenging. This study examined patients' perceptions of reassuring communications from surgical spine team practitioners attempting to deliver this message in a single consultation.
Learn More >In recent years, the delivery of health services has undergone a major paradigm shift towards expanded outpatient services and widespread use of telemedicine. Post herpetic neuralgia (PHN) is a treatment recalcitrant neuropathic pain condition referring to pain persisting more than three months from the initial onset of an acute herpes zoster. QUTENZA® (capsaicin 8% patch) is a single 1-hour localized treatment for PHN and can provide several months of pain relief per application. However, patient access to capsaicin 8% patch is limited due to sensitive handling protocols that require the patch application to occur under physicians or healthcare professionals under the close supervision of a physician. Herein, we describe the first successful treatment of PHN at-home, using capsaicin 8% patch, performed under full supervision and instruction from a physician using video telehealth services.
Learn More >Preclinical and clinical pain science have since long suffered from lack of joint ventures that, as securely as possible, have approached problems that are relevant for the understanding of clinical pain phenomenologies and treatment (Yezierski & Hansson, 2018), the core of translational pain medicine. The uncoupling of the two has led to loss of momentum and few novel efficacious treatment remedies where needed the most, i.e., in long term pain states. Here, the area of translational pain medicine is craving for a road map so that preclinical and clinical scientists can walk hand in hand into the future with a common agenda on how to approach the search for much needed improved treatment strategies.
Learn More >Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Despite the clinical association, no studies have directly assessed whether diet-induced obesity accelerates IVD degeneration, back pain, or investigated the biological mediators underlying this association. In this study, we examine the effects of chronic consumption of a high-fat or high-fat/high-sugar (western) diet on the IVD, knee joint, and pain-associated outcomes.
Learn More >Chronic pain is a common comorbidity in people with HIV (PWH), with prevalence estimates of 25-85%. Research in this area is growing, but significant gaps remain. A Global Task Force of HIV experts was organized to brainstorm a scientific agenda and identify measurement domains critical to advancing research in this field. Experts were identified through literature searches and snowball sampling. Two online questionnaires were developed by Task Force members. Questionnaire 1 asked participants to identify knowledge gaps in the field of HIV and chronic pain and identify measurement domains in studies of chronic pain in PWH. Responses were ranked in order of importance in Questionnaire 2, which was followed by a group discussion. 29 experts completed Questionnaire 1, 25 completed Questionnaire 2, and 21 participated in the group. Many important clinical and research priorities emerged, including the need to examine etiologies of chronic pain in PWH. Pain-related measurement domains were discussed, with a primary focus on domains that could be assessed in a standardized manner across various cohorts that include PWH in different countries. We collaboratively identified clinical and research priorities, as well as gaps in standardization of measurement domains, that can be used to move the field forward.
Learn More >Pain is one of the cardinal signs accompanying inflammation. The prostaglandins (PGs), synthetized from arachidonic acid by cyclooxygenase (COX)-2, are major bioactive lipids implicated in inflammation and pain. However, COX-2 is also able to metabolize other lipids, including the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA), to give glycerol ester (PG-G) and ethanolamide (PG-EA) derivatives of the PGs. Consequently, COX-2 can be considered as a hub not only controlling PG synthesis, but also PG-G and PG-EA synthesis. As they were more recently characterized, these endocannabinoid metabolites are less studied in nociception compared to PGs. Interestingly R-profens, previously considered as inactive enantiomers of nonsteroidal anti-inflammatory drugs (NSAIDs), are substrate-selective COX inhibitors. Indeed, R-flurbiprofen can selectively block PG-G and PG-EA production, without affecting PG synthesis from COX-2. Therefore, we compared the effect of R-flurbiprofen and S-flurbiprofen in models of inflammatory pain triggered by local administration of lipopolysaccharides (LPS) and carrageenan in mice. Remarkably, the effects of flurbiprofen enantiomers on mechanical hyperalgesia seem to depend on (i) the inflammatory stimuli, (ii) the route of administration, and (iii) the timing of administration. We also assessed the effect of administration of the PG-Gs, PG-EAs, and PGs on LPS-induced mechanical hyperalgesia. Our data support the interest of studying the nonhydrolytic endocannabinoid metabolism in the context of inflammatory pain.
Learn More >Recent studies have shown that ZBTB20, a zinc-finger protein containing transcription factor, is highly expressed in small-diameter primary sensory neurons in mice, and modulates pain through regulating TRP channels. However, whether ZBTB20 regulates itch sensation has not been demonstrated. In this study, small-diameter primary sensory neuron-specific ZBTB20 knockout (PN-ZB20KO) mice were used to investigate the role of ZBTB20 in the regulation of itch sensation. First, both histamine-dependent and non-histamine-dependent itch behaviors induced by injection of histamine and chloroquine (CQ) into the cheek were significantly diminished in PN-ZB20KO mice. Second, double immunohistochemistry showed that ZBTB20 was mainly expressed in CGRP-labeled small peptidergic neurons and was expressed at low levels in IB4-labeled small non-peptidergic and NF200-labeled large neurons in the trigeminal ganglia (TG). ZBTB20 was also expressed in most TRPV1 and TRPA1 neurons and to a lesser extent in TRPM8 neurons in the TG. Furthermore, cheek injection of histamine and CQ enhanced the mRNA expression of TRPV1 and TRPA1 but not TRPM8 in the TG. Moreover, TRPV1 and TRPA1 knockout (KO) mice exhibited attenuation of itch behavior induced by histamine and CQ, respectively. Finally, silencing endogenous ZBTB20 with recombinant lentivirus expressing a short hairpin RNA against ZBTB20 (LV-shZBTB20) in TG neurons attenuated histamine- and non-histamine-induced itch and downregulated TRP channels in the TG. Our study suggests that ZBTB20 plays an important role in mediating itch in small primary sensory neurons.
Learn More >The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because the many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations.
Learn More >Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to the underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free condition. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons.
Learn More >Cognitive impairment and chronic pain are amongst the most prevalent neurological sequelae of HIV infection, yet little is understood about the potential bidirectional relationship between the two conditions. Cognitive dysfunction can occur in chronic pain populations whilst those with cognitive impairment can display modified responses to experimentally induced painful stimuli. To date, this has not been explored in HIV cohorts.This study aimed to identify any contribution of chronic pain to cognitive impairment in HIV and to determine differences in pain characteristics between those with and without cognitive dysfunction.This was an observational cohort study involving people living with HIV ( = 148) in the United Kingdom. Participants underwent validated questionnaire-based measurement of pain severity, interference and symptom quality as well as conditioned pain modulation and quantitative sensory testing. All participants completed a computer-based cognitive function assessment.Fifty-seven participants met the criteria for cognitive impairment and 73 for chronic pain. The cognitive impairment group had a higher prevalence of chronic pain ( = 0.004) and reported more neuropathic symptoms ( = 0.001). Those with chronic pain performed less well in emotional recognition and verbal learning domains. The interaction identified between chronic pain and cognitive dysfunction warrants further exploration to identify causal links or shared pathology.
Learn More >To analyze industry payments to pain medicine physicians in the United States.
Learn More >Older adults with multiple chronic conditions (MCCs) vary in their health outcome goals and the health care that they prefer to receive to achieve these goals.
Learn More >Pain is the most distressing and disruptive feature of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) resulting in low quality of life (QOL) and disabilities. There is no single, characteristic pain pattern in patients with RAP and CP. Abdominal imaging features of CP accurately reflect morphologic features but they do not correlate with pain. Pain is the major driver of poor quality of life (QOL) and it is the constant pain, rather than intermittent pain that drives poor QOL. Furthermore, the most severe constant pain experience in CP is also a complex condition. The ability to target the etiopathogenesis of severe pain requires new methods to detect the exact pain mechanisms in an individual at cellular, tissue, system and psychiatric levels. In patients with complex and severe disease, it is likely that multiple overlapping mechanisms are simultaneously driving pain, anxiety and depression. Quantitative sensory testing (QST) shows promise in detecting alterations in central processing of pain signals and to classify patients for mechanistic and therapeutic studies. New genetic research suggests that genetic loci for severe pain in CP overlap with genetic loci for depression and other psychiatric disorders, providing additional insights and therapeutic targets for individual patients with severe CP pain. Well-designed clinical trials that integrate clinical features, QST, genetics and psychological assessments with targeted treatment and assessment of responses are required for a quantum leap forward. A better understanding of the context and mechanisms contributing to severe pain experiences in individual patients is predicted to lead to better therapies and quality of life.
Learn More >To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans.
Learn More >While multiple pharmacological and non-pharmacological interventions treating chronic non-specific low back pain (CLBP) are available, they have been shown to produce at best modest effects. Interventions such as repetitive transcranial magnetic stimulation (rTMS), a form of non-invasive brain stimulation, have exhibited promising results to alleviate chronic pain. However, evidence on the effectiveness of rTMS for CLBP is scarce due to limited rigorous clinical trials. Combining rTMS with motor control exercises (MCE) may help to address both central and nociceptive factors contributing to the persistence of LBP. The primary aim of this randomised controlled trial is to compare the effectiveness of a combination of rTMS and MCE to repeated rTMS sessions alone, sham rTMS and a combination of sham rTMS and MCE on pain intensity.
Learn More >Unlike motor symptoms, the effects of deep brain stimulation (DBS) on non-motor symptoms associated with dystonia remain unknown.
Learn More >Pain is reported as the leading cause of disability in the common forms of inflammatory arthritis conditions. Acting as a key player in nociceptive processing, neuroinflammation, and neuron-glia communication, the chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how the CCL2/CCR2 system in the dorsal root ganglion (DRG) contributes to the peripheral inflammatory pain sensitization.
Learn More >There is a clear need for novel and improved therapeutic strategies for alleviating chronic neuropathic pain, as well as a need for better understanding of brain mechanisms of neuropathic pain, which are less understood than spinal and peripheral mechanisms. The G protein-coupled receptor 55 (GPR55), is a lysophosphatidylinositol (LPI)-sensitive receptor that has also been involved in cannabinoid signaling. It is expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain control system. Behaviors, pharmacology, biochemistry tools, and stereotaxic microinjections were used to determine if GPR55 plays a role in pain control in a chronic constriction injury (CCI) neuropathic pain model in rats. It was found that the blockade of GPR55 action in the PAG can restore and drive a descending control system to mitigate neuropathic pain. Our data demonstrate that GPR55 play a role in the descending pain control system, and identify GPR55 at supraspinal level as a neuropathic pain brain mechanism.
Learn More >The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway has recently emerged as a novel therapeutic target in treating various diseases. Therefore, the present study aimed to assess the protective role of the Nrf2 activator, dimethyl fumarate (DMF) in the complete Freund's adjuvant (CFA)- induced arthritis model. DMF (25, 50, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered for 14 days. Pain-related tests, paw volume, and arthritic scores were measured weekly. Serum TNF-α, IL-1β, cyclic citrullinated peptide (CCP), C-reactive protein (CRP), and rheumatoid factor (RF) levels were estimated. Nitrite, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and myeloperoxidase (MPO) levels were also evaluated. NF-κB, Nrf2, HO-1, and COX-2 levels were estimated in the joint tissue. DMF treatment exerted anti-arthritic activity by enhancing the nociceptive threshold, improving arthritis scores, and reducing paw edema. Also, DMF suppressed changes in oxidative stress markers and inflammatory mediators and enhanced Nrf2 and HO-1 levels in CFA-injected rats. These findings indicate that the anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.
Learn More >Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3Kγ-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl/6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis of , and . This pathway was downregulated in the spinal cord with increased expression in the sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We also observed a significant increase in phosphorylated- JNK levels in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance in the peripheral nervous system. Continued research into this pathway will contribute to the development of new analgesic drug therapies.
Learn More >There is a large body of research exploring what it means for a person to live with chronic pain. However, existing research does not help us understand what it means to recover. We aimed to identify qualitative research that explored the experience of living with chronic pain published since 2012 and to understand the process of recovery.
Learn More >Long-term morphine use is associated with serious side effects, such as morphine-induced hyperalgesia and analgesic tolerance. Previous investigations have documented the association between dopamine (DA) neurons in the ventral tegmental area (VTA) and pain. However, whether VTA DA neurons are implicated in morphine-induced hyperalgesia and analgesic tolerance remains elusive.
Learn More >Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel activated by various physical stimuli such as cell swelling and shear stress. TRPV4 is expressed in bladder sensory nerves and epithelium, and its activation produces urinary dysfunction in rodents. However, there have been few reports regarding its involvement in bladder pain. Therefore, we investigated whether TRPV4 is involved in bladder pain in mouse cystitis model. Intraperitoneal injection of cyclophosphamide (CYP; 300 mg/kg) produced mechanical hypersensitivity in the lower abdomen associated with a severe inflammatory bladder in mice. The mechanical threshold was reversed significantly in Trpv4-knockout (KO) mice. Repeated injections of CYP (150 mg/kg) daily for 4 days provoked mild bladder inflammation and persistent mechanical hypersensitivity in mice. Trpv4-KO mice prevented a reduction of the mechanical threshold without an alteration in bladder inflammation. A selective TRPV4 antagonist also reversed the mechanical threshold in chronic cystitis mice. Although expression of Trpv4 was unchanged in the bladders of chronic cystitis mice, the level of phosphorylated TRPV4 was increased significantly. These results suggest involvement of TRPV4 in bladder pain of cystitis mice. A TRPV4 antagonist might be useful for patients with irritable bladder pain such as those with interstitial cystitis/painful bladder syndrome.
Learn More >Chemotherapy-induced neuropathic pain (CINP) is one of the most common complications of chemotherapeutic drugs which limits the dose and duration of potentially life-saving anticancer treatment and compromises the quality of life of patients. Our previous studies have reported that molecular hydrogen (H) can be used to prevent and treat various diseases. But the underlying mechanism remains unclear. The aim of the present study was to explore the effects of hydrogen-rich water on gut microbiota in CINP.
Learn More >To detect the spatio-temporal expression of S100A4 in a spinal nerve ligation (SNL) rat model. Also to figure out which other molecules directly interact with S100A4 to explore the possible mechanisms which might be involved in neuropathic pain.
Learn More >Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been any direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1β production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.
Learn More >Intervertebral disc (IVD) degeneration is characterised by catabolic and inflammatory processes that contribute largely to tissue degradation and chronic back pain. The disc cells are responsible for the pathological production of pro-inflammatory cytokines and catabolic enzymes leading to degeneration. However, this phenotypical change is poorly understood. Growing evidence in animal and human studies implicates Toll-like receptors (TLR) and their activation through danger-associated alarmins, found increasingly in degenerating IVDs. TLR signalling results in the release of pro-inflammatory cytokines and proteolytic enzymes that can directly cause IVD degeneration and back pain. This review aims to summarise the current literature on TLR activation in IVD degeneration and discuss potential treatment modalities to alleviate the inflammatory phenotype of disc cells in order to arrest IVD degeneration and back pain.
Learn More >Identifying pain-related response patterns and understanding functional mechanisms of symptom formation and recovery are important for improving treatment.
Learn More >To assess long-term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients.
Learn More >This review aims to summarize interventions used in the perioperative period to reduce the development of new persistent postoperative opioid use in opioid-naïve patients.
Learn More >Resilience represents a fundamental element in the experience of pain, as it allows adaptation to suffering and increases psychological social well-being and quality of life (QoL). We investigated resilience in patients affected by urologic chronic pelvic pain (UCPP) and the relationships with pain severity and distribution, catastrophizing and psychological distress.
Learn More >To assess the prevalence of migraine or severe headache among US adults by inflammatory bowel disease (IBD) status.
Learn More >Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear.
Learn More >With the aging population, it is clear that the demand for future chronic pain treatment modalities is at an all-time high. One of the newest treatment modalities that is gaining popularity with both practitioners and patients alike is that of regenerative medicine and the use of stem cells to treat chronic painful conditions. This article aims to distill the most recent, available data from both laboratory research and clinical trials to better illuminate the potentials for these therapies in the treatment of chronic pain.
Learn More >Dual enkephalinase inhibitors (DENKIs) are pain medications that indirectly activate opioid receptors and can be used as an alternative to traditional opioids. Understanding the physiology of enkephalins and their inhibitors and the pharmacology of these drugs will allow for proper clinical application for chronic pain patients in the future.
Learn More >Chronic pain is not well understood in opioid-dependent populations. We report the prevalence of chronic pain and pain characteristics in an opioid-dependent population by treatment type and gender.
Learn More >Most SARS-CoV-2-infected individuals never require hospitalization. However, some develop prolonged symptoms. We sought to characterize the spectrum of neurologic manifestations in non-hospitalized Covid-19 "long haulers".
Learn More >Numerous studies support the effectiveness of Acceptance and Commitment Therapy (ACT) for chronic pain, yet little research has been conducted about its underlying mechanisms of change, especially regarding patients with comorbid mental disorders. The present investigation addressed this issue by examining associations of processes targeted by ACT (pain acceptance, mindfulness, psychological flexibility) and clinical outcomes (pain intensity, somatic symptoms, physical health, mental health, depression, general anxiety).
Learn More >chronic pain, a common complaint among older adults, affects physical and mental well-being. While opioid use for pain management has increased over the years, pain management in older adults remains challenging, due to potential severe adverse effects of opioids in this population.
Learn More >Naturally occurring spine osteoarthritis is clinically associated with the manifestation of chronic inflammatory muscle (myofascial) disease. The purpose of this study was to investigate the causal association between experimentally induced spine osteoarthritis and neurogenic inflammatory responses within neurosegmentally linked myotomes. Wistar Kyoto rats were randomly assigned to spine facet compression surgery (L4-L6) or sham surgery. Animals exposed to facet compression surgery demonstrated radiographic signs of facet-osteoarthritis (L4-L6 spinal levels) and sensory changes (allodynia, thermal hyperalgesia) at 7, 14 and 21 days post-intervention, consistent with the induction of central sensitization; no radiologic or sensory changes were observed after sham surgery. Increased levels of proinflammatory biomarkers including substance P (SP), calcitonin gene related peptide (CGRP), protease-activated receptor-2 (PAR2) and calcium/calmodulin dependent protein kinase II (CaMKII) were observed post-surgery within neurosegmentally-linked rectus femoris (L2-L5) muscle when compared to the non-segmentally linked biceps brachii (C4-C7) muscle; no differences were observed between muscles in the sham surgery group. These findings offer novel insight into the potential role of spine osteoarthritis and neurogenic inflammatory mechanisms in the pathophysiology of chronic inflammatory muscle (myofascial) disease.
Learn More >Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT-2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn. The effects of forskolin and 6-Bnz-cAMP were not additive with NMDA-induced substance P release and were decreased by the NMDA receptor blocker MK-801. In cultured dorsal horn neurons, forskolin increased NMDA-induced Ca entry and the phosphorylation of the NR1 and NR2B subunits of the NMDA receptor. Therefore, cAMP-induced substance P release is mediated by the activating phosphorylation by PKA of NMDA receptors. Voltage-gated Ca channels, but not by TRPV1 or TRPA1, also contributed to cAMP-induced substance P release. Activation of PKA was required for the effects of forskolin and the three cAMP analogs. Epac2 contributed to the effects of forskolin and CPTOMe-cAMP, signaling through a Raf – mitogen-activated protein kinase pathway to activate Ca channels. Epac1 inhibitors induced NK1R internalization independently of substance P release. In rats with latent sensitization to pain, the effect of 6-Bnz-cAMP was unchanged, whereas the effect of forskolin was decreased due to the loss of the stimulatory effect of Epac2. Hence, substance P release induced by cAMP decreases during pain hypersensitivity.
Learn More >Despite the high prevalence of sleep disturbance, stress, and depressive symptoms among patients with episodic migraine, there has been limited prospective research examining how these comorbid symptoms relate to future headache risk.
Learn More >Migraine headache prevalence, etiology, and clinical presentations change from childhood to adulthood. Dural innervation plays a role in headache symptomatology, but the changes in innervation during development have not been fully explored in the literature.
Learn More >Adrenic acid (AdA, 22:4) is an ω-6 polyunsaturated fatty acid (PUFA), derived from arachidonic acid. Like other PUFAs, it is metabolized by cytochrome P450s to a group of epoxy fatty acids (EpFAs), epoxydocosatrienoic acids (EDTs). EpFAs are lipid mediators with various beneficial bioactivities, including exertion of analgesia and reduction of endoplasmic reticulum (ER) stress, that are degraded to dihydroxy fatty acids by the soluble epoxide hydrolase (sEH). However, the biological characteristics and activities of EDTs are relatively unexplored, and, alongside dihydroxydocosatrienoic acids (DHDTs), they had not been detected . Herein, EDT and DHDT regioisomers were synthesized, purified, and used as standards for analysis with a selective and quantitative high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Biological verification in AdA-rich tissues suggests that basal metabolite levels are highest in the liver, with 16,17-EDT concentrations consistently being the greatest across the analyzed tissues. Enzyme hydrolysis assessment revealed that EDTs are sEH substrates, with greatest relative rate preference for the 13,14-EDT regioisomer. Pretreatment with an EDT methyl ester regioisomer mixture significantly reduced the onset of tunicamycin-stimulated ER stress in human embryonic kidney cells. Finally, administration of the regioisomeric mixture effectively alleviated carrageenan-induced inflammatory pain in rats. This study indicates that EDTs and DHDTs are naturally occurring lipids, and EDTs could be another therapeutically relevant group of EpFAs.
Learn More >Our aim was to analyse body core temperature and peripheral vascular microcirculation at skin hypothenar eminence of the hands and its relationship to symptoms in fibromyalgia syndrome (FMS). A total of 80 FMS women and 80 healthy women, matched on weight, were enrolled in this case-control study. Thermography and infrared thermometer were used for evaluating the hypothenar regions and core body temperature, respectively. The main outcome measures were pain pressure thresholds (PPTs) and clinical questionnaires. Significant associations were observed between overall impact [ = 0.033; 95% confidence interval (95%CI) = 0.003, 0.062; = 0.030], daytime dysfunction ( = 0.203; 95%CI = 0.011, 0.395; = 0.039) and reduced activity ( = 0.045; 95%CI = 0.005, 0.085; = 0.029) and core body temperature in FMS women. PPTs including greater trochanter dominant ( = 0.254; 95%CI = 0.003, 0.504; = 0.047), greater trochanter non-dominant ( = 0.650; 95%CI = 0.141, 1.159; = 0.013), as well as sleeping medication ( = -0.242; 95%CI = -0.471, -0.013; = 0.039) were also associated with hypothenar eminence temperature. Data highlighted that FMS women showed correlations among body core temperature and hand temperature with the clinical symptoms.
Learn More >Interleukin-1β (IL-1β) is an important cytokine that modulates peripheral and central pain sensitization at the spinal level. Among its effects, it increases spinal cord excitability by reducing inhibitory Glycinergic and GABAergic neurotransmission. In the brain, IL-1β is released by glial cells in regions associated with pain processing during neuropathic pain. It also has important roles in neuroinflammation and in regulating NMDA receptor activity required for learning and memory. The modulation of glycine-mediated inhibitory activity via IL-1β may play a critical role in the perception of different levels of pain. The central nucleus of the amygdala (CeA) participates in receiving and processing pain information. Interestingly, this nucleus is enriched in the regulatory auxiliary glycine receptor (GlyR) β subunit (βGlyR); however, no studies have evaluated the effect of IL-1β on glycinergic neurotransmission in the brain. Hence, we hypothesized that IL-1β may modulate GlyR-mediated inhibitory activity via interactions with the βGlyR subunit. Our results show that the application of IL-1β (10 ng/ml) to CeA brain slices has a biphasic effect; transiently increases and then reduces sIPSC amplitude of CeA glycinergic currents. Additionally, we performed molecular docking, site-directed mutagenesis, and whole-cell voltage-clamp electrophysiological experiments in HEK cells transfected with GlyRs containing different GlyR subunits. These data indicate that IL-1β modulates GlyR activity by establishing hydrogen bonds with at least one key amino acid residue located in the back of the loop C at the ECD domain of the βGlyR subunit. The present results suggest that IL-1β in the CeA controls glycinergic neurotransmission, possibly via interactions with the βGlyR subunit. This effect could be relevant for understanding how IL-1β released by glia modulates central processing of pain, learning and memory, and is involved in neuroinflammation.
Learn More >Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.
Learn More >Spinal cord injury (SCI) is one of the main causes leading to neuropathic pain. Here, we aim to explore the molecular mechanism and function of lncRNA PVT1 in neuropathic pain induced by SCI. The expression of lncRNA PVT1, microRNA (miR) - 186-5p was measured via quantitative reverse transcription PCR (qRT-PCR), and the activation of astrocytes (labeled by GFAP) was detected by immunohistochemistry. Western blot was conducted to detect the expression of chemokine ligand 13 (CXCL13), chemokine receptor 5 (CXCR5), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP) in spinal cord injury lesions. The levels of inflammatory cytokines (including IL-1β and IL-6) and MDA in tissues were examined via Enzyme-linked immunosorbent assay (ELISA). In vitro experiments were also conducted in primary cultured astrocyte to explore the response of astrocyte to lipopolysaccharide (LPS). What's more, the PVT1-miR-186-5p interaction was verified via the dual luciferase activity assay and RNA immunoprecipitation (RIP) assay. The results demonstrated that the levels of PVT1, CXCL13 and CXCR5 were upregulated, while miR-186-5p were decreased in SCI rats' spinal cord and LPS-mediated astrocytes. In the SCI model, PVT1 depletion significantly alleviated neuropathic pain, astrocytic activation and reduced the expression of neuroinflammatory factors and proteins. The relevant mechanism studies confirmed that PVT1 is a competitive endogenous RNA (ceRNA) of miR-186-5p, targets and inhibits its expression and promotes the expression of CXCL13/CXCR5, while miR-186-5p targets CXCL13. In conclusion, inhibition of lncRNA PVT1 alleviates neuropathic pain in SCI rats by upregulating miR-186-5p and down-regulating CXCL13/CXCR5. The PVT1/miR-186-5p/CXCL13/CXCR5 axis can be used as a new therapeutic target for neuropathic pain.
Learn More >The association between depression and chronic pain is well established. However, few studies have examined the pathways from depression to chronic pain. The present cross-cultural study aimed to test the mediating effects of pain catastrophizing on associations between depression and chronic pain (eg, pain severity, pain intensity) among Korean American elderly.
Learn More >Treatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA.
Learn More >Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. IR has been associated with multiple conditions, including chronic pain. Fibromyalgia (FM) is one of the common generalized chronic painful conditions with an incidence rate affecting 3% to 6% of the population. Substantial interest and investigation into FM continue to generate many hypotheses.The relationship between IR and FM has not been explored. IR is known to cause abnormalities in the cerebral microvasculature, leading to focal hypoperfusion. IR also has been shown to cause cognitive impairment in FM patients, as in parkinsonism. As demonstrated by advanced imaging methods, similar brain perfusion abnormalities occur in the brain of patients with FM as with IR.
Learn More >Although conventional pain relief therapeutics have centered around mu-opioid agonists, these drugs are limited by adverse side effects, including respiratory depression and addiction potential. The ongoing opioid epidemic has galvanized research into novel analgesic therapies with more favorable profiles. New pharmacologic agents have been developed to target neuronal pathways involved in pain sensation. Certain receptors have been recognized to mediate nociceptive transmission, central sensitization, and the development of chronic pain states.
Learn More >To evaluate gender differences in clinical characteristics of migraine by examining presence and severity of cutaneous allodynia, migraine-related disability, neck pain and its associated disability, passive mobility of the upper cervical spine, and performance of the deep neck flexor muscles.
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