Sensory Neurons, Neuroimmunity, and Pain Modulation by Sex Hormones

Abstract

The inclusion of females in preclinical pain studies has become more commonplace in the last decade, as the National Institutes of Health (NIH) “Sex as a Biological Variable” (SABV) mandate was released. 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 in both 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.

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice

“…We demonstrate robustly sex-specific evidence of changing pain levels over time and an apparent male-specific effect of SNI-induced chronic pain (but not SNI surgery itself) on lifespan. These findings represent yet more evidence of sex differences in pain biology (see Refs. 11, 17, 26 for recent reviews).…”

Associations between pain and physical activity among older adults

“…The exact mechanisms underlying gender differences in pain are unknown but have been hypothesised to be an interaction between biological, psychological, and sociocultural factors [35]. Differences in levels of sex hormones, such as oestrogen, progesterone, and testosterone, may contribute to the marked sex-related differences in pain [35][36][37]. Hormonal differences may also affect the processing of painrelated stimuli in the brain, with women showing lower activation in pain inhibitory brain regions [38].…”

Revealing the Central Mechanism of Acupuncture for Primary Dysmenorrhea Based on Neuroimaging: A Narrative Review

“…Pain is an unpleasant sensory and emotional experience [ 65 ]. Moreover, sex hormones were thought to be involved in modulating pain [ 66 – 68 ]. Therefore, PD should be viewed holistically, incorporating psychological, sex hormone levels, and quality of life scores.…”