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Review
. 2024 Oct 22;15(1):82.
doi: 10.1186/s13293-024-00660-w.

The influence of sex on neuroimmune communication, pain, and physiology

Shevon N Alexander  1 , Audrey R Green  1 , Emily K Debner  1 , Lindsey E Ramos Freitas  1 , Hanna M K Abdelhadi  1 , Thomas A Szabo-Pardi  1 , Michael D Burton  2
Affiliations
Review

The influence of sex on neuroimmune communication, pain, and physiology

Shevon N Alexander et al. Biol Sex Differ. .

Abstract

With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.

Keywords: Hormones; Neuroimmune; Pain; Physiology; Sex differences; Translational.

Plain language summary

In the last decade, NIH-funded basic and clinical research studies have been mandated to include sex as a biological variable, and this has resulted in a boom of studies discovering sex differences. We know that females are more likely than males to develop chronic pain conditions and experience higher levels of pain for longer periods of time. Conditions that demonstrate this include migraine, arthritis, and peripheral neuropathy. Furthermore, these sex differences extend to surgical outcomes and are observable at the molecular, cellular, and systemic levels. Although pain perception pathways differ by sex, studies are also focusing on differences in the “conversation” between the immune system and the nervous system while addressing implications of sex hormones to gain a better understanding of the impact on pain, physiology, and behavior. Lifestyle factors such as diet and alcohol consumption also play a role in affecting the perception and impact of pain conditions. As this area of research continues to grow, the development and availability of sex-specific treatment options will grow and lead to improved patient outcomes and more effective pain management strategies.

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Conflict of interest statement

The authors (Alexander, S.N, Green, A.R., Debner, E.K., Abdelhadi, H.M.K., Ramos Freitas, L.E., Szabo-Pardi, T.A., Burton, M.D) have no conflict of interests to declare.

Figures

Fig. 1
Fig. 1
The ascending pain pathway (Red). Noxious stimuli, such as thermal, chemical, or mechanical stimuli, or inflammatory stimuli, such as lipopolysaccharide (LPS), are detected by receptors expressed on nociceptors innervating peripheral tissue. Thermal stimuli activate TRP channels, such as TRPV1, while inflammatory stimuli activate other receptors, like activation of TLR4 by LPS. Following stimulation, nociceptors initiate pain transmission by propagating information to sensory neuron cell bodies located in dorsal root ganglia (DRG). These neurons synapse onto second order neurons within the dorsal horn of the spinal cord which in turn transmit nociceptive signals to the brain where it is interpreted as pain. Neuroimmune interactions within different levels of the ascending pain pathway influence the development and maintenance of pain in a sex- and cell-specific manner. Differences in arrow sizes indicate level of contribution, with larger arrows demonstrating greater impact, and are used to highlight sex-specific differences
Fig. 2
Fig. 2
Sexual dimorphic mechanisms in neuroimmune signaling driven by interactions with sensory neurons. In females, sensory neurons are thought to be the main drivers in pain signaling as seen by the female-skewed pathways
Fig. 3
Fig. 3
Sexual dimorphic mechanisms in neuroimmune signaling driven by interactions with macrophages. In males, immune cells are thought to be the main drivers in pain signaling, such as through TLR4 signaling
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