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Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in murine dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of translation and Inflammatory cues promote local translation of Arc in the skin. Arc-deficient male mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles (EVs), we hypothesized that intercellular Arc signaling regulates the inflammatory response in skin. We found that the excessive thermal responses and vasodilation observed in Arc defective mice are rescued by injection of Arc-containing EVs into the skin. Our findings suggest that activity-dependent production of Arc in afferent fibers regulates neurogenic inflammation potentially through intercellular signaling.Nociceptors play prominent roles in pain and inflammation. We examined rapid changes in the landscape of nascent translation in cultured dorsal root ganglia (DRGs) treated with a combination of inflammatory mediators using ribosome profiling. We identified several hundred transcripts subject to rapid preferential translation. Among them is the immediate early gene (IEG) Arc. We provide evidence that Arc is translated in afferent fibers in the skin. Arc-deficient mice display several signs of exaggerated inflammation which is normalized on injection of Arc containing extracellular vesicles (EVs). Our work suggests that noxious cues can trigger Arc production by nociceptors which in turn constrains neurogenic inflammation in the skin.
Learn More >Human NaV1.9 (hNaV1.9), encoded by SCN11A, is preferentially expressed in nociceptors, and its mutations have been linked to pain disorders. NaV1.9 could be a promising drug target for pain relief. However, the modulation of NaV1.9 activity has remained elusive. Here, we identified a new candidate NaV1.9-interacting partner, protein arginine methyltransferase 7 (PRMT7). Whole-cell voltage clamp recordings showed that coelectroporation of human SCN11A and PRMT7 in dorsal root ganglia (DRG) neurons of Scn11a-/- mice increased the hNaV1.9 current density. In contrast, a Prmt7 inhibitor (DS-437) reduced mNaV1.9 currents in Scn11a+/+ mice. Using the reporter molecule CD4, we observed an increased distribution of hLoop1 on the cell surface of PRMT7-overexpressing HKE293T cells. Furthermore, we found that PRMT7 mainly binds to residues 563-566 within the first intracellular loop of hNaV1.9 (hLoop1) and methylates hLoop1 at arginine residue 519. Moreover, overexpression of Prmt7 increased the number of action potential fired in DRG neurons of Scn11a+/+ mice but not Scn11a-/- mice. However, DS-437 significantly inhibited the action potential frequency of DRG neurons and relieved pain hypersensitivity in Scn11aA796G/A796G mice. In summary, our observations revealed that PRMT7 modulates neuronal excitability by regulating NaV1.9 currents, which may provide a potential method for pain treatment.
Learn More >The existence of a trigeminocervical complex (TCC) has been suggested based on animal data, but only indirect evidence exists in humans. We investigated the functional relationship between the trigeminal and the occipital region by stimulating one region and measuring electrical pain thresholds (EPTs) of the corresponding opposite region. This study consists of two single-blinded, randomized protocols. 40 healthy participants were recruited in the propaedeutic Protocol I. EPTs were measured on the V1 and the greater occipital nerve (GON) dermatome bilaterally as well as on the left forearm longitudinally before and after application of topical capsaicin. Protocol II was then online pre-registered and, additionally, the ipsilateral trigeminal dermatomes V2 and V3 were tested. GON stimulation increased the EPT ipsilateral at V1 after 20 minutes (p=0.006) compared to baseline, whereas trigeminal stimulation increased the EPT at the ipsilateral (p=0.023) as well as the contralateral GON (p=0.001) following capsaicin application. Protocol II confirmed these results and additionally showed that GON stimulation with capsaicin increased EPTs ipsilateral at all three trigeminal dermatomes and that trigeminal stimulation on V1 led to an ipsilateral increase of EPTs at GON, V2 and V3. Our data suggest a strong functional interplay between the trigeminal and occipital system in humans. The fact that stimulation of one of these dermatomes increases the electrical pain threshold of the respective other nerve could be explained by segmental inhibition on brainstem level.
Learn More >Reports have emerged of abrupt tapering among recipients of long-term prescription opioids to conform to new prescribing guidelines. We conducted a population-based, repeated cross-sectional time-series study among very high-dose (≥200 MME) opioid recipients in Ontario, Canada, to examine changes in the monthly prevalence of rapid tapering from 2014 to 2018, defined as recipients experiencing either a ≥50% reduction in daily doses or abrupt discontinuation sustained for 30 days. Interventional autoregressive integrated moving average (ARIMA) models were used to test for significant changes following key guidelines, and drug policies and programs. A sensitivity analysis examined rapid tapering sustained for 90 days. The monthly prevalence of rapid tapering events was stable from January 2014 to September 2016 (average monthly prevalence: 1.4%), but increased from 1.4% in October 2016 to 1.8% in April 2017 (p=0.001), coincident with Ontario's Fentanyl Patch-for-Patch Return Program implementation. Transient spikes in the prevalence of rapid tapering also occurred two months following Ontario's delisting of publicly funded high-strength opioids and the release of updated Canadian Opioid Prescribing Guideline for Chronic Pain, reaching 2.3% in March 2017 and July 2017, respectively. However this prevalence decreased to 1.2% in December 2018 (p<.0001). Although the prevalence of abrupt opioid discontinuation was lower, similar trends were observed. Our sensitivity analysis examining longer-lasting rapid tapering found similar trends but lower prevalence, with no changes in complete discontinuation. These temporary increases in rapid tapering events highlight the need for improved communication and evidence-based resources for prescribers to minimize negative consequences of evolving policies and guidelines.
Learn More >In recent years, long-term prescribing and use of strong opioids for chronic non-cancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses (MAs) compared the efficacy, safety and tolerability of strong opioids with placebo/non-opioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in four electronic databases (Medline, Web of Science, Cochrane Library and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled RCTs for CLBP and five studies (2 RCTs and 3 non-randomized studies) of opioids vs non-opioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise MAs were performed for efficacy, safety and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low- to low-certainty findings suggest that 4-15 weeks (short-/intermediate term) opioid therapy in CLBP (compared to placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events (AEs), with likely no effect on disability. In contrast, long-term opioid therapy (≥ 6 months) in CNCP may not be superior to non-opioids in improving pain or disability/pain-related function, but seems to be associated with more AEs, opioid abuse/dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.
Learn More >Neuropathic pain is more prevalent in women. However, females are under-represented in animal experiments, and the mechanisms of sex differences remain inadequately understood. We used the spared nerve injury (SNI) model in rats to characterize sex differences in pain behaviour, unbiased RNA-Seq and proteomics to study the mechanisms. Male and female rats were subjected to SNI- and sham-surgery. Mechanical and cold allodynia were assessed. Ipsilateral lumbar dorsal root ganglia (DRG) and spinal cord (SC) segments were collected for RNA-seq analysis with DESeq2 on Day 7. Cerebrospinal fluid (CSF) samples for proteomic analysis and DRGs and SCs for analysis of IB-4 and CGRP, and IBA1 and GFAP, respectively, were collected on Day 21. Females developed stronger mechanical allodynia. There were no differences between the sexes in CGRP and IB-4 in the DRG or glial cell markers in the SC. No CSF protein showed change following SNI. DRG and SC showed abundant changes in gene expression. Sexually dimorphic responses were found in genes related to T-cells (cd28, ctla4, cd274, cd4, prf1), other immunological responses (dpp4, c5a, cxcr2 and il1b), neuronal transmission (hrh3, thbs4, chrna4 and pdyn), plasticity (atf3, c1qc and reg3b), and others (bhlhe22, mcpt1l, trpv6). We observed significantly stronger mechanical allodynia in females and numerous sexually dimorphic changes in gene expression following SNI in rats. Several genes have previously been linked to NP, while some are novel. Our results suggest gene targets for further studies in the development of new, possibly sex-specific, therapies for NP.
Learn More >Spinal fusion surgery is associated with severe acute postsurgical pain and high rates of chronic postsurgical pain in adolescents. Psychological distress, sleep disturbance, and low pain self-efficacy predict higher acute pain and likelihood of developing chronic postsurgical pain. Interventions targeting baseline psychosocial risk factors have potential to interrupt a negative trajectory of continued pain and poor health-related quality of life (HRQL) over time but have not yet been developed and evaluated. This randomized controlled trial will test effectiveness of a digital peri-operative cognitive-behavioral intervention (SurgeryPal) vs. education-control delivered to adolescents and their parents to improve acute and chronic pain and health outcomes in adolescents undergoing spine surgery.
Learn More >Headache is identified as a common post-COVID sequelae experienced by COVID-19 survivors. The aim of this pooled analysis is to synthesize the prevalence of post-COVID headache in hospitalized and non-hospitalized patients recovered from SARS-CoV-2 infection.
Learn More >Chronic pain is a complex disease that affects a large proportion of the population. With little to no effective treatments currently available for patients, this malady presents a large burden to society. has been previously used to describe conserved molecular components of nociception in larvae and adults. However, adult assays tend to rely on avoidance behaviours, and whilst larval acute thermal avoidance assays exist, larvae are not best suited to a chronic pain scenario as the condition must be long-term. Therefore, an adult thermal nociception response assay was required to study injury-evoked changes in heat nociception threshold (allodynia and hyperalgesia) over time, and we describe such a protocol here. Following leg amputation, flies display increased thermal sensitivity (allodynia) to innocuous temperatures but not an increase in magnitude of response (hyperalgesia) to noxious heat. Our method allows for individualised analysis of both allodynia and hyperalgesia.
Learn More >Neuronal calcium sensor 1 (NCS1), a calcium-binding protein, and transient receptor potential V4 (TRPV4), a plasma membrane calcium channel, are fundamental in the regulation of calcium homeostasis. The interactions of these proteins and their regulation by paclitaxel (PTX) were investigated using biochemical, pharmacological, and electrophysiological approaches in both a breast cancer epithelial cell model and a neuronal model. TRPV4 and NCS1 reciprocally immunoprecipitated each other, suggesting that they comprise a signaling complex. The functional consequence of this physical association was that TRPV4 currents increased with increased NCS1 expression. Calcium fluxes through TRPV4 correlated with the magnitude of TRPV4 currents and these calcium fluxes depended on NCS1 expression levels. Exposure to PTX amplified the acute effects of TRPV4 expression, currents, and calcium fluxes, but decreased the expression of NCS1. These findings augment the understanding of the properties of TRPV4, the role of NCS1 in the regulation of TRPV4, and the cellular mechanisms of PTX-induced neuropathy. TRPV4 and NCS1 physically and functionally interact. Increased expression of NCS1 enhances TRPV4 dependent currents, which are further amplified by treatment with the chemotherapeutic drug, paclitaxel, an effect associated with adverse effects of chemotherapy, including neuropathy.
Learn More >To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
Learn More >the interest of clinical reaseach in polymorphisms and epigenetics in migraine has been growing over the years. Due to the new era of preventative migraine treatment opened by monoclonal antibodies (mAbs) targeting the signaling of the calcitonin-gene related peptide (CGRP), the present systematic review aims at identifying genetic variants occurring along the CGRP pathway and at verifying whether these can affect the clinical features and the course of disease and the responsiveness of patients to therapy.
Learn More >Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM.
Learn More >The use of the Injustice Experience Questionnaire (IEQ) in psychological assessment of individuals with chronic pain is supported by research. The psychometric properties of the Swedish version, the IEQ-S, has not yet been evaluated. Hence, the aim was to investigate structural validity, and concurrent criterion validity of the IEQ-S against the Work Ability Index (WAI), the Pain Catastrophizing Scale (PCS-SW), the Patient Health Questionnaire 9-item depression module (PHQ-9), and the Generalized anxiety disorder 7-item scale (GAD-7). Internal consistency and test-retest reliability were also studied.
Learn More >Opioids are still widely prescribed to long-term pain patients although they are no longer recommended for long-term treatments due to poor evidence for long-term efficacy, risks of serious side effects, and the possibility of inducing opioid hyperalgesia. In a Cochrane study from 2017, the authors identified an urgent need for more randomized controlled trials investigating the efficiency and effects of opioid tapering. The study aimed to assess (1) the efficiency of a structured intervention in causing stable reductions of opioid consumption in a population with long-term non-malignant pain and (2) effects on pain, pain cognitions, physical and mental health, quality of life, and functioning in response to opioid tapering.
Learn More >To evaluate fidelity of delivery of a nurse-led non-pharmacological complex intervention for knee pain.
Learn More >We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST).
Learn More >The contact burn injury model is an experimental contact thermode-based physiological pain model primarily applied in research of drug efficacy in humans. The employment of the contact burn injury model across studies has been inconsistent regarding essential methodological variables, challenging the validity of the model. This systematic review analyzes methodologies, outcomes, and research applications of the contact burn injury model. Based on these results, we propose an improved contact burn injury testing paradigm. A literature search was conducted (15-JUL-2020) using PubMed, EMBASE, Web of Science, and Google Scholar. Sixty-four studies were included. The contact burn injury model induced consistent levels of primary and secondary hyperalgesia. However, the analyses revealed variations in the methodology of the contact burn injury heating paradigm and the post-burn application of test stimuli. The contact burn injury model had limited testing sensitivity in demonstrating analgesic efficacy. There was a weak correlation between experimental and clinical pain intensity variables. The data analysis was limited by the methodological heterogenicity of the different studies and a high risk of bias across the studies. In conclusion, although the contact burn injury model provides robust hyperalgesia, it has limited efficacy in testing analgesic drug response. Recommendations for future use of the model are being provided, but further research is needed to improve the sensitivity of the contact burn injury method. The protocol for this review has been published in PROSPERO (ID: CRD42019133734).
Learn More >To evaluate the efficacy of a pediatric headache infusion center (HIC) in alleviating the symptoms and preventing future visits to the emergency department (ED).
Learn More >There is a lack of knowledge on coping with pain and sub-group specific pain-coping profiles among older home care receivers with chronic pain. To describe pain-coping strategies, identify subgroups based on cognitive and behavioral pain-coping strategies and pain-related psychological impairment and to compare these groups with regard to socio-demographic, medical, pharmacological and psychological characteristics.
Learn More >Migraine is a very prevalent disease worldwide and is a major cause of disability. As known for a long time, migraine is associated with neurogenic inflammation. Epidemiological studies have shown that migraine is comorbid with several chronic inflammatory diseases, including multiple sclerosis (MS), chronic inflammatory rheumatic diseases (CIRDs) and inflammatory bowel diseases (IBDs). This brief narrative review highlights some recent data supporting a link between migraine and these three chronic inflammatory diseases. Studies found that migraine prevalence is approximately two-fold higher in these diseases compared to the general population. The causal link between migraine and these chronic inflammatory diseases has not been identified yet. Here, we suggest that systemic mediators (such as cytokines) and gut microbiome make migraine worse or add significant risks. Systemic inflammation biomarkers and gut microbiome modification are certainly avenues worth exploring.
Learn More >Epidural injections are one of the commonly performed procedures in managing low back and lower extremity pain. In the past, Pinto et al and Chou et al performed systematic reviews and meta-analyses with a recent update from Oliveira et al showing lack of effectiveness of epidural steroid injections in managing lumbar radiculopathy. In contrast, multiple other systematic reviews and meta-analyses have supported the efficacy and use of epidural injections utilizing fluoroscopic guidance.
Learn More >The role of psychological factors influencing chronic pain has been well documented. This review includes a historical perspective and current examination of the literature on psychological and behavioral health characteristics and their influence on chronic pain.
Learn More >Infraorbital nerve-chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision-making performance as well as synaptic and large-scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION-CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potential in the trigeminal ganglia-SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA-ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision-making in chronic TNP state.
Learn More >The aim of this observational study was to describe social support and patterns of attachment among patients with migraine. We hypothesized that in comparison to the general population, insecure attachment is overrepresented in migraine patients, and that these patients have less social support. We also aimed to study the specific relationship between attachment and social support. We hypothesized that patients with an insecure attachment style have less social support than patients with a secure attachment style. A total of 101 consecutive patients (88.1% women) aged between 25 and 60 (average age = 41.4) were recruited at the Specialized Center for the Consultation of Primary Headaches at the Regional University Hospital Center of Besançon (France). Migraine impact and disability were evaluated using the Headache Impact Test (HIT-6) questionnaire and Migraine Disability Assessment (MIDAS) questionnaire. Patients also completed several self-administered psychological questionnaires in their validated French versions: the Medical Outcome Survey 36-Item Short-Form Health Survey, the Cungi Scale, the State-Trait Anxiety Inventory, the Beck Depression Inventory, the Relationship Scales Questionnaire and the Sarason's Social Support Questionnaire. The distribution of attachment profiles was different from that of the general population, with an overrepresentation of insecure attachment styles ( = 0.018). Our study showed that migraine patients had less social support than the general population, both in terms of the number of people providing support ( = 0.002) and the level of satisfaction concerning this social support (p = 0.000). We also found that neither the number of available persons score nor the satisfaction score were statistically different between the four attachment categories ( = 0.49). Patient's attachment style and social support influence the patient-doctor relationship, the therapeutic alliance and health behaviors such as treatment adherence. Based on the data we obtained, we developed applications in patient care for people with particular attachment styles and low social support. A treatment plan adapted to the patient's attachment profile should be created to develop "precision medicine" using a personalized approach to the doctor-patient relationship. We would also recommend encouraging patients to participate in support groups, in order to strengthen their attachment systems and gain social support. https://clinicaltrials.gov/ct2/show/NCT03577548, identifier NCT03577548.
Learn More >A scoping review to synthesize evidence and assess articles describing the use of beta-endorphins as a pain biomarker in chronic pain patients treated with non-invasive brain stimulation techniques was systematically performed with respect to the study quality, the technique employed and the results. Independent reviewers determined if the article met the study criteria at each stage for it to be included. Content analysis was applied and summarized. The results are described in a narrative form grouped by pain condition, type of intervention, stimulation protocol, outcome measures and main results. A total of 67 of 73 references were excluded, and 6 identified studies met the inclusion criteria. The study design, sample size, stimulation type, session protocol and the main findings of each study were extracted. The studies in this scoping review ranged from unsatisfactory to good based on the adopted criteria, with no study achieving an excellent rating. There is limited evidence on the dosage of beta-endorphin in chronic pain conditions during treatment with NIBS. Based on this literature, evidence suggests that BE may not only be useful for acute and persistent pain, but also for a variety of chronic pain states in which opioids are not effective.
Learn More >Sleep problems and regular leisure time physical activity (LTPA) are interrelated and have contrasting effects on risk of back pain. However, no studies have investigated the influence of long-term poor sleep quality on risk of back-related disability, or if LTPA modifies this association. The study comprised data on 8601 people who participated in three consecutive surveys over ~ 22 years, and who reported no chronic back pain at the two first surveys. Adjusted risk ratios (RRs) for back-related disability were calculated at the last survey, associated with the joint effect of changes in sleep quality between the two first surveys and meeting physical activity guidelines at the second survey. Compared to people with long-term good sleep, people with long-term poor sleep had nearly twice the risk of back-related disability (RR 1.92, 95% CI 1.48-2.49). There was no statistical interaction between sleep and LTPA but people who reported long-term poor sleep and meeting the physical activity guidelines had 35% lower risk of back-related disability compared to people with same level of sleep problems, but who not met the guidelines. These findings suggest that long-term poor sleep quality contributes to a substantially increased risk of chronic and disabling back pain irrespective of LTPA.
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