I am a
Home I AM A Search Login

Papers: 6 Feb 2021 - 12 Feb 2021

Share this

The effect of the anti-diabetic drug metformin on musculoskeletal pain: a cross-sectional study with 21,889 individuals from the UK Biobank.

Although metformin there is growing evidence of metformin's pleiotropic effects, including possible effects on pain, there is a lack of study investigating the association of metformin with the prevalence of musculoskeletal pain among a large type 2 diabetes cohort.

Learn More >

Effects of Trigger Point Dry Needling for Nontraumatic Shoulder Pain of Musculoskeletal Origin: A Systematic Review and Meta-Analysis.

The purpose of this study was to evaluate the effects of trigger point (TrP) dry needling alone or as an adjunct to other interventions on pain intensity and related disability in nontraumatic shoulder pain.

Learn More >

Kappa Opioid Signaling at the Crossroads of Chronic Pain and Opioid Addiction.

Pain is complex and is a unique experience for individuals in that no two people will have exactly the same physiological and emotional response to the same noxious stimulus or injury. Pain is composed of two essential processes: a sensory component that allows for discrimination of the intensity and location of a painful stimulus and an emotional component that underlies the affective, motivational, unpleasant, and aversive response to a painful stimulus. Kappa opioid receptor (KOR) activation in the periphery and throughout the neuroaxis modulates both of these components of the pain experience. In this chapter we focus on recent findings that KORs contribute to the emotional, aversive nature of chronic pain, including how expression in the limbic circuitry contributes to anhedonic states and components of opioid misuse disorder. While the primary focus is on preclinical pain models, we also highlight clinical or human research where there is strong evidence for KOR involvement in negative affective states associated with chronic pain and opioid misuse.

Learn More >

Derivation of peripheral nociceptive, mechanoreceptive, and proprioceptive sensory neurons from the same culture of human pluripotent stem cells.

The three peripheral sensory neuron (SN) subtypes, nociceptors, mechanoreceptors, and proprioceptors, localize to dorsal root ganglia and convey sensations such as pain, temperature, pressure, and limb movement/position. Despite previous reports, to date no protocol is available allowing the generation of all three SN subtypes at high efficiency and purity from human pluripotent stem cells (hPSCs). We describe a chemically defined differentiation protocol that generates all three SN subtypes from the same starting population, as well as methods to enrich for each individual subtype. The protocol yields high efficiency and purity cultures that are electrically active and respond to specific stimuli. We describe their molecular character and maturity stage and provide evidence for their use as an axotomy model; we show disease phenotypes in hPSCs derived from patients with familial dysautonomia. Our protocol will allow the modeling of human disorders affecting SNs, the search for treatments, and the study of human development.

Learn More >

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel.

The endocannabinoid system is a promising target to mitigate pain as the endocannabinoids are endogenous ligands of the pain-mediating receptors-cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Herein, we report on a class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl-serotonin (NA5HT) by epoxygenases. EpoNADA and epoNA5HT are dual-functional rheostat modulators of the endocannabinoid-TRPV1 axis. EpoNADA and epoNA5HT are stronger modulators of TRPV1 than either NADA or NA5HT, and epoNA5HT displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. These epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1β, TNF-α and nitrous oxide and raise anti-inflammatory IL-10 cytokine in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of anandamide. Detailed kinetics and molecular dynamics simulation studies provide evidence for this potentiation using the epoxygenase human CYP2J2. Taken together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are potent, multi-faceted molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors.

Learn More >

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine.

Learn More >

Sensory Nerves Regulate Transcriptional Dynamics of Lymph Node Cells.

The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of lymph nodes (LN) by nerves remains largely unknown. Huang et al. demonstrate that LNs are innervated by unique peptidergic nociceptors that signal to various endothelial, stromal, and immune cell types in LNs.

Learn More >

Immunosensation: Neuroimmune Cross Talk in the Skin.

Classically, skin was considered a mere structural barrier protecting organisms from a diversity of environmental insults. In recent decades, the cutaneous immune system has become recognized as a complex immunologic barrier involved in both antimicrobial immunity and homeostatic processes like wound healing. To sense a variety of chemical, mechanical, and thermal stimuli, the skin harbors one of the most sophisticated sensory networks in the body. However, recent studies suggest that the cutaneous nervous system is highly integrated with the immune system to encode specific sensations into evolutionarily conserved protective behaviors. In addition to directly sensing pathogens, neurons employ novel neuroimmune mechanisms to provide host immunity. Therefore, given that sensation underlies various physiologies through increasingly complex reflex arcs, a much more dynamic picture is emerging of the skin as a truly systemic organ with highly coordinated physical, immunologic, and neural functions in barrier immunology. Expected final online publication date for the , Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Learn More >

Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study.

To examine county level associations between the prevalence of medical and recreational cannabis stores (referred to as dispensaries) and opioid related mortality rates.

Learn More >

Cannabis liberalisation and the US opioid crisis.

Learn More >

Convergence of peptidergic and non-peptidergic protein markers in the human dorsal root ganglion and spinal dorsal horn.

Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina 1-2, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences. This article is protected by copyright. All rights reserved.

Learn More >

Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats.

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Learn More >

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site.

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

Learn More >

Pharmacological restoration of anti-nociceptive functions in the prefrontal cortex relieves chronic pain.

Chronic pain affects one in four adults, and effective non-sedating and non-addictive treatments are urgently needed. Chronic pain causes maladaptive changes in the cerebral cortex, which can lead to impaired endogenous nociceptive processing. However, it is not yet clear if drugs that restore endogenous cortical regulation could provide an effective therapeutic strategy for chronic pain. Here, we studied the nociceptive response of neurons in the prelimbic region of the prefrontal cortex (PL-PFC) in freely behaving rats using a spared nerve injury (SNI) model of chronic pain, and the impact of AMPAkines, a class of drugs that increase central glutamate signaling, on such response. We found that neurons in the PL-PFC increase their firing rates in response to noxious stimulations; chronic neuropathic pain, however, suppressed this important cortical pain response. Meanwhile, CX546, a well-known AMPAkine, restored the anti-nociceptive response of PL-PFC neurons in the chronic pain condition. In addition, both systemic administration and direct delivery of CX546 into the PL-PFC inhibited symptoms of chronic pain, whereas optogenetic inactivation of the PFC neurons or administration of AMPA receptor antagonists in the PL-PFC blocked the anti-nociceptive effects of CX546. These results indicate that restoration of the endogenous anti-nociceptive functions in the PL-PFC by pharmacological agents such as AMPAkines constitutes a successful strategy to treat chronic neuropathic pain.

Learn More >

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks.

Learn More >

Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis.

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis.

Learn More >

Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study.

We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks.

Learn More >

Change in brain oscillations as a mechanism of mindfulness-meditation, cognitive therapy, and mindfulness-based cognitive therapy for chronic low back pain.

Psychological treatments for chronic low back pain (CLBP) are effective. However, limited research has investigated their neurophysiological mechanisms. This study examined electroencephalography- (EEG-) assessed brain oscillation changes as potential mechanisms of cognitive therapy (CT), mindfulness-meditation (MM), and mindfulness-based cognitive therapy (MBCT) for CLBP. The a priori bandwidths of interest were changes in theta, alpha and beta power, measured at pre- and post-treatment.

Learn More >

Noncanonical scaffolding of G and β-arrestin by G protein-coupled receptors.

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific G protein subtypes and β-arrestin adaptor proteins. G protein- and β-arrestin-mediated signaling have been considered separable. We show GPCRs promote a direct interaction between G protein subtype family members and β-arrestins, regardless of their canonical G protein subtype coupling. G:β-arrestin complexes bound extracellular signal-regulated kinase (ERK) and their disruption impaired both ERK activation and cell migration, consistent with β-arrestins requiring a functional interaction with G for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of G:β-arrestin signaling complexes.

Learn More >

Junctophilin-4 facilitates inflammatory signaling at plasma membrane-endoplasmic reticulum junctions in sensory neurons.

Rat somatosensory neurons express junctional protein, junctophilin-4 (JPH4) JPH4 is necessary for the formation of store operated Ca entry (SOCE) complex at the junctions between plasma membrane and endoplasmic reticulum in these neurons. Knockdown of JPH4 impairs endoplasmic reticulum Ca store refill and junctional Ca signalling in sensory neurons. In vivo knockdown of JPH4 in the dorsal root ganglion (DRG) sensory neurons significantly attenuated experimentally-induced inflammatory pain in rats. Junctional nanodomain Ca signalling maintained by JPH4 is an important contributor to the inflammatory pain mechanisms.

Learn More >

Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

Learn More >

Efficacy and Safety of N-acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review & Meta-analysis.

To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain.

Learn More >

Real-world efficacy, tolerability, and safety of ubrogepant.

To assess the real-world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center.

Learn More >

Basophils getting on your nerves? Itching for clarity on flares in atopic dermatitis.

Flares of acute itch in the setting of atopic dermatitis may engage a novel neuroimmune axis that includes basophils, LTC4, and sensory neurons.

Learn More >

The influence of cognitive behavioral therapy on lumbar spine surgery outcomes: a systematic review and meta-analysis.

As more patients undergo lumbar spine surgery, novel interventions may improve physical and mental health outcomes. Few studies summarize the benefit of cognitive behavioral therapy (CBT) among lumbar spine surgery patients. This study collects randomized control trial data to investigate the influence of CBT on patient reported outcomes among lumbar spine surgery patients.

Learn More >

Chronic Pain in Young Athletes: The Impact of Athletic Identity on Pain-related Distress and Functioning.

It is common for youth to engage in sport and unfortunately also common for chronic pain to emerge in childhood. The convergence of chronic pain and sports participation in youth has not been extensively studied.

Learn More >

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy.

Distal sensory polyneuropathy (DSP) is a disabling consequence of HIV, leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms, however there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.

Learn More >

Peritraumatic Vitamin D levels predict chronic pain severity and contribute to racial differences in pain outcomes following Major Thermal Burn Injury.

Major thermal burn injuries result in approximately 40,000 hospitalizations in the United States each year. Chronic pain affects up to 60% of burn survivors, Black Americans have worse chronic pain outcomes than White Americans. Mechanisms of chronic pain pathogenesis after burn injury, and accounting for these racial differences, remain poorly understood. Due to socioeconomic disadvantage and differences in skin absorption, Black Americans have an increased prevalence of Vitamin D deficiency. We hypothesized that peritraumatic Vitamin D levels predict chronic pain outcomes after burn injury and contribute to racial differences in pain outcomes. Among burn survivors (n=77, 52% White, 48% Black, 77% male), peritraumatic Vitamin D levels were more likely to be deficient in Blacks vs. Whites (27/37 (73%) vs. 14/40 (35%), p<.001). Peritraumatic Vitamin D levels were inversely associated with chronic post-burn pain outcomes across all burn injury survivors, including those who were and were not Vitamin D deficient, and accounted for approximately 1/3 of racial differences in post-burn pain outcome. Future studies are needed to evaluate potential mechanisms mediating the effect of Vitamin D on post-burn pain outcomes and the potential efficacy of Vitamin D in improving pain outcomes and reducing racial differences.

Learn More >

Combination of acupuncture and medical training therapy on tension type headache: Results of a randomised controlled pilot study.

The aim of this study was to compare the effects of acupuncture and medical training therapy alone and in combination with those of usual care on the pain sensation of patients with frequent episodic and chronic tension-type headache.

Learn More >

Estimating the population health burden of musculoskeletal conditions using primary care electronic health records.

Better indicators from affordable, sustainable data sources are needed to monitor population burden of musculoskeletal conditions. We propose five indicators of musculoskeletal health and assessed if routinely available primary care electronic health records (EHR) can estimate population levels in musculoskeletal consulters.

Learn More >

The association between exposure to domestic abuse in women and the development of syndromes indicating central nervous system sensitisation: a retrospective cohort study using UK primary care records.

Domestic abuse is a global public health issue. The association between the development of central sensitivity syndromes (CSS) and previous exposure to domestic abuse has been poorly understood particularly within European populations.

Learn More >

Effect of galcanezumab on severity and symptoms of migraine in phase 3 trials in patients with episodic or chronic migraine.

Galcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days compared with placebo. Here, we analyze data from 3 randomized clinical trials (2 episodic trials [EVOLVE-1, EVOLVE-2] and 1 chronic trial [REGAIN]), to examine if galcanezumab also alleviates the severity and symptoms of migraine.

Learn More >

Longitudinal Narrative Analysis of Parent Experiences During Graded Exposure Treatment for Children with Chronic Pain.

Parents have a vital influence over their child's chronic pain treatment and management. Graded exposure in-vivo treatment (GET) is emerging as a promising intervention for youth with chronic pain. Yet, little is known about how parents perceive GET and its impact on their child's pain condition. This study aimed to characterize caregivers' experiences over the course of their child's GET using longitudinal coding and thematic analysis of parent narratives.

Learn More >

TRV130 partial agonism and capacity to induce antinociceptive tolerance revealed through reducing available μ opioid receptor number.

β-arrestin2 recruitment to μ receptors may contribute to the development opioid analgesics side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β-arrestin2 recruitment in favour of G protein signalling. However, low efficacy for β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to the overexpression of μ receptors.

Learn More >

Electroacupuncture activates inhibitory neural circuits in the somatosensory cortex to relieve neuropathic pain.

Electroacupuncture (EA) has been accepted to effectively relieve neuropathic pain. Current knowledge of its neural modulation mainly covers the spinal cord and subcortical nuclei, with little evidence from the cortical regions. Using two-photon imaging in mice with chronic constriction injury, we found that EA treatment systemically modulated the Ca activity of neural circuits in the primary somatosensory cortex, including the suppression of excitatory pyramidal neurons, potentiation of GABAergic somatostatin-positive interneurons, and suppression of vasoactive intestinal peptide-positive interneurons. Furthermore, EA-mediated alleviation of pain hypersensitivity and cortical modulation were dependent on the activation of endocannabinoid receptor 1. These findings collectively reveal a cortical circuit involved in relieving mechanical or thermal hypersensitivity under neuropathic pain and identify one molecular pathway directing analgesic effects of EA.

Learn More >

Pruriplastic Itch-A Novel Pathogenic Concept in Chronic Pruritus.

The International Association for the Study of Pain (IASP) defined three descriptors for pain: nociceptive pain is "pain that arises from actual or threatened damage to non neural tissue and is due to the activation of nociceptors"; neuropathic pain is "pain caused by a lesion or disease of the somatosensory nervous system"; and nociplastic pain is "pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain." Based on clinical and pathophysiological arguments, a similar definition of "pruriplastic pruritus" should be made. Pruriplastic pruritus would include psychogenic pruritus, as well as some cases of pruritus ani, vulvar pruritus, sensitive skin or other poorly understood cases of pruritus. This new descriptor of itch could serve as systematic screening for altered pruriceptive function in patients who suffer from chronic itch and it may also help in defining better tailored treatment by identifying patients who are likely to respond better to centrally rather than to peripherally targeted therapies.

Learn More >

Meta-epidemiological study of publication integrity, and quality of conduct and reporting of randomized trials included in a systematic review of low back pain.

To comprehensively describe the quality of conduct, reporting, and publication integrity characteristics for all trials included in a large Cochrane review, comparing those published by presumed predatory publishers with those published by non-predatory publishers.

Learn More >

Injectable Capsaicin for the Management of Pain Due to Osteoarthritis.

Capsaicin is a potent agonist of the TRPV1 channel, a transduction channel that is highly expressed in nociceptive fibers (pain fibers) throughout the peripheral nervous system. Given the importance of TRPV1 as one of several transduction channels in nociceptive fibers, much research has been focused on the potential therapeutic benefits of using TRPV1 antagonists for the management of pain. However, an antagonist has two limitations. First, an antagonist in principle generally only affects one receptor. Secondly, most antagonists must have an ongoing presence on the receptor to have an effect. Capsaicin overcomes both liabilities by disrupting peripheral terminals of nociceptive fibers that express TRPV1, and thereby affects all of the potential means of activating that pain fiber (not just TRPV1 function). This disruptive effect is dependent on the dose and can occur within minutes. Thus, unlike a typical receptor antagonist, continued bioavailability at the level of the receptor is not necessary. By disrupting the entire terminal of the TRPV1-expressing nociceptive fiber, capsaicin blocks all the activation mechanisms within that fiber, and not just TRPV1 function. Topical capsaicin, an FDA approved treatment for neuropathic pain, addresses pain from abnormal nociceptor activity in the superficial layers of the skin. Effects after a single administration are evident over a period of weeks to months, but in time are fully reversible. This review focuses on the rationale for using capsaicin by injection for painful conditions such as osteoarthritis (OA) and provides an update on studies completed to date.

Learn More >

Health-related quality of life in tension-type headache: a population-based study.

Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH.

Learn More >

Acceptability of psychologically-based pain management and online delivery for people living with HIV and chronic neuropathic pain: a qualitative study.

Chronic neuropathic pain is common in people living with HIV. Psychological treatments can improve quality of life for people with chronic pain in general, and online delivery can increase access to these treatments. However, the acceptability of psychological treatment and online delivery have not been investigated in-depth in people living with HIV and chronic neuropathic pain. Therefore, a qualitative study was undertaken to explore views about a psychological treatment for pain management in this population and to investigate the acceptability of online treatment delivery.

Learn More >

Low-Dose Dextromethorphan for the Treatment of Fibromyalgia Pain: Results from a Longitudinal, Single-Blind, Placebo-Controlled Pilot Trial.

Fibromyalgia (FM) is a debilitating chronic pain condition with few treatment options. Central sensitization and neuroinflammation have been forwarded as models of FM pathophysiology, both of which indicate dextromethorphan (DXM) as a potential treatment. DXM is an NMDA-receptor antagonist and microglial modulator with anti-neuroinflammatory properties at low doses. It is available for clinical use but has not been tested as a treatment for FM at low dosages. This study evaluated the effectiveness of DXM in treating FM-associated symptoms.

Learn More >

microRNA let-7i-5p mediates the relationship between muscle fat infiltration and neck pain disability following motor vehicle collision: a preliminary study.

Persistent neck-pain disability (PNPD) is common following traumatic stress exposures such as motor vehicle collision (MVC). Substantial literature indicates that fat infiltration into neck muscle (MFI) is associated with post-MVC PNPD. However, little is known about the molecular mediators underlying this association. In the current study, we assessed whether microRNA expression signatures predict PNPD and whether microRNA mediate the relationship between neck MFI and PNPD. A nested cohort of 43 individuals from a longitudinal study of MVC survivors, who provided blood (PAXgene RNA) and underwent magnetic resonance imaging (MRI), were included in the current study. Peritraumatic microRNA expression levels were quantified via small RNA sequencing, neck MFI via MRI, and PNPD via the Neck Disability Index two-weeks, three-months, and twelve-months following MVC. Repeated measures regression models were used to assess the relationship between microRNA and PNPD and to perform mediation analyses. Seventeen microRNA predicted PNPD following MVC. One microRNA, let-7i-5p, mediated the relationship between neck MFI and PNPD. Peritraumatic blood-based microRNA expression levels predict PNPD following MVC and let-7i-5p might contribute to the underlying effects of neck MFI on persistent disability. In conclusion, additional studies are needed to validate this finding.

Learn More >

Clinical and cost-effectiveness of an online-delivered group-based pain management programme in improving pain-related disability for people with persistent pain-protocol for a non-inferiority randomised controlled trial (iSelf-help trial).

Persistent non-cancer pain affects one in five adults and is more common in Māori-the Indigenous population of New Zealand (NZ), adults over 65 years, and people living in areas of high deprivation. Despite the evidence supporting multidisciplinary pain management programmes (PMPs), access to PMPs is poor due to long waiting lists. Although online-delivered PMPs enhance access, none have been codesigned with patients or compared with group-based, in-person PMPs. This non-inferiority trial aims to evaluate the clinical and cost-effectiveness of a cocreated, culturally appropriate, online-delivered PMP (iSelf-help) compared with in-person PMP in reducing pain-related disability.

Learn More >

Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman’s life: Implications for the efficacy and safety of novel antimigraine medications.

Migraine is a neurovascular disorder that is three times more prevalent in women than in men and represents a large socio-economic burden. Therefore, the development of new preventive medications is an urgent matter. Currently, calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal fibres, is an important target for migraine treatment. Accordingly, antibodies directed against CGRP or its receptor, as well as small-molecule CGRP receptor antagonists, have been developed for the prophylactic and acute treatment of migraine. Results from clinical phase III trials show a significant decrease in migraine days and relatively mild side-effects. However, CGRP is not only present in the trigeminal nerve, but it is also abundant in perivascular nerve fibres. Moreover, CGRP levels and hormones vary between sexes and during different life stages, and hormones affect CGRP, with a seemingly greater role for CGRP in females. In this review we discuss whether these aspects could be associated with differences in response and efficacy of drugs interfering with the CGRP pathway. Furthermore, CGRP has been described as playing a protective role in ischemic events, and CGRP seems to play a larger role in cardiac ischemic events in female patients. As cardiovascular risk is increased in female migraine patients and also increases significantly in females after menopause, further research into the risk of blocking CGRP in these patients is needed.

Learn More >

Music intervention to relieve anxiety and pain in adults undergoing cardiac surgery: a systematic review and meta-analysis.

Previous studies have reported beneficial effects of perioperative music on patients' anxiety and pain. We performed a systematic review and meta-analysis of randomised controlled trials investigating music interventions in cardiac surgery.

Learn More >

Efficacy and safety of weekly vitamin D in patients with fibromyalgia: 12-week, double-blind, randomized, controlled placebo trial.

FM is a chronic musculoskeletal disorder characterized by the presence of generalized pain. There are contradictory results regarding the prevalence and supplementation effect of vitamin D deficiency on FM patients. We aim to determine the safety and efficacy of a 12-week vitamin D supplementation on FM patients.

Learn More >

A cross-sectional study of pain status and psychological distress among individuals living with chronic pain: the Chronic Pain & COVID-19 Pan-Canadian Study.

The COVID-19 pandemic has had a disproportionate impact on vulnerable populations, including individuals with chronic pain. We examined associations between geographical variations in COVID-19 infection rates, stress and pain severity, and investigated factors associated with changes in pain status and psychological distress among individuals living with chronic pain during the pandemic.

Learn More >

TRPV1 feed-forward sensitisation depends on COX2 upregulation in primary sensory neurons.

Increased activity and excitability (sensitisation) of a series of molecules including the transient receptor potential ion channel, vanilloid subfamily, member 1 (TRPV1) in pain-sensing (nociceptive) primary sensory neurons are pivotal for developing pathological pain experiences in tissue injuries. TRPV1 sensitisation is induced and maintained by two major mechanisms; post-translational and transcriptional changes in TRPV1 induced by inflammatory mediators produced and accumulated in injured tissues, and TRPV1 activation-induced feed-forward signalling. The latter mechanism includes synthesis of TRPV1 agonists within minutes, and upregulation of various receptors functionally linked to TRPV1 within a few hours, in nociceptive primary sensory neurons. Here, we report that a novel mechanism, which contributes to TRPV1 activation-induced TRPV1-sensitisation within ~ 30 min in at least ~ 30% of TRPV1-expressing cultured murine primary sensory neurons, is mediated through upregulation in cyclooxygenase 2 (COX2) expression and increased synthesis of a series of COX2 products. These findings highlight the importance of feed-forward signalling in sensitisation, and the value of inhibiting COX2 activity to control pain, in nociceptive primary sensory neurons in tissue injuries.

Learn More >

Specialized, pro-resolving mediators as potential therapeutic agents for alleviating fibromyalgia symptomatology.

To present a hypothesis on a novel strategy in the treatment of fibromyalgia (FM).

Learn More >

Nabiximols in chronic neuropathic pain: a meta-analysis of randomized placebo-controlled trials.

Pooled analysis of nabiximols and placebo in randomized controlled studies (RCTs) of chronic neuropathic pain.

Learn More >

Treatment of patients with chronic pruritus of unknown origin with dupilumab.

Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab.

Learn More >

Arbiters of endogenous opioid analgesia: role of CNS estrogenic and glutamatergic systems.

Nociception and opioid antinociception in females are pliable processes, varying qualitatively and quantitatively over the reproductive cycle. Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception. This provides a window into pharmacologically accessing intrinsic opioid analgesic/anti-allodynic systems. In diestrus, membrane estrogen receptor alpha (mERα) signals via mGluR to suppress spinal endomorphin 2 (EM2) analgesia. Strikingly, in the absence of exogenous opioids, interfering with this suppression in a chronic pain model elicits opioid anti-allodynia, revealing contributions of endogenous opioid(s). In proestrus, robust spinal EM2 analgesia is manifest but this requires spinal dynorphin/KOR and glutamate-activated mGluR. Furthermore, spinal mGluR blockade in a proestrus chronic pain animal (eliminating spinal EM2 analgesia) exacerbates mechanical allodynia, revealing tempering by endogenous opioid(s). A complex containing mu-opioid receptor, KOR, aromatase, mGluRs, and mERα are foundational to eliciting endogenous opioid anti-allodynia. Aromatase-mERα oligomers are also plentiful, in a central nervous system region-specific fashion. These can be independently regulated and allow estrogens to act intracellularly within the same signaling complex in which they are synthesized, explaining asynchronous relationships between circulating estrogens and central nervous system estrogen functionalities. Observations with EM2 highlight the translational relevance of extensively characterizing exogenous responsiveness to endogenous opioids and the neuronal circuits that mediate them along with the multiplicity of estrogenic systems that concomitantly function in phase and out-of-phase with the reproductive cycle.

Learn More >

Risk for persistent post-delivery pain – increased by pre-pregnancy pain and depression. Similar to persistent post-surgical pain in general?

Learn More >

A Phase 1, Randomized, Double-blind, Placebo-controlled, Crossover Study to Evaluate the Pharmacodynamic Effects of VX-150, a highly selective NaV1.8 inhibitor, in Healthy Male Adults.

To evaluate the analgesic potential, safety, tolerability and pharmacokinetics of VX-150, a pro-drug of a highly selective NaV1.8 inhibitor, in healthy subjects.

Learn More >

Refractory Chronic Pain and Obesity: Promising Implications for Multidisciplinary Pain Rehabilitation.

Individuals with obesity frequently contend with chronic pain, but few studies address the clinical impact of coordinated pain services on this population. The current study addresses this topic by comparing the effectiveness of a comprehensive pain rehabilitation program for patients with and without obesity.

Learn More >

Pharmacokinetics, Safety, and Tolerability of Lasmiditan in Pediatric Patients with Migraine.

Lasmiditan is a selective serotonin (5-HT1F) receptor agonist approved in the US for the acute treatment ofmigraine in adults. This phase I, open-label, two-cohort study assessed the pharmacokinetics (PK), safety, and tolerability of lasmiditan in patients with migraine aged 6 to < 18 years.

Learn More >

The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function.

CACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming Caα subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Learn More >

Movement to the Clinic of Soluble Epoxide Hydrolase Inhibitor EC5026 as an Analgesic for Neuropathic Pain and for Use as a Nonaddictive Opioid Alternative.

This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammation-resolving CYP450 branch of the arachidonate cascade.

Learn More >

Pharmacotherapy to Manage Central Post-Stroke Pain.

Central post-stroke pain is a chronic neuropathic pain syndrome following a cerebrovascular accident. The development of central post-stroke pain is estimated to occur in 8 to 55% of stroke patients and is described as constant or intermittent neuropathic pain accompanied by dysesthesia of temperature and/or pressure sensations. These pain and sensory deficits are within the area of the body corresponding to the stroke lesion. The onset of pain is usually gradual, though it can develop either immediately after stroke or years after. Given the diversity in its clinical presentation, central post-stroke pain is a challenging diagnosis of exclusion. Furthermore, central post-stroke pain is often resistant to pharmacological treatment options and a clear therapeutic algorithm has not been established. Based on current evidence, amitriptyline, lamotrigine, and gabapentinoids should be used as first-line pharmacotherapy options when central post-stroke pain is suspected. Other drugs, such as fluvoxamine, steroids, and Intravenous infusions of lidocaine, ketamine, or even propofol, can be considered in intractable cases. In addition, interventional therapies such as motor cortex stimulation or transcranial magnetic stimulation have been shown to provide relief in difficult-to-treat patients.

Learn More >

Distinct neural networks subserve placebo analgesia and nocebo hyperalgesia.

Neural networks involved in placebo analgesia and nocebo hyperalgesia processes have been widely investigated with neuroimaging methods. However, few studies have directly compared these two processes and it remains unclear whether common or distinct neural circuits are involved. To address this issue, we implemented a coordinate-based meta-analysis and compared neural representations of placebo analgesia (30 studies; 205 foci; 677 subjects) and nocebo hyperalgesia (22 studies; 301 foci; 401 subjects). Contrast analyses confirmed placebo-specific concordance in the right ventral striatum, and nocebo-specific concordance in the dorsal anterior cingulate cortex (dACC), left posterior insula and left parietal operculum during combined pain anticipation and administration stages. Importantly, no overlapping regions were found for these two processes in conjunction analyses, even when the threshold was low. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity (RSFC) analyses on key regions further confirmed the distinct brain networks underlying placebo analgesia and nocebo hyperalgesia. Together, these findings indicate that the placebo analgesia and nocebo hyperalgesia processes involve distinct neural circuits, which supports the view that the two phenomena may operate via different neuropsychological processes.

Learn More >

Behavioral Test (BAT-Back): Preliminary Evidence for a Successful Predictor of Treatment Outcome after Exposure Treatment for Chronic Low Back Pain.

Although several questionnaires assessing fear of movement exist, it still is challenging to identify individuals who might benefit more from exposure for chronic pain than from other psychological approaches, and vice versa. Psychological approaches for chronic pain cannot advance towards the often called-for "tailored approaches" because of limited knowledge about treatment predictors. Our aim was to evaluate the additional predictive value of avoidance behavior based on behavioral observation.

Learn More >

Macrophages are activated in the rat anterior pituitary under chronic inflammatory conditions.

In the anterior lobe of the pituitary gland (AP), non-endocrine cells regulate hormone secretion by endocrine cells. However, the functions of non-endocrine cells in the AP during chronic pain are largely unclear. Here, we show that macrophages, but not folliculostellate (FS) cells, were selectively increased in the AP in the complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model in rats. In addition, IL-1β expression was increased in the AP, and the IL-1β-immunopositive cells were identified as macrophages. On the other hand, increased macrophage density and IL-1β expression were not detected in a neuropathic pain model induced by partial sciatic nerve ligation (PSL). Furthermore, we found c-Fos expression specifically in the somatotrophs under the chronic inflammatory pain condition. Because IL-1β promotes growth hormone (GH) synthesis and release, our results suggest that AP macrophage contributes to GH release through IL-1βduring chronic inflammatory pain. .

Learn More >

Women Veterans’ Experiences with Integrated, Biopsychosocial Pain Care: A Qualitative Study.

Biopsychosocial, integrated pain care models are increasingly implemented in the Veterans Health Administration to improve chronic pain care and reduce opioid-related risks, but little is known about how well these models address women veterans' needs.

Learn More >

Erenumab for the preventive treatment of chronic migraine complicated with medication overuse headache: an observational, retrospective, 12-month real-life study.

Erenumab is a monoclonal antibody blocking the calcitonin gene-related peptide receptor, which has been approved for the preventive treatment of chronic migraine (CM). The aim of this study was to explore the safety and effectiveness of erenumab in patients suffering from CM and medication overuse headache (MOH) in a real-life setting, up to 1 year.

Learn More >

Psychological Factors Are Associated with Pain at All Time Frames After Breast Cancer Surgery: A Systematic Review with Meta-Analyses.

This systematic review aimed to 1) assess associations between psychological factors and pain after breast cancer (BC) treatment and 2) determine which preoperative psychological factors predicted pain in the acute, subacute, and chronic time frames after BC surgery.

Learn More >

Spreading of Pain in Patients with Chronic Pain is Related to Pain Duration and Clinical Presentation and Weakly Associated with Outcomes of Interdisciplinary Pain Rehabilitation: A Cohort Study from the Swedish Quality Registry for Pain Rehabilitation (S

The extent to which pain is distributed across the body (spreading of pain) differs largely among patients with chronic pain conditions and widespread pain has been linked to poor quality of life and work disability. A longer duration of pain is expected to be associated with more widespread pain, but studies are surprisingly scarce. Whether spreading of pain is associated with clinical presentation and treatment outcome in patients seen in interdisciplinary multimodal pain rehabilitation programs (IMMRPs) is unclear. The association between spreading of pain and (1) pain duration (2) clinical presentation (eg, pain intensity, pain-related cognitions, psychological distress, activity/participation aspects and quality of life) and (3) treatment outcome were examined.

Learn More >

Prenylated quinolinecarboxylic acid compound-18 prevents sensory nerve fiber outgrowth through inhibition of the interleukin-31 pathway.

Interleukin-31 (IL-31) is involved in excessive development of cutaneous sensory nerves in atopic dermatitis (AD), leading to severe pruritus. We previously reported that PQA-18, a prenylated quinolinecarboxylic acid (PQA) derivative, is an immunosuppressant with inhibition of p21-activated kinase 2 (PAK2) and improves skin lesions in Nc/Nga mice as an AD model. In the present study, we investigate the effect of PQA-18 on sensory nerves in lesional skin. PQA-18 alleviates cutaneous nerve fiber density in the skin of Nc/Nga mice. PQA-18 also inhibits IL-31-induced sensory nerve fiber outgrowth in dorsal root ganglion cultures. Signaling analysis reveals that PQA-18 suppresses phosphorylation of PAK2, Janus kinase 2, and signal transducer and activator of transcription 3 (STAT3), activated by IL-31 receptor (IL-31R), resulting in inhibition of neurite outgrowth in Neuro2A cells. Gene silencing analysis for PAK2 confirms the requirement for STAT3 phosphorylation and neurite outgrowth elicited by IL-31R activation. LC/MS/MS analysis reveals that PQA-18 prevents the formation of PAK2 activation complexes induced by IL-31R activation. These results suggest that PQA-18 inhibits the IL-31 pathway through suppressing PAK2 activity, which suppresses sensory nerve outgrowth. PQA-18 may be a valuable lead for the development of a novel drug for pruritus of AD.

Learn More >

Development of depression-like behavior and altered hippocampal neurogenesis in a mouse model of chronic neuropathic pain.

Chronic-pain patients often suffer from depression. In rodent models of neuropathic pain, animals develop depression-like and anxiety behaviors, indicating a relationship between chronic pain and affective disorders. However, the underlying neurobiological mechanisms linking chronic pain and depression are not yet fully understood. Neurogenesis in the hippocampus is a fundamental process related to brain plasticity. Reduced neurogenesis has been associated with the development of mood disorders and cognitive impairments. The current study aims to elucidate the underlying long-term changes in brain plasticity induced by neuropathic pain in mice at a time point when depression-like behavior has already developed. Furthermore, our focus is set on alterations in neurogenesis in the hippocampus. We found that manifestation of anxiety- and depressive-like behavior as well as cognitive impairment co-occur with decreased survival of newly generated cells but not with impaired proliferative activity or reduced number of immature neurons in the dentate gyrus area of the hippocampus. Moreover, we detected an impairment of differentiation of newly generated cells into mature calbindin-positive neurons, accompanied with a shift towards increased differentiation into astroglial cells. These findings indicate that a reduction in mature functional neurons, rather than reduced proliferation or neuronal progenitor cells, are the long-term changes in hippocampal plasticity that manifest in neuropathic pain conditions after depression-like behavior has developed.

Learn More >

Postoperative psychosocial factors in health functioning and health-related quality of life after knee arthroplasty: A 6-month follow up prospective observational study.

Knee arthroplasty (KA) is an effective and cost-effective treatment for end-stage knee osteoarthritis. Despite high surgical success rates, as many as 25% of patients report compromised postoperative functioning, persistent pain, and reduced quality of life. The purpose of this study was to assess the predictive value of psychological factors in health functioning and quality of life, during a 6-month period after KA.

Learn More >

Post-traumatic stress disorder and risky opioid use among persons living with HIV and chronic pain.

Persons with HIV (PWH) experience chronic pain and Post-Traumatic Stress Disorder (PTSD) at higher rates than the general population, and more often receive opioid medications to treat chronic pain. A known association exists between PTSD and substance use disorders, but less is known about the relationship between PTSD and risky opioid use among PWH taking prescribed opioid medications. In this observational study of PWH on long-term opioid medications for pain we examined associations between PTSD symptom severity based on the Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5, response range 0-80) and the following outcomes: 1) risk for opioid misuse (COMM score ≥13); 2) risky alcohol use (AUDIT score ≥8); 3) concurrent benzodiazepine prescription; and 4) morphine equivalent dose. Among 166 patients, 38 (23%) had a PCL-5 score over 38, indicating high PTSD symptom burden. Higher PCL-5 score (per 10 point difference) was associated with increased odds of opioid misuse (aOR 1.55; 95%CI: 1.31-1.83) and risky drinking (aOR: 1.28;1.07-1.52). No significant association was observed between PCL-5 score and benzodiazepine prescriptions or morphine equivalent dose. These findings suggest that when addressing alcohol and opioid use in PWH on long term opioid therapy, attention to PTSD symptoms is especially important given the higher risk for risky alcohol and opioid use among patients with this common comorbid condition.

Learn More >

Association Between Lifetime History of Traumatic Brain Injury, Prescription Opioid Use and Persistent Pain: A Nationally Representative Study.

Pain is common among adults with traumatic brain injury (TBI), yet little data exists regarding prevalence of opioid use in this population. The objective of this retrospective cohort study was to evaluate the association between lifetime TBI exposure, opioid use, and pain in a nationally-representative sample of 1,022 adults aged 50+ who participated in the Health and Retirement Study (HRS). Our primary exposure was lifetime TBI history measured via the Ohio State University TBI Identification Method. We evaluated three alternate TBI exposures (years since most recent TBI, age at first TBI, and number of lifetime TBIs) in sensitivity analyses. We evaluated two outcomes: recent opioid medication use, and moderate-to-severe pain measured over two HRS waves. We classified three pain groups (persistent, intermittent, and no pain). Prevalence of opioid use among individuals with and without TBI were 19.7% and 13.6%, respectively. After adjustment for age, sex, and race, individuals with TBI had a 52% increased risk for opioid use compared to individuals without TBI (RR=1.52, 95% CI: 1.11, 2.04). Individuals with recent TBI (1-10 years ago), first TBI after age 40+, and 2+ lifetime TBIs had greatest risk for opioid use. Compared to individuals without TBI, individuals with TBI had 4.9-times increased odds for persistent versus no pain, and 1.9-times increased odds of intermittent versus no pain. Persistent pain among adults with lifetime TBI is elevated compared to the general population, which may contribute to increased opioid use among persons with TBI, particularly those with recent injuries or multiple lifetime TBIs.

Learn More >

“Big girls don’t cry”: the effect of the experimenter’s sex and pain catastrophising on pain.

The expression of pain in males and females involves complex socio-psychological mechanisms. Males may report lower pain to a female experimenter to appear strong, whereas females may report higher pain to a male experimenter to appear weak and to seek protection. However, evidence to support these stereotypes is inconclusive. Individuals who catastrophise about pain rate higher pain than those who do not. How pain catastrophising interacts with the effect of the experimenter's sex on pain reports is yet to be explored. Thus, the aim of this study was to determine whether pain catastrophising moderated the effect of the experimenter's sex on pain reports in healthy males and females.

Learn More >

Neuroprotective effect of Val variant of BDNF Val66Met polymorphism on hippocampus is modulated by the severity of menstrual pain.

Primary dysmenorrhea (PDM) refers to menstrual pain of which the pathological cause(s) are unknown. This study examined the associations among BDNF Val66Met polymorphisms, menstrual pain severity, and hippocampal volume among young PDM subjects. We recruited 115 PDM subjects, including severe cases (n = 66) and moderate cases (n = 44), and 117 young females (aged 20-30 years) as a control group (CON) for BDNF Val66Met genotyping and MRI examination. The assessment of hippocampal volume involved analysis at various anatomical resolutions, i.e., whole hippocampal volume, hippocampal subfields, and voxel-based morphometry (VBM) volumetric analysis. Two-way ANOVA analyses with planned contrasts and Bonferroni correction were conducted for the assessment of hippocampal volume. Linear regression was used to test for BDNF Val66Met Val allele dosage-dependent effects. We observed no main effects of group, genotype, or group-genotype interactions on bilateral whole hippocampal volumes. Significant interactions between PDM severity and BDNF Val66Met genotype were observed in the right whole hippocampus, subiculum, and molecular layer. Post-hoc analysis revealed that the average hippocampal volume of Val/Val moderate PDM subjects was greater than that of Val/Val severe PDM subjects. Note that right hippocampal volume was greater in the Val/Val group than in the Met/Met group, particularly in the right posterior hippocampal region. Dosage effect analysis revealed a positive dosage-dependent relationship between the Val allele and volume of the right whole hippocampus, subiculum, molecular layer, and VBM-defined right posterior hippocampal region in the moderate PDM subgroup only. These findings indicate that Val/Val PDM subjects are resistant to intermittent moderate pain-related stress, whereas Met carrier PDM subjects are susceptible. When confronted with years of repeated PDM stress, the hippocampus can undergo differential structural changes in accordance with the BDNF genotype and pain severity. This triad study on PDM (i.e., combining genotype with endophenotype imaging results and clinical phenotypes), underscores the potential neurobiological consequences of PDM, which may prefigure in neuroimaging abnormalities associated with various chronic pain disorders. Our results provide evidence for Val allele dosage-dependent protective effects on the hippocampal structure; however, in cases of the Val variant, these effects were modulated in accordance with the severity of menstrual pain.

Learn More >

The dopamine D1-D2DR complex in the rat spinal cord promotes neuropathic pain by increasing neuronal excitability after chronic constriction injury.

Dopamine D1 receptor (D1DR) and D2 receptor (D2DR) are closely associated with pain modulation, but their exact effects on neuropathic pain and the underlying mechanisms remain to be identified. Our research revealed that intrathecal administration of D1DR and D2DR antagonists inhibited D1-D2DR complex formation and ameliorated mechanical and thermal hypersensitivity in chronic constriction injury (CCI) rats. The D1-D2DR complex was formed in the rat spinal cord, and the antinociceptive effects of D1DR and D2DR antagonists could be reversed by D1DR, D2DR, and D1-D2DR agonists. Gαq, PLC, and IP3 inhibitors also alleviated CCI-induced neuropathic pain. D1DR, D2DR, and D1-D2DR complex agonists all increased the intracellular calcium concentration in primary cultured spinal neurons, and this increase could be reversed by D1DR, D2DR antagonists and Gαq, IP3, PLC inhibitors. D1DR and D2DR antagonists significantly reduced the expression of p-PKC γ, p-CaMKII, p-CREB, and p-MAPKs. Levo-corydalmine (l-CDL), a monomeric compound in Corydalis yanhusuo W.T. Wang, was found to obviously suppress the formation of the spinal D1-D2DR complex to alleviate neuropathic pain in CCI rats and to decrease the intracellular calcium concentration in spinal neurons. l-CDL-induced inhibition of p-PKC γ, p-MAPKs, p-CREB, and p-CaMKII was also reversed by D1DR, D2DR, and D1-D2DR complex agonists. In conclusion, these results indicate that D1DR and D2DR form a complex and in turn couple with the Gαq protein to increase neuronal excitability via PKC γ, CaMKII, MAPK, and CREB signaling in the spinal cords of CCI rats; thus, they may serve as potential drug targets for neuropathic pain therapy.

Learn More >

The Effect of Spinal Cord Stimulation Frequency on the Neural Response and Perceived Sensation in Patients With Chronic Pain.

The effect of spinal cord stimulation (SCS) amplitude on the activation of dorsal column fibres has been widely studied through the recording of Evoked Compound Action Potentials (ECAPs), the sum of all action potentials elicited by an electrical stimulus applied to the fibres. ECAP amplitude grows linearly with stimulus current after a threshold, and a larger ECAP results in a stronger stimulus sensation for patients. This study investigates the effect of stimulus frequency on both the ECAP amplitude as well as the perceived stimulus sensation in patients undergoing SCS therapy for chronic back and/or leg pain.

Learn More >

Intracolonic Mustard Oil Induces Visceral Pain in Mice by TRPA1-Dependent and -Independent Mechanisms: Role of Tissue Injury and P2X Receptors.

Both TRPA1 and purinergic P2X receptors have been proposed as potential targets for the treatment of visceral pain. We found that the intracolonic administration of a low dose mustard oil (0.5%), a well-known TRPA1 agonist, produced nociceptive responses and abdominal wall referred mechanical hyperalgesia, without inducing apparent tissue damage. Both nociceptive responses and referred hyperalgesia were abolished by the ablation of TRPV1-expressing neurons (and the consequent ablation of TRPA1+ nociceptors) by resiniferatoxin (RTX) treatment, and by the TRPA1 antagonist AP18. However, a higher dose of mustard oil (2.5%) damaged the colonic epithelium and induced pERK activation in the spinal cord, and these processes were clearly independent of TRPV1-expressing neurons ablated by RTX. This higher dose of mustard oil induced nociceptive responses and referred mechanical hyperalgesia which were insensitive or only slightly sensitive to resiniferatoxin or AP18, but were markedly reduced by the P2X antagonist TNP-ATP, which is known to inhibit nociceptive actions induced by ATP released from injured tissues. In conclusion, whereas a low dose of intracolonic mustard oil induces visceral pain in a manner fully dependent on TRPA1 actions, when a high dose of this chemical irritant is used, visceral pain becomes mostly independent of TRPA1 activation but clearly enhanced by ATP purportedly released by the damaged colonic epithelium. Therefore, TRPA1 inhibition is not sufficient to substantially decrease visceral pain during tissue injury, whereas purinergic antagonism appears to be a more effective strategy.

Learn More >

Can Yoga or Physical Therapy for Chronic Low Back Pain Improve Depression and Anxiety Among Adults from a Racially Diverse, Low-Income Community? A Secondary Analysis of a Randomized Controlled Trial.

To determine and compare the effect of yoga, physical therapy (PT), and education on depressive and anxious symptoms in patients with chronic low back pain (cLBP) DESIGN: Secondary analysis of a randomized controlled trial SETTING: Academic safety-net hospital and 7 community health centers PARTICIPANTS: 320 adults with cLBP INTERVENTION: Yoga classes, PT sessions, or an educational book OUTCOME MEASURE: Depression and anxiety were measured using the Patient Health Questionnaire (PHQ-8) and Generalized Anxiety Disorder (GAD-7) scale, respectively, at baseline, 12, and 52 weeks. We identified baseline and mid-treatment (6-week) factors associated with clinically meaningful improvements in depressive (≥3 points) or anxious (≥2 points) symptoms at 12 weeks.

Learn More >

Utility of Electrical Neuromodulation for Treating Chronic Pain Syndromes in the Pediatric Setting: A Systematic Review.

Chronic pain syndromes in children can carry significant threats to psychological well-being, opioid overuse, functional impairments, and severe disability. While several high-level studies, almost exclusively in adults, have demonstrated the utility of implantable electrical neuromodulation systems for treating various chronic pain syndromes, there exists a paucity of pediatric-specific evidence. Unfortunately, evidence and practice patterns established from adults may not be fully translatable to children given differences in disease manifestations and anatomical variances.

Learn More >

Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET.

Fibromyalgia (FM) and complex regional pain syndrome (CRPS) share many pathological mechanisms related to chronic pain and neuroinflammation, which may contribute to the multifactorial pathological mechanisms in both FM and CRPS. The aim of this study was to assess neuroinflammation in FM patients compared with that in patients with CRPS and healthy controls.

Learn More >

Macrophage-derived netrin-1 contributes to endometriosis-associated pain.

Endometriosis-associated pain can be considered a type of neuropathic pain. Netrin-1 is an axon guidance cue that regulates axonal attraction or rejection in neural injury and regeneration. However, whether netrin-1 plays a role in endometriosis-associated pain remains unclear. This study aimed to determine the role of netrin-1 in endometriosis-related pain.

Learn More >

Electrically Evoked Itch in Human Subjects.

Administration of chemicals (pruritogens) into the skin evokes itch based on signal transduction mechanisms that generate action potentials mainly in mechanically sensitive and sensitive primary afferent C-fibers (pruriceptors). These signals from peripheral neurons are processed in spinal and supra-spinal centers of the central nervous system and finally generate the sensation of itch. Compared to chemical stimulation, electrical activation of pruriceptors would allow for better temporal control and thereby a more direct functional assessment of their activation. Here, we review the electrical stimulation paradigms which were used to evoke itch in humans in the past. We further evaluate recent attempts to explore electrically induced itch in atopic dermatitis patients. Possible mechanisms underlying successful pruritus generation in chronic itch patients by transdermal slowly depolarizing electrical stimulation are discussed.

Learn More >

Validity and reliability of a novel numeric rating scale to measure skin-pain in adults with atopic dermatitis.

Little is known about the measurement properties of numeric rating scales (NRS) for pain in AD. We evaluated a novel NRS for skin-pain and existing NRS for average overall-pain in adults with AD. Self-administered questionnaires and skin-examination were performed in 463 AD patients (age 18-97 years) in a dermatology practice setting. Numeric rating scales skin-pain and average overall-pain had moderate correlations with each other, and multiple clinician-reported and patient-reported AD severity outcomes (Spearman correlations, P < 0.0001). There were significant and stepwise increases of NRS skin-pain and average overall-pain scores with patient-reported global severity (Wilcoxon rank-sum test, P < 0.0001). Floor-effects were observed for NRS skin-pain and average overall-pain. Changes from baseline in NRS skin-pain and average overall-pain showed weak-moderate correlations with changes of POEM, vIGA-AD*BSA, SCORAD, and DLQI. Using an anchoring approach, the optimal interpretability band for NRS skin-pain was clear = 0, mild = 1-3, moderate = 5-6, severe = 7-9, and very severe = 10 (weighted kappa = 0.4923). The thresholds for minimally clinically important difference for NRS skin-pain ranged from 2.2 to 2.9. NRS skin-pain and average overall-pain showed moderate-good reliability. Numeric rating scales skin-pain and average overall-pain had sufficient validity, reliability, responsiveness, and interpretability in adults with AD, and were inherently feasible as single-items for use in clinical trials and practice.

Learn More >

Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management.

Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear.

Learn More >

HEME: A Neglected Player in Nociception?

Despite increasing progress in the understanding of the pathophysiology of pain, current management of pain syndromes is still unsatisfactory. The recent discovery of novel pathways associated with pain insensitivity in humans represents a unique opportunity to improve our knowledge on the pathophysiology of pain. Heme metabolism recently emerged as a crucial regulator of nociception. Of note, alteration of heme metabolism has been associated with pain insensitivity in humans as well as with acute and chronic pain in porphyric neuropathy and hemolytic diseases. However, the molecular mechanisms linking heme to the pain pathways still remain unclear. The review focuses on the major heme-regulated processes relevant for sensory neurons' maintenance, peripheral and central sensitization as well as for pain comorbidities, like anxiety and depression. By discussing the body of knowledge on the topic, we provide a novel perspective on the molecular mechanisms linking heme to nociception.

Learn More >

Assessment of small fiber neuropathy in patients carrying the non-classical Fabry variant p.D313Y.

The pathophysiological significance of the Fabry-related, non-classical variant p.D313Y still remains to be solved. This study assesses the involvement of the peripheral nervous system with respect to small fiber neuropathy and neuropathic pain in female patients carrying p.D313Y.

Learn More >

“Living Well with Chronic Pain”: Integrative Pain Management via Shared Medical Appointments.

To evaluate the effectiveness of a multidisciplinary, nonpharmacological, integrative approach that uses shared medical appointments to improve health-related quality of life and reduce opioid medication use in patients with chronic pain.

Learn More >

Memory complaints and cognitive performance in fibromyalgia and chronic pain: The key role of depression.

To explore the relationship between perceived cognitive problems and cognitive performance in three different samples, taking into account the possible influence of depression, catastrophizing, pain intensity, or medication. Seventy individuals with fibromyalgia, 74 with non-malignant chronic pain and 40 pain-free controls, completed measures of verbal episodic memory, sustained attention, response inhibition, depression, catastrophizing, and pain intensity. Fibromyalgia and chronic pain patients performed worse than controls in verbal memory and sustained attention, but these differences disappeared when depressed participants were excluded from the analyses. Memory complaints were related with depression in all pain patients. However, in the case of fibromyalgia, memory complaints were also related by pain intensity and inversely related by short-term episodic memory. This case-control study shows the importance of jointly assessing cognitive performance and memory complaints and of controlling for variables such as depression, catastrophizing, pain intensity and medication in the studied samples. Accordingly, this study highlights the differences in memory complaints, between the patients with fibromyalgia and the patients with other chronic pain conditions. Finally, it has highlighted the important role played by depression in cognitive performance and memory complaints considering the Neurocognitive Model of Attention to pain.

Learn More >

Search