Sex differences in neuro(auto)immunity and chronic sciatic nerve pain

Abstract

Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.

Sex-related differences in experimental pain sensitivity in subjects with painful or painless neuropathy after surgical repair of traumatic nerve injuries

“…Although the risk of developing neuropathic pain is known to be greater in female participants, 27,42 the presence of chronic pain after traumatic nerve injuries could not confirm this general observation. Patients with peripheral nerve injuries with upper extremity involvement were more likely to be young male subjects in both severe trauma with multiple injuries 22 (78.6%) or localized hand and arm injuries (between 66.5%–74% and 80%).…”

“… 1 The current consensus is that estrogen reduces hyperpolarization postinjury of the peripheral nerve system and acts in a both preventive and hyperalgesic manner, whereas male hormones have antinociceptive effects. 27 Attention has been also focused on the action of sex hormones on endogenous pain modulation as a contributor to greater pain sensitivity and higher prevalence of many chronic pain conditions in women. 36 For instance, in some studies, male patients expressed more effective descending inhibition quantified by conditioned pain modulation (CPM).…”

Proteomic analysis of peripheral nerve myelin during murine aging

“…Furthermore, in this study we used mixed-sex nerve pools for myelin isolation and therefore cannot differentiate sex-specific effects on myelin proteome changes during aging. However, as sex differences have been described for the PNS in general, the development of peripheral neuropathy and regeneration, and age-related neuromuscular decline ( Kovacic et al, 2004 ; Linher-Melville et al, 2020 ; Xian et al, 2022 ; Guo et al, 2023 ), future studies should specifically investigate molecular differences in myelin composition between males and females during aging.…”

Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem

“…Due to the greater experimental tractability of the peripheral nervous system, better understanding of neuropathic pain mechanisms has come overwhelmingly from investigations of neuropathic pain hypersensitivity as a consequence of discrete lesioning of one or more peripheral nerves. Such peripheral nerve injury (PNI) drives waves of signaling changes in neurons, immune cells, and glial cells at the site of the lesion; in the dorsal root ganglia (DRG) (Figure 1), where the cell bodies of primary sensory neurons are located; in the dorsal horn of the spinal cord; and in the brain (10)(11)(12). PNIinduced alterations in the interplay between neurons, immune cells, and glia produce aberrant inputs from the periphery into the spinal cord and reconfigure processing in the somatosensory processing network in the dorsal horn such that there is pathological amplification of nociceptive Allodynia: pain due to a stimulus that does not normally evoke pain activity and unmasking of crosstalk between nonnociceptive (nonpain-producing) and nociceptive (pain-producing) pathways (13).…”