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.
Highlights
To improve the quality of life for many patients who cope daily with pain, appropriate disease-modifying strategies that examine biological risk factors, such as age, genetics, and sex, need to be universally implemented
The biological origins of sex differences that affect the outcome of pain are complex
One approach is through direct manipulation of gonadal hormones in relevant animal models of both sexes, at different life stages
Summary
To improve the quality of life for many patients who cope daily with pain, appropriate disease-modifying strategies that examine biological risk factors, such as age, genetics, and sex, need to be universally implemented. This latter type of “nerve signaling” represents an interesting means by which a distal factor known to be associated with inflammation [66], produced and released by peripheral tissue (for example, fibroblasts rapidly produce upregulated levels of NGF in response to pain-inducing cutaneous plantar [67] and deep muscle [68] incision in rats, and it is expressed by central and peripheral nerves, as well as microglia and peripheral immune cells [69]), is able to regulate the structure and function of sensory neurons.
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