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

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. 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. Immune cell types and molecular pathways drive sex specific differences in inflammatory and neuropathic pain.TLR4 involvement in pain pathways show contextual sex-specific variations and its interaction with TRPV1 channels adds complexity to nociceptor physiology.Female mice tend to exhibit stronger TRPV1-mediated pain responses compared to males due to estrogen enhancement of TRPV1 expression levels.The interplay between nuclear receptors (PPAR gamma, PPAR alpha) and prolactin receptors influences sex-specific neuroimmune interactions. In males, PPAR alpha impacts immune responses and neuroinflammation. In females, PPAR gamma activity influences pain perception and PRL influences pain sensitivity.Personalized approaches are needed for pain management in males and females due to sex differences in pain perception and treatment outcomes driven by variations in hormone levels, adiposity, and neuroimmune mechanisms of inflammation.