Brain abstract network
Credit: miakievy / Getty Images

Sex differences in nociceptors, the specialized nerve cells that produce pain, are substantive enough that they could impact treatment response, according to work by the University of Arizona Health Sciences researchers. A patient’s sex is currently not usually a consideration for the choice of pain therapy. But this team’s finding could lead to that practice changing and to new “sex-specific” pain relievers. Some promising candidates are already under study—prolactin inhibitors for females and orexin B signaling inhibitors for males.

Their paper, “Nociceptors are Functionally Male or Female: From Mouse to Monkey to Man,” appears in BRAIN. The lead author is Harrison Stratton. “To our knowledge, this is the first demonstration of functional sexual dimorphism in human sensory neurons,” they write.

A body of prior research suggests that males and females differ in their experience of pain, but until now it was not known why. These researchers may have discovered a key piece of that puzzle. Their findings support a precision medicine-based approach that considers patient sex as fundamental to choices involved in managing pain.

“We are bringing the concept of precision medicine—taking a patient’s genetics into account to design a therapy—to the treatment of pain,” said Frank Porreca, PhD, senior author and research director of the Comprehensive Center for Pain & Addiction at UArizona Health Sciences. “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.”

The team used patch clamp electrophysiology to evaluate excitability in neurons from male or female rodents, non-human primates, and humans. They focused their study on nociceptor cells located near the spinal cord in the dorsal root ganglion. Nociceptors, when activated by damage or injury, send a signal through the spinal cord to the brain that results in the perception of pain.

“Conceptually, this paper is a big advance in our understanding of how pain may be produced in males and females,” said Porreca. “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.”

Following up on prior research on the relationship between chronic pain and sleep, unexpected sex differences led Porreca to choose two substances—prolactin and orexin B— for this study. Prolactin is a hormone responsible for lactation and breast tissue development; orexin is a neurotransmitter that helps to promote staying awake. However, both prolactin and orexin have many other functions that are only now being revealed. 

The research team used tissue samples from male and female mice, nonhuman primates and humans to test the effect of prolactin and orexin B on nociceptor activation thresholds that can allow low-intensity stimuli to produce pain.

“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.”

Taking the research one step further, they then blocked prolactin signaling and orexin B signaling and examined the effect on the threshold for activation of the nociceptors. As anticipated, blocking prolactin signaling reduced nociceptor activation in females and had no effect in males, while blocking orexin B signaling was effective in males and not in females.

Also of Interest