Breakthrough study unveils sex differences in pain perception
In a groundbreaking study published in BRAIN [1], researchers from the University of Arizona Health Sciences have uncovered functional sex differences in nociceptors, the specialized nerve cells responsible for producing pain. This work provides a critical foundation for implementing a precision medicine approach to managing pain, considering patient sex as a fundamental factor in treatment selection.
Dr Frank Porreca, research director of the Comprehensive Center for Pain & Addiction at UArizona Health Sciences and professor and associate department head of pharmacology at the UArizona College of Medicine – Tucson, underscores the significance of this finding: “Conceptually, this paper is a big advance in our understanding of how pain may be produced in males and females. The outcomes of our study were strikingly consistent and support the remarkable conclusion that nociceptors, the fundamental building blocks of pain, are different in males and females. This provides an opportunity to treat pain specifically and potentially better in men or women, and that’s what we’re trying to do.”
Excitability of nociceptor cells
The study focused on the excitability of nociceptor cells located near the spinal cord in the dorsal root ganglion. Nociceptors, when activated by damage or injury, transmit signals through the spinal cord to the brain, resulting in the perception of pain. These cells exhibit adaptability in their response to injury, with high-intensity stimuli like touching a hot stove and low-intensity stimuli like a shirt collar rubbing against a sunburn both producing pain perception.
Building on previous research linking chronic pain and sleep, the team investigated the effects of prolactin, a hormone responsible for lactation and breast tissue development, and orexin B, a neurotransmitter involved in wakefulness promotion. Remarkably, their findings revealed a striking sex difference in the modulation of nociceptor activation thresholds.
Male nociceptors and female nociceptors
“What we found is that in males and females – animals or humans – what changes the thresholds of the nociceptors can be completely different,” Porreca said. “When we added the sensitizing substances that lower these thresholds for activation, we found that prolactin only sensitizes female cells and not male cells, and orexin B only sensitizes male cells and not female cells. The startling conclusion from these studies is that there are male nociceptors and female nociceptors, something that has never previously been recognized.”
Further experiments demonstrated that blocking prolactin signalling reduced nociceptor activation in females but not in males, while blocking orexin B signalling had the opposite effect, being effective in males and not in females.
Porreca emphasizes the paradigm shift this discovery represents: “Until now, the assumption has been that the driving mechanisms that produce pain are the same in men and women. What we found is that the basic, underlying mechanisms that result in the perception of pain are different in male and female mice, in male and female nonhuman primates, and in male and female humans.”
Implications for treatment
These findings have significant implications for the treatment of female-prevalent pain conditions, such as migraine and fibromyalgia. Porreca believes that preventing prolactin-induced nociceptor sensitization in females may represent a viable approach for treating these disorders, while targeting orexin B-induced sensitization could improve pain management in males.
Moving forward, Porreca and his team will continue exploring other sexually dimorphic mechanisms of pain while building on this study to seek viable ways to prevent nociceptor sensitization in both sexes. The recent discovery of a prolactin antibody and the availability of FDA-approved orexin antagonists for sleep disorders offer promising avenues for further research.
In Porreca’s words: “We are bringing the concept of precision medicine – taking a patient’s genetics into account to design a therapy – to the treatment of pain. The most basic genetic difference is, is the patient male or female? Maybe that should be the first consideration when it comes to treating pain.”
This groundbreaking study sheds light on the fundamental sex differences in pain perception and opens the door to a new era of precision pain management, tailoring treatments to the specific biological mechanisms underlying pain in males and females.
Reference:
1. Harrison Stratton, Grace Lee, Mahdi Dolatyari, et. al., Nociceptors are functionally male or female: from mouse to monkey to man, Brain, 2024;, awae179, https://doi.org/10.1093/brain/awae179
