Multi-omic integration with human DRG proteomics highlights TNFα signalling as a relevant sexually dimorphic pathway.

The peripheral nervous system has been widely implicated in pathological conditions that exhibit distinct clinical presentations in men and women, most notably in chronic pain disorders. Here, we explored this sexual dimorphism at a molecular level. We expanded the available omics landscape in the PNS to include quantitative proteomics of the human dorsal root ganglia (hDRG) and nerve.

Pregabalin produces analgesia in males but not females in an animal model of chronic widespread muscle pain.

Introduction: Pregabalin, which acts on the αδ-1 subunit of voltage-gated calcium channels, relieves ≥50% of pain in a third of individuals with fibromyalgia. Thus far, preclinical studies of pregabalin have predominantly used male animals.

Objectives: The purpose of our study was to investigate potential sex differences in the analgesic efficacy of pregabalin that may contribute to disparities in human outcomes.

Female specific interactions of serotonin and testosterone in the rostral ventromedial medulla after activity-induced muscle pain.

Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression.

Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy.

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons.

Categories of the Patient-Specific Functional Scale Activities in Chronic Neck Pain and Their Relationship to the Neck Disability Index.

Common outcome measures for chronic neck pain are the Patient-Specific Functional Scale (PSFS) and the neck disability index (NDI). The primary aim was to categorize the top-rated, patient-selected functional activity limitations of the PSFS to determine if there were consistent limited functional activities for individuals with chronic neck pain and how these compared to the constructs of activities on the NDI. The secondary aim was to determine the relationship between scores for individuals who completed both the NDI and PSFS.

Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy.

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons.

Local Synthesis of Estradiol in the Rostral Ventromedial Medulla Protects against Widespread Muscle Pain in Male Mice.

Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM).

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice.

Activity-induced muscle pain increases interleukin-1β (IL-1β) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1β in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1β activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation.

Brain-derived neurotrophic factor contributes to activity-induced muscle pain in male but not female mice.

Activity-induced muscle pain increases release of interleukin-1β (IL-1β) in muscle macrophages and the development of pain is prevented by blockade of IL-1β. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1β, which subsequently activate sensory neurons to secrete BDNF.

Neuroimmune Mechanisms Underlying Post-acute Sequelae of SARS-CoV-2 (PASC) Pain, Predictions from a Ligand-Receptor Interactome.

Purpose Of Review: Individuals with post-acute sequelae of SARS-CoV-2 (PASC) complain of persistent musculoskeletal pain. Determining how COVID-19 infection produces persistent pain would be valuable for the development of therapeutics aimed at alleviating these symptoms.

Recent Findings: To generate hypotheses regarding neuroimmune interactions in PASC, we used a ligand-receptor interactome to make predictions about how ligands from PBMCs in individuals with COVID-19 communicate with dorsal root ganglia (DRG) neurons to induce persistent pain.

Influence of routine exercise on the peripheral immune system to prevent and alleviate pain.

Routine physical activity reduces the onset of pain and exercise is a first line treatment for individuals who develop chronic pain. In both preclinical and clinical research regular exercise (routine exercise sessions) produces pain relief through multiple mechanisms such as alterations in the central and peripheral nervous system. More recently, it has been appreciated that exercise can also alter the peripheral immune system to prevent or reduce pain.

Preoperative Exercise Has a Modest Effect on Postoperative Pain, Function, Quality of Life, and Complications: A Systematic Review and Meta-Analysis.

Objective: Preoperative exercise (prehabilitation) is commonly used as a method to reduce pain and improve function postoperatively. The purpose of this systematic review was to determine therapeutic benefits of preoperative exercise on postoperative pain, function, quality of life (QOL), and risk of complications across various types of surgeries.

Methods: Three electronic databases were used to perform a literature search.

The impact of sex and physical activity on the local immune response to muscle pain.

Induction of muscle pain triggers a local immune response to produce pain and this mechanism may be sex and activity level dependent. The purpose of this study was to measure the immune system response in the muscle following induction of pain in sedentary and physically active mice. Muscle pain was produced via an activity-induced pain model using acidic saline combined with fatiguing muscle contractions.

P2X7-NLRP3-Caspase-1 signaling mediates activity-induced muscle pain in male but not female mice.

We developed an animal model of activity-induced muscle pain that is dependent on local macrophage activation and release of interleukin-1β (IL-1β). Activation of purinergic type 2X (P2X) 7 receptors recruits the NOD-like receptor protein (NLRP) 3 and activates Caspase-1 to release IL-1β. We hypothesized that pharmacological blockade of P2X7, NLRP3, and Caspase-1 would prevent development of activity-induced muscle pain in vivo and release of IL-1β from macrophages in vitro.

Standing on the shoulders of bias: lack of transparency and reporting of critical rigor characteristics in pain research.

Rigorous experimental design with transparent reporting in biomedical science reduces risk of bias and allows for scientists to judge the quality of the research. Basic factors of rigor such as blinding, randomization, power analysis, and inclusion of both sexes impact the reproducibility by reducing experimental bias. We designed a systematic study to analyze basic factors of rigor, inclusion of sex, and whether data were analyzed or disaggregated by sex over the past 10 years in the journal PAIN .

Selective androgen receptor modulator microparticle formulation reverses muscle hyperalgesia in a mouse model of widespread muscle pain.

Chronic pain is a significant health problem associated with disability and reduced quality of life. Current management of chronic pain is inadequate with only modest effects of pharmacological interventions. Thus, there is a need for the generation of analgesics for treating chronic pain.

A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study.

A growing number of individuals report prolonged symptoms following acute Coronavirus-19 (COVID-19) infection, known as post-COVID-19 condition (post-COVID-19). While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME). This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype with those with FMS and CFS.

Resistance training protects against muscle pain through activation of androgen receptors in male and female mice.

Resistance training-based exercise is commonly prescribed in the clinic for the treatment of chronic pain. Mechanisms of aerobic exercise for analgesia are frequently studied, while little is known regarding resistance training mechanisms. We developed a resistance training model in mice and hypothesized resistance training would protect against development of muscle pain, mediated through the activation of androgen receptors.

Mechanism of exercise-induced analgesia: what we can learn from physically active animals.

Physical activity has become a first-line treatment in rehabilitation settings for individuals with chronic pain. However, research has only recently begun to elucidate the mechanisms of exercise-induced analgesia. Through the study of animal models, exercise has been shown to induce changes in the brain, spinal cord, immune system, and at the site of injury to prevent and reduce pain.

Testosterone protects against the development of widespread muscle pain in mice.

Chronic widespread pain conditions are more prevalent in women than men, suggesting a role for gonadal hormones in the observed differences. Previously, we showed that female mice, compared to male, develop widespread, more severe, and longer-duration hyperalgesia in a model of activity-induced muscle pain. We hypothesized testosterone protects males from developing the female pain phenotype.

Chronic non-inflammatory muscle pain: central and peripheral mediators.

Conditions with chronic widespread non-inflammatory muscle pain, such as fibromyalgia, have complex etiologies with numerous proposed mechanisms for their pathophysiology of underlying chronic pain. Advancements in neuroimaging have allowed for the study of brain function and connectivity in humans with these conditions, while development of animal models have allowed for the study of both peripheral and central factors that lead to chronic pain. This article reviews the current literature surrounding the pathophysiology of chronic widespread non-inflammatory muscle pain focusing on both peripheral and central nervous system, as well as immune system, contributions to the development and maintenance of pain.

Ability of Isokinetic Dynamometer to Predict Isotonic Knee Extension 1-Repetition Maximum.

Context: Resistance training exercise prescription is often based on exercises performed at a percentage of a 1-repetition maximum (1RM). Following knee injury, there is no consensus when a patient can safely perform 1RM testing. Resistance training programs require the use of higher loads, and loads used in knee injury rehabilitation may be too low to elicit gains in strength and power.