Sex differences in neuroimmune and glial mechanisms of pain

Abstract

Pain is the primary motivation for seeking medical care. Although pain may subside as inflammation resolves or an injury heals, it is increasingly evident that persistency of the pain state can occur with significant regularity. Chronic pain requires aggressive management to minimize its physiological consequences and diminish its impact on quality of life. Although opioids commonly are prescribed for intractable pain, concerns regarding reduced efficacy, as well as risks of tolerance and dependence, misuse, diversion, and overdose mortality rates limit their utility. Advances in development of nonopioid interventions hinge on our appreciation of underlying mechanisms of pain hypersensitivity. For instance, the contributory role of immunity and the associated presence of autoimmune syndromes has become of particular interest. Males and females exhibit fundamental differences in innate and adaptive immune responses, some of which are present throughout life, whereas others manifest with reproductive maturation. In general, the incidence of chronic pain conditions, particularly those with likely autoimmune covariates, is significantly higher in women. Accordingly, evidence is now accruing in support of neuroimmune interactions driving sex differences in the development and maintenance of pain hypersensitivity and chronicity. This review highlights known sexual dimorphisms of neuroimmune signaling in pain states modeled in rodents, which may yield potential high-value sex-specific targets to inform future analgesic drug discovery efforts.

Delta Opioid Receptor in Astrocytes Contributes to Neuropathic Cold Pain and Analgesic Tolerance in Female Mice

“…Studies in rodents have reported either sex difference or no sex difference in pain behaviors and analgesia, a part of which may be strain-dependent (Mogil, 2020 ). The mechanisms leading to sex difference in neuropathic pain encompass differential nociceptive neuron transcriptome (Mecklenburg et al, 2020 ), translatome (Tavares-Ferreira et al, 2020 ), and preferential involvement of macrophages/microglia in males and T lymphocytes in females, although not all studies concur to this conclusion (see Price and Ray, 2019 ; Mogil, 2020 ; Gregus et al, 2021 for recent reviews). Neutrophils have also been reported to account for sex differences in pain and opioid-mediated analgesia (Scheff et al, 2018 , 2019 ).…”

“…As sex differences were found here for DOR-mediated chronic pain processing, the above questions are expected to be explored by considering both sexes. More broadly, the role of astrocytic-DOR in CNS inflammation in chronic pain condition (Giovannoni and Quintana, 2020 ), in astrocytes-neurons and astrocytes-microglia interactions (Greenhalgh et al, 2020 ; Vainchtein and Molofsky, 2020 ), and in astrocytes communication with immune cells from the periphery (Gregus et al, 2021 ) could allow to better understand the relationships between astrocytes and other cells involved in opioid effects and chronic pain.…”

“…The implication of astrocytic DOR in analgesia and analgesic tolerance to the DOR agonist SNC80 was also investigated. In addition, as sex differences are an important factor for chronic pain and the role of astrocytes in this sexual dimorphism is unclear (Mogil, 2020 ; Gregus et al, 2021 ), and therefore the role of astrocytic DOR was investigated in both males and females.…”

hsa-MiR-19a-3p and hsa-MiR-19b-3p Are Associated with Spinal Cord Injury-Induced Neuropathic Pain: Findings from a Genome-Wide MicroRNA Expression Profiling Screen

“…Although there is lack of consensus in the literature regarding male and female specific pain pathways, sex dimorphism has been reported in the development and maintenance of neuropathic pain. 38 This includes sex differences in immune-mediated pain and the effect of sex hormones on nociception and morphine tolerance. 38 In our study men reported higher levels of pain interference with mood in univariate analyses.…”

“… 38 This includes sex differences in immune-mediated pain and the effect of sex hormones on nociception and morphine tolerance. 38 In our study men reported higher levels of pain interference with mood in univariate analyses. However, sex was no longer significantly associated with pain interference with mood in multi-variable models.…”