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Review
. 2021 Aug 1;162(8):bqab109.
doi: 10.1210/endocr/bqab109.

Sensory Neurons, Neuroimmunity, and Pain Modulation by Sex Hormones

Melissa E Lenert  1 , Amanda Avona  1 , Katherine M Garner  1 , Luz R Barron  1 , Michael D Burton  1
Affiliations
Review

Sensory Neurons, Neuroimmunity, and Pain Modulation by Sex Hormones

Melissa E Lenert et al. Endocrinology. .

Abstract

The inclusion of women in preclinical pain studies has become more commonplace in the last decade as the National Institutes of Health (NIH) released its "Sex as a Biological Variable" mandate. Presumably, basic researchers have not had a comprehensive understanding about neuroimmune interactions in half of the population and how hormones play a role in this. To date, we have learned that sex hormones contribute to sexual differentiation of the nervous system and sex differences in behavior throughout the lifespan; however, the cycling of sex hormones does not always explain these differences. Here, we highlight recent advances in our understanding of sex differences and how hormones and immune interactions influence sensory neuron activity to contribute to physiology and pain. Neuroimmune mechanisms may be mediated by different cell types in each sex, as the actions of immune cells are sexually dimorphic. Unfortunately, the majority of studies assessing neuronal contributions to immune function have been limited to males, so it is unclear if the mechanisms are similar in females. Finally, pathways that control cellular metabolism, like nuclear receptors, have been shown to play a regulatory role both in pain and inflammation. Overall, communication between the neuroimmune and endocrine systems modulate pain signaling in a sex-dependent manner, but more research is needed to reveal nuances of these mechanisms.

Keywords: bidirectional; hormone; neuroendocrine; neuroimmune; pain; sensory neuron; sex differences.

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Figures

Figure 1.
Figure 1.
Interactions between sensory neurons, immune system, and endocrine system to produce pain in a sex-biased manner. External and internal noxious stimuli are detected by sensory neurons, which communicate to the immune and endocrine systems to modulate pain outcomes. Interactions between these systems are further affected by changes in cellular metabolism. Chronic pain disorders are more commonly diagnosed in women. Furthermore, women are disproportionately affected by chronic pain disorders, such as fibromyalgia and migraine, suggesting female-biased mechanisms in pain signaling and communication between the nervous, immune, and endocrine systems.
Figure 2.
Figure 2.
Sex-biased mechanisms in pain signaling involving the immune system, endocrine system, and cellular metabolism. Neuroimmune signaling in chronic pain potentially uses alternate pathways and cell types in males and females. In males (left), immune cells are thought to be prominent drivers of pain signaling, for example, through toll-like receptor 4 (TLR4) signaling. After infection, injury, or inflammation, TLR4 on immune cells (microglia in the central nervous system [CNS] and macrophages in the periphery) detects damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) to promote proinflammatory cytokine release and subsequent pain signaling in sensory neurons. In females, sensory neurons directly drive pain signaling (such as through direct TLR4 activation), whereas immune cells tend to have a more anti-inflammatory phenotype. However, neuroimmune interactions may be modulated by sex hormone signaling and cell metabolism. Fluctuations in estrogen levels may contribute to increased pain sensitivity in females, despite promotion of protective immune responses. Testosterone, on the other hand, promotes pain relief by inhibiting proinflammatory cytokines like interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα). Prolactin (PRL) promotes pain signaling by sensitizing sensory neurons in females, but not males. Neuroimmune and endocrine interactions can also occur by modulation of cellular metabolism. Metformin, an activator of adenosine 5′-monophosphate–activated protein kinase (AMPK), decreases the proinflammatory actions of macrophages in males. In females, AMPK activation contributes to decreasing estrogen levels and can be used to treat polycystic ovary syndrome (PCOS). AMPK activity in immune cells contributes to anti-inflammatory phenotypes and subsequent pain relief.
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