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In mice, spared nerve injury replicates symptoms of human neuropathic pain and induces upregulation of many genes in somatosensory neurons. Here we used single cell transcriptomics to probe the effects of partial infraorbital transection of the trigeminal nerve at the cellular level. Uninjured neurons were unaffected by transection of major nerve branches, segregating into many different classes. In marked contrast, axotomy rapidly transformed damaged neurons into just two new and closely-related classes where almost all original identity was lost. Remarkably, sensory neurons also adopted this transcriptomic state following various minor peripheral injuries. By genetically marking injured neurons, we showed that the injury-induced transformation was reversible, with damaged cells slowly reacquiring normal gene expression profiles. Thus, our data expose transcriptomic plasticity, previously thought of as a driver of chronic pain, as a programed response to many types of injury and a potential mechanism for regulating sensation during wound healing.
Learn More >Neuropathic pain caused by nerve injury presents with severe spontaneous pain and a variety of comorbidities, including deficits in higher executive functions. None of these clinical problems are adequately treated with current analgesics. Targeting of the mitogen-activated protein kinase-interacting kinase (MNK1/2) and its phosphorylation target, the mRNA cap binding protein eIF4E, attenuates many types of nociceptive plasticity induced by inflammatory mediators and chemotherapeutic drugs but inhibiting this pathway does not alter nerve injury-induced mechanical allodynia. We used genetic manipulations and pharmacology to inhibit MNK-eIF4E activity in animals with spared nerve injury, a model of peripheral nerve injury (PNI)-induced neuropathic pain. We assessed the presence of spontaneous pain using conditioned place preference. We also tested performance in a medial prefrontal cortex (mPFC)-dependent rule-shifting task. WT neuropathic animals showed signs of spontaneous pain and were significantly impaired in the rule-shifting task while genetic and pharmacological inhibition of the MNK-eIF4E signaling axis protected against and reversed spontaneous pain and PNI-mediated cognitive impairment. Additionally, pharmacological and genetic inhibition of MNK-eIF4E signaling completely blocked and reversed maladaptive shortening in the length of axon initial segments (AIS) in the mPFC of PNI mice. Surprisingly, these striking positive outcomes on neuropathic pain occurred in the absence of any effect on mechanical allodynia, a standard test for neuropathic pain efficacy. Our results illustrate new testing paradigms for determining preclinical neuropathic pain efficacy and point to the MNK inhibitor tomivosertib (eFT508) as an important drug candidate for neuropathic pain treatment.
Learn More >Tactile stimuli are integrated and processed by neuronal circuits in the deep dorsal horn of the spinal cord. Several spinal interneuron populations have been implicated in tactile information processing. However, dorsal horn projection neurons that contribute to the postsynaptic dorsal column (PSDC) pathway transmitting tactile information to the brain are poorly characterized. Here, we show that spinal neurons marked by the expression of Zic2cre mediate light touch sensitivity and textural discrimination. A subset of Zic2cre neurons are PSDC neurons that project to brainstem dorsal column nuclei, and chemogenetic activation of Zic2 PSDC neurons increases sensitivity to light touch stimuli. Zic2 neurons receive direct input from the cortex and brainstem motor nuclei and are required for corrective motor movements. These results suggest that Zic2 neurons integrate sensory input from cutaneous afferents with descending signals from the brain to promote corrective movements and transmit processed touch information back to the brain.
Learn More >Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain's energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. Technological advances have enabled the examination of different aspects of cerebral metabolism in patients with migraine, and complementary animal research has highlighted possible metabolic mechanisms in migraine pathophysiology. An increasing amount of evidence – much of it clinical – suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. Greater understanding of metabolism in migraine offers novel therapeutic opportunities. In this Review, we describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data (including neuroimaging, biochemical, genetic and therapeutic studies), and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. We discuss experimental data to consider potential mechanisms by which metabolic abnormalities could generate attacks. Finally, we highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions.
Learn More >Patient beliefs and perceptions about the causes and meaning of their chronic pain are related to their psychosocial functioning. Beliefs and perceptions about chronic pain held by spouses may also be related to patient functioning. We used a laboratory procedure to evaluate whether spouse beliefs about and perceptions of chronic pain were related to spouse negative responses toward patients with chronic low back pain during a conflictual discussion and to their attributions about patient pain behavior during a subsequent pain-induction task. Patients (n = 71) and their spouses (n = 71) participated in a 10-minute discussion followed by the patient undergoing a 10-minute structured pain behavior task. Findings were that a) spouse perceptions that patient's pain was a mystery were significantly related to greater patient perceived spouse critical/invalidating responses toward the patient during the discussion; and b) spouse perceptions that patient's pain was a mystery were related to internal and negative attributions spouses made while observing patients display pain behaviors during the structured pain behavior task. Inasmuch as both spouse critical/invalidating speech toward patients and negative attributions regarding the cause of patient behavior are related to poor patient functioning, spouse uncertainty about the source and potential legitimacy of their partner's pain may play crucial roles in affecting patient well-being. PERSPECTIVE: Spouse beliefs about and perceptions of patient chronic pain were related to spouse behavior toward patients during a discussion and to attributions explaining patient pain during physical activity. If spouse confusion and doubt about patient pain is related to negative behavior and attributions, then modifying these perceptions may be a fundamental intervention target.
Learn More >Our objective was to develop comprehensive national estimates of the total burden of HZ among US adults, including direct (ie, medical costs) and indirect (ie, productivity losses) costs, as well as its psychosocial impact (ie, quality of life losses).Using a patient-level microsimulation model, we projected health and economic outcomes among US adults aged 18 years and older using a 10-year time horizon. We conducted a comprehensive systematic literature review to generate parameter values and conducted simulation modeling to generate our outcomes, including numbers of cases of uncomplicated HZ, postherpetic neuralgia (PHN), and ocular complications, productivity losses, and losses in quality adjusted life years (QALYs). We used a societal perspective for outcomes; the costing year was 2015.Projected outcomes for an unvaccinated population included 1.1 million HZ cases, 114,000 PHN cases, and 43,000 ocular complications annually, resulting in approximately 67,000 QALYs lost. HZ and its complications would incur costs of $2.4 billion in direct medical costs and productivity losses annually.Projected QALY-losses were most sensitive to HZ and PHN health utility values in the model. Cost estimates were most sensitive to the probability of HZ and to the costs per episode of PHN.The national burden of direct, indirect, and psychosocial HZ costs is substantial. Our results can inform economic analyses for HZ vaccines. Comprehensive, national assessments of the total burden of other painful conditions would be very informative.
Learn More >Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N=155 NAs, N=150 non-Hispanic Whites, NHW). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, electric), and subjective (eg, pain ratings, pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.
Learn More >We conducted a multicenter, randomized, patient and assessor-blinded, sham-controlled trial to investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) in patients with neuropathic pain. Patients were randomly assigned to receive five daily sessions of active or sham rTMS of M1 corresponding to the part of the body experiencing the worst pain (500 pulses per session at 5 Hz). Responders were invited to enroll in an open-label continuous trial involving four weekly sessions of active rTMS. The primary outcome was a mean decrease in a visual analogue scale (VAS) of pain intensity (scaled 0-100 mm) measured daily during the daily sessions in an intention-to-treat population. Secondary outcomes were other pain scores, quality-of-life measures, and depression score. 144 patients were assigned to the active or sham stimulation groups. The primary outcome, mean VAS decreases, was not significantly different (p=0.58) between the active stimulation group (mean, 8.0) and the sham group (9.2) during the daily sessions. The secondary outcomes were not significantly different between two groups. The patients enrolled in the continuous weekly rTMS achieved more pain relief in the active stimulation group compared with the sham (p<0.01). No serious adverse events were observed. Five daily sessions of rTMS with stimulus conditions used in this trial were ineffective in short-term pain relief in the whole study population with various neuropathic pain. Long-term administration to the responders should be investigated for the clinical use of rTMS on neuropathic pain in the future trials.
Learn More >A child maltreatment history is reported more frequently among adults with chronic pain compared to the general population; unfortunately, studies have primarily relied upon retrospective maltreatment reports by adults with chronic pain. This prospective study assessed pain symptoms in a cohort of young adult women with a documented history of child maltreatment, compared with a matched cohort of women who did not experience childhood maltreatment. Young women (N = 477) were recruited between ages 14-17 years and followed annually to age 19. Of these women, 57% experienced maltreatment (i.e., physical, sexual, or emotional abuse, neglect; n = 273) substantiated by child welfare record. Maltreated women were demographically-matched to non-maltreated women, also confirmed by child welfare record. In adolescence, post-traumatic stress was assessed. Women were contacted as young adults (Mage = 24.76; n = 383) and surveyed about their pain experiences, including the presence of pain in the past week, pain severity (0-10), and number of body areas with pain. Mediation path analyses examining the impact of maltreatment and adolescent post-traumatic stress on young adult pain were estimated via structural equation modeling. As adults, women who had experienced child maltreatment reported higher pain intensity, a greater number of pain locations, and were more likely to experience pain in the previous week than non-maltreated women. Adolescent post-traumatic stress partially explained the effects of maltreatment on pain. Young adult women who experienced child maltreatment are at higher risk for pain, particularly when they also experienced post-traumatic stress as adolescents.
Learn More >Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1Tac1 nociceptor-MRGPRB2 mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
Learn More >Insufficient perioperative pain treatment is known as a highly predictive risk factor for the development of chronic postoperative pain. Remifentanil is an ultrashort-acting opioid that provides quick and efficient analgesia but is associated with the induction of opioid-induced hyperalgesia. Despite these well-known characteristics, this substance is being increasingly used in anesthesia and in a variety of medical fields, such as intensive-care medicine and obstetrics.The aim of our study was to reveal whether remifentanil influences postoperative pain, the requirement for postoperative analgesics, and requirement of antiemetics (as indirect indicator of postoperative nausea and vomiting (PONV), as well as the effects on time to extubation and length of stay in the postanesthesia care-unit (PACU) in daily clinical routine.From an electronic medical records database of 55,693 anesthesias, we analyzed data from all patients receiving intraabdominal surgery (visceral, gynecological and urological) under general anesthesia or combined general-epidural anesthesia by propensity score matching.The administration of remifentanil was associated with higher postoperative pain scores despite a higher requirement of postoperative analgesics. Additional epidural analgesia was not able to avoid this finding.The intraoperative use of remifentanil is associated with a deterioration of pain levels and postoperative analgesic requirement, wherefore the potential benefit of this substance seems to be outweighed by its potential disadvantages. Especially in operative procedures in which high postoperative pain scores are expected, the unreflective use should be critically questioned.
Learn More >Migraine is characterized by an increased sensitivity to visual stimuli that worsens during attacks. Recent evidence has shown that feedforward volleys carrying incoming visual information induce high frequency (gamma) oscillations in the visual cortex, while feedback volleys arriving from higher order brain areas induce oscillatory activity at lower frequencies (theta/alpha/low-beta). We investigated visually induced high (feedforward) and low (feedback) frequency activations in healthy subjects and various migraine patients. Visual evoked potentials from 20 healthy controls and 70 migraine patients (30 inter-ictal and 20 ictal episodic migraineurs, 20 chronic migraineurs) were analysed in the frequency domain. We compared power in the theta-alpha-low beta and gamma range between groups, and searched for correlations between the low-to-high frequency activity ratio and number of monthly headache and migraine days. Compared to healthy controls, inter-ictal migraine patients had increased visually induced low frequency (feedback) activity. Conversely, ictal and chronic migraine patients showed an augmented gamma band (feedforward) power. The low-frequency-to-gamma (feedback/feedforward) activity ratio correlated negatively with monthly headache days and tended to do so with migraine days. Our findings show that visual processing is differentially altered depending on migraine cycle and type. Feedback control from higher order cortical areas predominates interictally in episodic migraine while migraine attacks and chronic migraine are associated with enhanced incoming afferent activity, confirming their similar electrophysiological profile. The presence of headache is associated with proportionally higher gamma (feedforward) activities. Perspective: This study provides an insight into the pathophysiology of migraine headache from the perspective of cortical sensory processing dynamics. Patients with migraine present alterations in feedback and feedforward visual signalling that differ with the presence of headache.
Learn More >All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.
Learn More >Humanized monoclonal antibody galcanezumab, which binds to calcitonin gene-related peptide, has shown efficacy for episodic and chronic migraine prevention. These analyses evaluated galcanezumab response for migraine headache prevention in patients who previously failed onabotulinumtoxinA ("nonresponse" or "inadequate response" or safety reasons).
Learn More >Agonists at the δ opioid receptor are known to be potent anti-hyperalgesics in chronic pain models and to be effective in models of anxiety and depression. However, some δ opioid agonists have pro-convulsant properties whilst tolerance to the therapeutic effects can develop. Previous evidence indicates that different agonists acting at the δ opioid receptor differentially engage signalling and regulatory pathways with significant effects on behavioural outcomes. As such, interest is now growing in the development of biased agonists as a potential means to target specific signalling pathways and potentially improve the therapeutic profile of δ opioid agonists. Here we report on PN6047 (3-[[4-(dimethylcarbamoyl)phenyl]-[1-thiazol-5-ylmethyl)-4-piperidylidene]methyl]benzamide) a novel G protein-biased and selective δ opioid agonist. In cell based assays PN6047 fully engages G protein signalling but is a partial agonist in both the arrestin recruitment and internalisation assays. PN6047 is effective in rodent models of chronic pain but shows no detectable analgesic tolerance following prolonged treatment. In addition, PN6047 exhibited antidepressant-like activity in the forced swim test and importantly, the drug had no effect on chemically induced seizures. PN6047 did not exhibit reward-like properties in the conditioned place preference test or induce respiratory depression. Thus, δ opioid ligands with limited arrestin signalling such as PN6047 may be therapeutically beneficial in the treatment of chronic pain states. SIGNIFICANCE STATEMENT: PN6047 is a selective, G protein-biased δ opioid agonist with efficacy in preclinical models of chronic pain. No analgesic tolerance was observed after prolonged treatment and PN6047 does not display pro-convulsant activity or other opioid-mediated adverse effects. Our data suggest that δ opioid ligands with limited arrestin signalling will be beneficial in the treatment of chronic pain.
Learn More >Migraine and vasovagal syncope are comorbid conditions that may share part of their pathophysiology through autonomic control of the systemic circulation. Nitroglycerin can trigger both syncope and migraine attacks, suggesting enhanced systemic sensitivity in migraine. We aimed to determine the cardiovascular responses to nitroglycerin in migraine.
Learn More >CGRP plays a major role in the pathophysiology of migraine. Concomitant, CGRP plays a role in endogenous neurovascular protection from severe vasoconstriction associated with e.g. cerebral or cardiac ischemia. The CGRP antagonistic antibodies Fremanezumab (TEVA Pharmaceuticals) and Erenumab (Novartis/Amgen) have successfully been developed for the prevention of frequent migraine attacks. Whereas these antibodies might challenge endogenous neurovasular protection during severe cerebral or coronary vasoconstriction, potential future therapeutic CGRP agonists might induce migraine-like headaches in migraineurs. In the current study segments of cerebral artery have been used to obtain mechanistic insight of the CGRP-neutralizing anti-body Fremanezumab in neurovascular regulation in vitro. The basilar artery was selected due to its relevance in subarachnoid hemorrhage (SAH). Erenumab is known to block the human CGRP receptor and Fremanezumab to neutralize both human and rat CGRP. Results confirmed that Erenumab does not block the rat CGRP receptor and that Fremanezumab inhibits the vasodilatory effect induced by both human CGRP, rat CGRP and the metabolically stable CGRP analog, SAX in rat basilar artery. Fremanezumab also inhibits the vasodilatory effect of capsaicin in constricted segments of basilar artery. Capsaicin is used as a pharmacological tool to induce secretion of endogenous perivascular CGRP and our studies confirm that the antibody reach the perivascular sensory synaptic cleft and blocks the vasodilatory response of released CGRP in the present in vitro model. Thus, CGRP neutralization might have the mechanistic potential to block vasoprotective responses to severe vasoconstriction provided they reach the site of action and Fremanezumab is an important tool for future investigations of the impact of CGRP physiology.
Learn More >Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder in which the two main clinical features are pelvic pain and lower urinary tract symptoms. There are currently many approaches for its management, using both pharmacological and non-pharmacological interventions. The National Institute of Health – Chronic Prostatitis Symptom Index (NIH-CPSI) score is a validated measure commonly used to measure CP/CPPS symptoms. We considered a 25% decrease of NIH-CPSI baseline score or a six-point reduction as MCID.
Learn More >Opioid prescriptions for chronic pain and subsequent opioid-related complications have risen dramatically in the US. Recent data suggest that medical marijuana laws have been associated with lower state-level opioid overdose mortality. In a national survey, we examined the prevalence of substitution of marijuana for opioids among US adults taking opioids for pain.Using GfK's KnowledgePanel, we conducted an Internet-based survey of a nationally representative sample of 16,280 adults in 2017 about individual perceptions and use of marijuana. We developed questions designed to assess the extent and reasons for substitution of marijuana for opioids. We examined opioid substitution among respondents with a history of ever using marijuana who used opioids in the past 12 months. There were 9,003 respondents, corresponding to a 55.3% response rate. The mean age was 48 years. Among the 5% (n = 486) who reported ever using marijuana and using opioids in the past year, 43% used opioids daily, and 23% reported current (past 30 day) marijuana use. Forty-one percent reported a decrease or cessation of opioid use due to marijuana use; 46% reported no change in opioid use; and 8% reported an increase in opioid use. We found that a substantial number of US adults reported that they substituted marijuana for opioids.
Learn More >The blood-brain (BBB) and blood-nerve barriers ensure protection of the nervous system but pose a challenge for treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood-neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thioglitazone type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood-neural barriers. The peak ELB00824/ pioglitazone concentration (Cmax) in the brain was 5.4 versus 0.2 µM in blood at equivalent doses (10 mg/kg i.p.). The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long-term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.
Learn More >This systematic review and meta-analysis aimed to examine the effects of physical exercise cum cognitive-behavioural therapy (CBT) on alleviating pain intensity, functional disabilities, and mood/mental symptoms in those suffering with chronic musculoskeletal pain. MEDLINE, EMBASE, PubMEd, PsycINFO and CINAHL were searched to identify relevant randomised controlled trials from inception to 31 December 2018. The inclusion criteria were: (a) adults ≥18 years old with chronic musculoskeletal pain ≥3 months, (b) randomised controlled design, (c) a treatment arm consisting of physical intervention and CBT combined, (d) the comparison arm being waitlist, usual care or other non-pharmacological interventions such as physical exercise or CBT alone, and (e) outcomes including pain intensity, pain-related functional disabilities (primary outcomes), or mood/mental symptoms (secondary outcome). The exclusion criteria were: (a) the presence of comorbid mental illnesses other than depression and anxiety and (b) non-English publication. The search resulted in 1696 records and 18 articles were selected for review. Results varied greatly across studies, with most studies reporting null or small effects but a few studies reporting very large effects up to 2-year follow-up. Pooled effect sizes (Hedges' g) were ~1.00 for pain intensity and functional disability, but no effect was found for mood/mental symptoms. The effects were mainly driven by several studies reporting unusually large differences between the exercise cum CBT intervention and exercise alone. When these outliers were removed, the effect on pain intensity disappeared at post-intervention while a weak effect (g = 0.21) favouring the combined intervention remained at follow-up assessment. More consistent effects were observed for functional disability, though the effects were small (g = 0.26 and 0.37 at post-intervention and follow-up respectively). More importantly, the value of adding CBT to exercise interventions is questionable, as consistent benefits were not seen. The clinical implications and directions for future research are discussed.
Learn More >Background and aims Persons with chronic widespread pain (CWP) have poor medical outcomes and increased mortality. But there are no universally accepted criteria for CWP or of methods to assess it. The most common criteria come from the 1990 American College of Rheumatology (ACR) fibromyalgia (FM) criteria, but that method (WP1990) can identify CWP with as few as three pain sites, and in subjects with wide differences in illness severity. Recently, to correct WP1990 deficiencies, the 2016 fibromyalgia criteria provided a modified CWP definition (WP2016) by dividing the body into five regions of three pain sites each and requiring a minimum of four regions of pain. Although solving the geographic problem of pain distribution, the problem of just how many pain sites (pain diffuseness) are required remained a problem, as WP2016 required as few as four painful sites. To better characterize CWP, we compared four CWP definitions with respect to symmetry, extent of pain sites and association with clinical severity variables. Methods We characterized pain in 40,960 subjects, including pain at 19 individual sites and five pain regions, and calculated the widespread pain index (WPI) and polysymptomatic distress scales (PDS) from epidemiology, primary care and rheumatology databases. We developed and evaluated a new definition for CWP, (WP2019), defined as pain in four or five regions and a pain site score of at least seven of 15 sites. We also tested a definition based on the number of painful sites (WPI ≥ 7). Results In rheumatology patients, WP1990 and WPI ≥ 7 classified patients with <4 regions as WSP. CWP was noted in 51.3% by WP1990, 41.7% by WP2016, 37.6% of WPI ≥ 7 and 33.9% by WP2019. 2016 FM criteria was satisfied in WP1990 (51.1%), WP2016 (63.3%), WPI ≥ 7 (69.0%) and WP2019 (76.6%). WP2019 positive patients had more severe clinical symptoms compared with WP1990, WP2016 and WPI ≥ 7, and similar to but less than FM 2016 positive patients. In stepwise fashion, scores for functional disability, visual analog scale fatigue and pain, WPI, polysymptomatic distress score and Patient Health Questionnaire 15 (PHQ-15) worsened from WP1990 through WP2016, WPI ≥ 7 and WP2019. Conclusions WP2019 combines the high WPI scores of WPI ≥ 7 and the symmetry of WP2016, and is associated with the most abnormal clinical scores. The WP1990 does not appear to be an effective measure. We suggest that CWP can be better defined by combining 4-region pain and a total pain site score ≥7 (WP2019). This definition provides a simple, unambiguous measure that is suitable for clinical and research use as a standalone diagnosis that is integrated with fibromyalgia definitions. Implications Definitions of CWP in research and clinic care are arbitrary and have varied, and different definitions of CWP identify different sets of patients, making a universal interpretation of CWP uncertain. In addition, CWP is a mandatory component of some fibromyalgia criteria. Our study provides quantitative data on the differences between CWP definitions and their criteria, allowing better understanding of research results and a guide to the use of CWP in clinical care.
Learn More >Low back pain (LBP) is a widespread problem and the leading cause of disability worldwide. While the cause of LBP is multifactorial, several studies suggested that inflammatory mediators in damaged subchondral plates of degenerating discs may lead to chemical sensitization and mechanical stimulation, eventually causing pain. The goal of this study was to explore associations between such changes and LBP related disability using Dynamic Contrast Enhanced MRI.
Learn More >This protocol describes the objective and methods of a systematic review of the association between quantitative sensory testing (QST) measures and pain intensity or disability in paediatric chronic pain (PCP). The review will also assess whether the relationship strength is moderated by variables related to the QST method and pain condition; the use of QST in PCP (modalities, outcome measures and anatomical test sites as well as differentiating between pain mechanisms (eg, neuropathic vs nociceptive) and in selecting analgesics); the reliability of QST across the paediatric age range; the ability of QST to differentiate patients with chronic pain from healthy controls; and differences between anatomical test sites.
Learn More >The opioid-mediated analgesic activity of mucosal CD4 T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4 T lymphocytes alleviate from inflammation-induced abdominal pain in mice with defective immune regulation.
Learn More >Neuropathic pain is highly prevalent in pathological conditions such as diabetes, herpes zoster, trauma, etc. The severity and refractoriness to treatments make neuropathic pain a significant health concern. The transforming growth factor (TGF-β) family of cytokines is involved in pain modulation. Bone morphogenetic proteins (BMPs) constitute the largest subgroup within the TGF-β family. BMP-7 induces the transcription of genes coding endogenous opioid precursors in vitro. However, a nociception modulatory function for this cytokine remains unexplored in vivo. Herein, we show that BMP-7 and its type I receptors were detected in regions of the nervous system involved in pain transmission, processing, and modulation. BMP-7 haploinsufficiency confers to male and female mice a tactile hyperalgesia phenotype to mechanical stimuli, both at baseline and after sciatic nerve injury (SNI). The administration of recombinant BMP-7 (rBMP-7) reduced the severity of the allodynia after SNI in rodents without sexual dimorphism. Central administration of rBMP-7 delayed allodynia development after SNI and reduced the severity of allodynia. The opioid antagonist naloxone antagonized the antinociceptive effect of rBMP-7 in rats. The analgesic effect of morphine was significantly attenuated in BMP-7 mice. The antiallodynic effect of voluntary exercise after SNI, whose mechanism involves the endogenous opioid system, was hampered by BMP-7 deficiency while potentiated by rBMP-7. Our results suggest that BMP-7 may constitute a novel therapeutic target for the treatment of neuropathic pain, which improves the function of the endogenous pain-resolution mechanisms to alleviate chronic pain.
Learn More >Neurotensin (NT) exerts its analgesic effects through activation of the G protein-coupled receptors NTS1 and NTS2. This opioid-independent antinociception represents a potential alternative for pain management. While activation of NTS1 also induces a drop in blood pressure and body temperature, NTS2 appears to be an analgesic target free of these adverse effects. Here, we report modifications of NT at Tyr11 to increase selectivity towards NTS2, complemented by modifications at the N-terminus to impair proteolytic degradation of the biologically active NT(8-13) sequence. Replacement of Tyr11 by either 6-OH-Tic or 7-OH-Tic resulted in a significant loss of binding affinity to NTS1 and subsequent NTS2 selectivity. Incorporation of the unnatural amino acid β3hLys at position 8 increased the half-life to over 24 h in plasma. Simultaneous integration of both β3hLys8 and 6-OH-Tic11 into NT(8-13) produced a potent and NTS2-selective analogue with strong analgesic action after intrathecal delivery in the rat formalin-induced pain model with an ED50 of 1.4 nmol. Additionally, intravenous administration of this NT analogue did not produce persistent hypotension or hypothermia. These results demonstrate that NT analogues harbouring unnatural amino acids at positions 8 and 11 can enhance crucial pharmacokinetic and pharmacodynamic features for NT(8-13) analogues, i.e., proteolytic stability, NTS2 selectivity and an improved analgesic/adverse effect ratio.
Learn More >Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.
Learn More >Background and aims Traumatic anterior shoulder dislocation (ASD) is frequent in active populations and associated with a 39% higher risk of recurrent dislocation, which may cause persistent shoulder problems, pain, and impaired shoulder-related quality of life. While local and distant pressure pain sensitivity has been demonstrated in other shoulder conditions, little is known about the link between pressure pain sensitivity and ASD. The interesting aspect is whether recurrent dislocation – resulting in symptoms of longer duration – is associated with more pronounced pressure pain sensitivity, or if presence of pressure pain sensitivity may be part of the reasons why patients develop recurrent dislocation. Therefore, this study aimed at evaluating whether patients with recurrent ASD display greater pressure pain sensitivity and more painful body sites than patients with first-time ASD. Methods This was a cross-sectional analysis of baseline data from a randomized controlled trial including 34 patients with first-time ASD [82% male, mean (SD) age 26 (7) years] and 22 patients with recurrent ASD [96% male, mean (SD) age 25 (5) years]. Patients were assessed as follows: (1) assessment of local and distant pressure pain sensitivity evaluated by pressure pain thresholds (PPTs) using a handheld algometer on mm. trapezius superior, levator scapula, pectorales major, deltoideus, and tibialis anterior, (2) pain intensity at rest during the previous 24 h, (3) number of ASD, and (4) number of painful body sites on a region-divided body chart. Results The PPTs were not significantly different between first-time and recurrent ASD [mean (SD) kPa for m. trapezius superior 264 (110) vs. 261 (88), m. levator scapula 301 (157) vs. 325 (163), m. pectorales major 234 (163) vs. 269 (130), m. deltoideus 290 (166) vs. 352 (173), m. tibialis anterior 420 (202) vs. 449 (184)], two-way ANCOVA, adjusted for sex and age, F (4,263) = 0.29, p = 0.88. For both groups, the PPTs were lower at the shoulder sites than at m. tibialis anterior (difference 117-184 kPa, 95% CI range 33-267). Females had lower PPTs than males (difference 124 kPa, 95% CI 64-183). The number (SD) of painful body sites were 2.2 (1.9) for first-time ASD and 2.6 (5.4) for recurrent ASD, with no between-group differences, one-way ANCOVA, adjusted for sex and age, F (1, 52) = 0.24, p = 0.63. There was a strong correlation between PPTs at the shoulder and lower leg, r = 0.84, p < 0.01. Conclusions This study demonstrated no differences in local and distant pressure pain sensitivity or number of painful body sites between patients with first-time and recurrent ASD. Females had lower PPTs than males, and a strong correlation was found between PPTs at the shoulder and lower leg. Implications Patients with first-time and recurrent ASD seem to have similar pressure pain sensitivity, but lower PPTs compared to existing normative data, suggesting that it is relevant to evaluate the status of the pain system in these patients to prevent triggering or worsening of their symptoms. However, it remains unanswered how these changes affect the patients' ability to undergo rehabilitation, symptom response and long-term shoulder function.
Learn More >Vestibular migraine (VM) is the most common cause of spontaneous vertigo but remains poorly understood. We investigated the hypothesis that central vestibular pathways are sensitized in VM by measuring self-motion perceptual thresholds in patients and control subjects and by characterizing the vestibulo-ocular reflex (VOR) and vestibular and headache symptom severity. VM patients were abnormally sensitive to roll tilt, which co-modulates semicircular canal and otolith organ activity, but not to motions that activate the canals or otolith organs in isolation, implying sensitization of canal-otolith integration. When tilt thresholds were considered together with vestibular symptom severity or VOR dynamics, VM patients segregated into two clusters. Thresholds in one cluster correlated positively with symptoms and with the VOR time constant; thresholds in the second cluster were uniformly low and independent of symptoms and the time constant. The VM threshold abnormality showed a frequency-dependence that paralleled the brain stem velocity storage mechanism. These results support a pathogenic model where vestibular symptoms emanate from the vestibular nuclei, which are sensitized by migraine-related brainstem regions and simultaneously suppressed by inhibitory feedback from the cerebellar nodulus and uvula, the site of canal-otolith integration. This conceptual framework elucidates VM pathophysiology and could potentially facilitate its diagnosis and treatment.
Learn More >It has been suggested that alterations in inflammation molecules maintain chronic pain although little is known about how these factors influence homeostatic and inflammatory events in common chronic pain conditions. Nonpharmacological interventions might be associated with alterations in inflammation markers in blood. This study of patients with chronic pain investigates whether an interdisciplinary multimodal rehabilitation program (IMMRP) was associated with significant alterations in the plasma pattern of 68 cytokines/chemokines 1 year after rehabilitation and whether such changes were associated with clinical changes. Blood samples and self-reports of pain, psychological distress, and physical activity of 25 complex chronic pain patients were collected pre-IMMRP and at 12-month follow-up. Analyses of inflammatory proteins (cytokines/chemokines/growth factors) were performed directly in plasma using the multiplex immunoassay technology Meso Scale Discovery. This explorative pilot study found that 12 substances, mainly pro-inflammatory, decreased after IMMRP. In two other relatively small IMMRP studies, four of these proinflammatory markers were also associated with decreases. The pattern of cytokines/chemokines pre-IMMRP was associated with changes in psychological distress but not with pain or physical activity. The present study cannot impute cause and effect. These results together with the results of the two previous IMMRP studies suggest that there is a need for larger and more strictly controlled studies of IMMRP with respect to inflammatory markers in blood. Such studies need to consider responders/non-responders, additional therapies, involved pain mechanisms and diagnoses. This and the two other studies open up for developing biologically measurable outcomes from plasma. Such biomarkers will be an important tool for further development of IMMRP and possibly other treatments for patients w ith chronic pain.
Learn More >Endometriosis has a significant cost of illness burden in Europe, UK and the USA, with the majority of costs coming from reductions in productivity. However, information is scarce on if there is a differing impact between endometriosis and other causes of chronic pelvic pain, and if there are modifiable factors, such as pain severity, that may be significant contributors to the overall burden.
Learn More >To compare adverse childhood experiences (ACEs) in women with chronic pelvic pain with a control group, and describe occurrence of specific ACEs in women with chronic pelvic pain.
Learn More >Pediatric patients with chronic musculoskeletal conditions such as idiopathic scoliosis awaiting surgical correction can experience pain that interferes with their daily functioning. Reports of this interference are commonly gathered from patients through the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference Scale and through parent-proxy scores. However, the child and parent/caregiver reports vary. In order to provide appropriate treatment for young patients with pain, the nature of the discrepancies and under which circumstances the reports differ needs to be understood. This report offers new information on the level of concordance among parent and child report of pain interference within this patient population, and which parent and child characteristics may influence concordance rates.
Learn More >To determine the magnitude of the association between cardiovascular disease and chronic musculoskeletal pain.
Learn More >Chronic low back pain (LBP) is a leading cause of disability worldwide. Biopsychosocial rehabilitation programs have been advocated for its management, especially since the widespread acceptance of the biopsychosocial model of chronic pain. Despite extensive evidence of its short-term benefits, few studies have reported on its long-term effect and more specifically on indirect outcomes such as return to work and quality of life (QoL). The present study evaluated the long-term effect of a multidisciplinary biopsychosocial rehabilitation (MBR) program for patients with chronic LBP, for which short- and intermediate-term efficacy had been established, with an emphasis on recovering work capability.
Learn More >Examine the interrelationship between smoking and pain in the US population.
Learn More >Among painful disorders, migraine is distinguishable by its chronic pathology and episodic clinical manifestation. Only a small percentage of patients with migraine progress to a chronic form of migraine. Both peripheral and central portions of the trigeminal system are involved in the pathophysiology of migraine pain, as they are involved in the processes of peripheral and central sensitization, alongside various subcortical and cortical brain structures. This review focuses on clinical, neurophysiological, and neuroimaging data underscoring cortical pain processing in migraine. Data obtained from quantitative sensory testings are inconclusive and support the involvement of the peripheral portion of the trigeminovascular system as indirect evidence of peripheral sensitization, solely during the headache phase. The assessment of subjective pain intensity in response to several painful modalities has not been conclusive for the clear state of central sensitization in between migraine attacks but for the subclinical allodynia state that defines the boundary between behavioural responses and an irritable nervous state. Modulation of the brainstem and midbrain pain pathways, in conjunction with the thalamic and thalamocortical pathways, may be critical for the initiation and maintenance of migraine attacks. Several studies using different neuroimaging techniques have demonstrated that brains experiencing migraine undergo plastic changes in both microstructure and macrostructure and in the functioning of cortical networks, which may manifest early in the life of a patient with migraine. Further studies are required to understand how specific these results are to migraine relative to other painful disorders.
Learn More >Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia . Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoidmediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.
Learn More >The number of unintentional deaths due to prescription drug overdose has risen in recent years due to the increased utilization of opioid analgesics. Pain is one of the most common reasons for patients to visit an emergency department (ED) and is often treated with opioid analgesics. In 2016, the Centers for Disease Control and Prevention (CDC) released guidelines for primary care providers on prescribing opioids for chronic pain.
Learn More >Sickle cell disease is a uniquely complex painful disease, with lifelong episodes of unpredictable acute pain and superimposed chronic pain in adulthood. Both painful crises and chronic pain in sickle cell disease lack strong objective pathological correlates and their mechanisms are poorly understood. Opioids have emerged as the standard of care for severe acute pain in sickle cell disease and many patients with chronic pain are maintained on chronic opioid therapy. The strong association between recurrent acute pain and chronic pain in SCD blurs the distinction between acute and chronic opioid management paradigms. In addition, opioid management for SCD is dogged by stigma and concerns regarding addiction. This review aims to synthesize the broad literature on opioids to highlight the clinical complexity of opioid management in sickle cell disease and suggest directions for future research and clinical innovation.
Learn More >Fibromyalgia (FM) is a chronic condition characterized by chronic pain, fatigue and loss of function which significantly impairs quality of life. Although treatment of FM remains disputed, some studies point at the efficacy of interdisciplinary therapy. This study aims to analyze the effectiveness, cost-utility and benefits of a multicomponent therapy on quality of life (main variable), functional impact, mood and pain in people suffering from FM that attend primary care centers (PCCs) of the Catalan Institute of Health (ICS).
Learn More >To explore strategies used by people living with chronic pain when participating in physical activity and exercise and their recommendations for health care providers when promoting participation in physical activity and exercise.
Learn More >Various features of the cerebral cortex and white matter have been extensively investigated in migraine with aura (MwA), but the morphological characteristics of subcortical structures have been largely neglected. The aim of this study was to identify possible differences in subcortical structures between MwA patients and healthy subjects (HS), and also to determine the correlations between the characteristics of migraine aura and the volumes of subcortical structures.
Learn More >: Pruritus is a well-recognized paraneoplastic phenomenon. Previous studies have examined the association of itch with a variety of malignancies in adults. However, no large study has examined this association in a pediatric population. : A retrospective study was conducted of patients age 18 or less seen at Johns Hopkins Health System between 2012 and 2019. : A pediatric hospital population of 1,042,976 patients was reviewed. Pruritus was observed in 3836 pediatric patients of whom 130 also had cancer. Pediatric patients with pruritus were significantly more likely to have concomitant malignancy compared to pediatric patients without pruritus (OR 12.84; 95% CI 10.73-15.35, < 0.001). Malignancies most strongly associated with pruritus included neoplasms of the blood (OR 14.38; 95% CI 11.30-18.29, < 0.001), bone (OR 29.02, 95% CI 18.28-46.06, < 0.001) and skin (OR 22.76, 95% CI 9.14-56.72, < 0.001. : Pruritus is significantly associated with malignancy in the pediatric hospital population. Clinicians should also be aware of the high burden of itch in pediatric malignancies and the variation in pruritus across malignancies.
Learn More >Fibromyalgia-associated chronic pain occurring without organic causes exerts negative effects on patients' quality of life, thereby necessitating the development of superior drugs. Since non-organic pain in patients with fibromyalgia occurs without external stimuli, an endpoint measure that reflects patients' spontaneous pain should be implemented in preclinical research. The present study is the first to apply the rat grimace scale (RGS), a facial expression-dependent measure developed for quantifying spontaneous pain, to the rat with reserpine-induced myalgia, an animal model of fibromyalgia exhibiting non-organic pain. Animals were videotaped and still images of facial expressions were captured and scored in a blind fashion. The reserpine-induced myalgia rats exhibited a significant increase in the RGS score, which was sustained for 2 weeks or more after the induction of fibromyalgia-like state by reserpine injection. The period of RGS score elevation was similar to that of reduced paw withdrawal threshold (PWT) measured using the von Frey filament test, a conventional measure of evoked pain. The elevated RGS score and the decreased PWT were relieved by gabapentin (an αδ subunit ligand) and duloxetine (a serotonin and noradrenaline reuptake inhibitor), but not by diclofenac (a nonsteroidal anti-inflammatory drug), buprenorphine (a mu-opioid receptor agonist), or diazepam (a benzodiazepine). The present study suggests that facial expressions in reserpine-induced myalgia rats simulate non-organic pain occurring spontaneously in patients with fibromyalgia. This finding achieves a coordination of pain measures between the animal model and patients with fibromyalgia and would improve the translation of analgesic efficacies between them.
Learn More >Chronic pain is a common condition that affects the physical, emotional, and mental well-being of patients and can significantly diminish their quality of life. Due to growing concerns about the substantial risks of long-term opioid use, both governmental agencies and professional societies have recommended prioritizing the use of nonpharmacologic treatments, when suitable, in order to reduce or eliminate the need for opioid use. The use of 10 kHz spinal cord stimulation (10 kHz SCS) is one such nonpharmacologic alternative for the treatment of chronic, intractable pain of the trunk and limbs. This review examines published clinical data regarding the efficacy of 10 kHz SCS for decreasing chronic pain in patients and its potential to reduce or eliminate opioid usage. Multiple prospective and retrospective studies in patients with intractable pain demonstrated that 10 kHz SCS treatment provided ≥50% pain relief in >70% patients after at least 1 year of treatment. Pain relief with 10 kHz SCS therapy ranged from 54% to 87% in the studies. More importantly, the mean daily dose of opioids required by patients in these studies was reduced after 10 kHz SCS treatment, and on average over 60% patients in studies either reduced or eliminated opioids at the last follow-up.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition which occurs as a consequence of cancer chemotherapy with anti-cancer agents like paclitaxel, oxaliplatin, etc. Despite immense research in the pathological pathways involved in CIPN, treatment options still remain limited. Recently, pathological involvement of Wnt signaling has been investigated in various neuropathic pain models, however there are no reports as yet on the role of Wnt signaling in CIPN. In the present study, we have investigated the neuroprotective effects of Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU76454 (β-catenin inhibitor) in paclitaxel-induced neuropathic pain. Paclitaxel (2 mg/kg, i. p.) was administered to male Sprague Dawley rats on four alternate days. After 21 days, paclitaxel-treated rats showed reduced behavioral pain thresholds (cold allodynia, heat & mechanical hyperalgesia) and nerve functions (nerve conduction velocity and nerve blood flow). Moreover, Wnt signaling proteins (Wnt3a, β-catenin, c-myc and Dvl1), inflammatory marker (matrix metalloproteinase 2) and endoplasmic reticulum stress marker (GRP78) were found to be upregulated in the sciatic nerves of paclitaxel-treated rats accompanied with loss of intraepidermal nerve fiber density as compared to the control rats. Intrathecal administration of Wnt inhibitors (each at dose of 10 and 30 μM) for three consecutive days to paclitaxel-treated rats, significantly improved behavioral pain thresholds and nerve functional parameters by inhibition of Wnt signaling, inflammation, endoplasmic reticulum stress and improvement of intraepidermal nerve fiber density. All these results suggested the neuroprotective potential of Wnt signaling inhibitors in CIPN.
Learn More >P2Y purinergic receptors expressed in neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG) contributes to inflammatory and neuropathic pain. P2Y receptor expression is reported in the spinal cord, dorsal root ganglion (DRG), and TG. In present study, the role of P2Y receptor in the TG in inflammatory orofacial pain of Sprague-Dawley (SD) rats was investigated. Peripheral injection of complete Freund's adjuvant (CFA) induced mechanical hyperalgesia with the rapid upregulation of P2Y receptor, glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), C-C chemokine CCL2, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated p38 (p-p38) proteins in the TG. Furthermore, immunofluorescence staining confirmed the CFA-induced upregulation of P2Y receptor. Double immunostaining showed that P2Y receptor colocalized with glutamine synthetase (GS) and neuronal nuclei (NeuN). Finally, trigeminal injection of a selective antagonist (PPTN) of P2Y receptor attenuated CFA-induced mechanical hyperalgesia. PPTN also decreased the upregulation of the GFAP, IL-1β, TNF-α, CCL2, p-ERK1/2, and p-p38 proteins. Our findings showed that P2Y receptor in TG may contribute to orofacial inflammatory pain via regulating SGCs activation, releasing cytokines (IL-1β, TNF-α, and CCL2), and phosphorylating ERK1/2 and p38.
Learn More >Fibromyalgia (FM) is a prevalent chronic pain disorder associated with large suffering and substantial societal costs. Pain-related avoidance behaviour and hypervigilance to bodily symptoms are common in FM and contribute in maintaining and exacerbating the disorder. Exposure therapy targeting avoidance behaviours and hypervigilance has shown promise in the treatment of FM. The present study investigated mediators of treatment outcome in exposure therapy for FM. We used data from a randomised trial, where 140 participants were allocated to 10-week internet-delivered exposure therapy or to a waiting-list control condition. The main outcome variable (FM symptoms) and the hypothesized mediators (FM-related avoidance behaviour, mindful non-reactivity and FM-related worry) were measured weekly throughout treatment. Mediation analyses were conducted using linear mixed effects models with bootstrap replication and time-lagged analysis. Results indicated that all three process variables were significant mediators of FM severity. However, in the time-lagged analyses, only FM-related avoidance behaviour displayed a unidirectional relationship over time with FM symptoms, suggesting a causal effect. Thus, results illustrate that changes in avoidance behaviour mediate the outcome of exposure on FM symptoms, which implies that avoidance behaviour is an important treatment target in exposure therapy.
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