A recent study from the University of Arizona Health Sciences discovered sex-specific differences in nociceptors, the nerve cells responsible for pain perception. Research reveals that men and women experience pain differently due to distinct activation thresholds in nociceptor cells, influenced by hormones like prolactin and orexin B. These findings suggest the need for sex-specific treatments to pain management, challenging previous assumptions and paving the way for precision medicine approaches that consider patient gender as a critical factor.
Researchers have discovered sex-specific differences in the nerve cells that generate pain, paving the way for personalized pain management treatments based on the patient’s sex.
Research indicates that men and women experience pain differently, but the reasons for this remain unclear. A new study from University of Arizona Health Sciences, published in BRAINhas now identified functional sex differences in nociceptors, the specialized nerve cells that produce pain.
The results support the implementation of an approach based on precision medicine that considers the patient’s gender as fundamental in the choice of treatment to manage pain.
“Conceptually, this paper represents a major advance in our understanding of how pain may be produced in men and women,” said Frank Porreca, PhD, research director of the Comprehensive Center for Pain. & Addiction at UArizona Health Sciences and associate professor and department head. in pharmacology at the UArizona College of Medicine – Tucson. “The results of our study were surprisingly consistent and support the remarkable conclusion that nociceptors, the fundamental building blocks of pain, are different in men and women. This offers the possibility of treating pain specifically and potentially better in men or women, and that’s what we’re trying to do.
Porreca and the research team focused their study on the excitability of nociceptor cells located near the spinal cord in the dorsal root ganglion. Nociceptors, when activated by damage or injury, send a signal via the spinal cord to the brain that results in the perception of pain. Nociceptors are also adaptable in their response to injury.
For example, touching a hot stove is a high-intensity stimulus, while a shirt collar rubbing a sunburn is low-intensity, but both produce a perception of pain. In cases of injuries such as sunburn, analgesics, including nonsteroidal anti-inflammatory drugs such as ibuprofen, work by normalizing the threshold for nociceptor activation, thereby blocking the pain produced by low-intensity stimuli such as rubbing a shirt.
Hormonal influence on pain perception
Following previous research on the relationship between chronic pain and sleep, unexpected gender differences led Porreca to choose two substances – prolactin and orexin B – for this study. Prolactin is a hormone responsible for lactation and the development of breast tissue; Orexin is a neurotransmitter that helps you stay 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, non-human primates and humans to test the effect of prolactin and orexin B on nociceptor activation thresholds that can allowing low intensity stimuli to produce pain.
“What we found is that in men and women – animals or humans – what changes nociceptor thresholds can be completely different,” Porreca said. “When we added the sensitizing substances that lower these activation thresholds, we found that prolactin only sensitizes female cells and not male cells, and that orexin B only sensitizes male cells and not female cells. The surprising conclusion from these studies is that there are male nociceptors and female nociceptors, which has never been recognized before.
Taking the research a step further, they then blocked prolactin and orexin B signaling and examined the effect on the nociceptor activation threshold. As expected, blocking prolactin signaling reduced nociceptor activation in women and had no effect in men, while blocking orexin B signaling was effective in men and not in women.
“Until now, the hypothesis has been that the motor mechanisms that produce pain are the same in men and women,” Porreca said. “What we found is that the fundamental underlying mechanisms that drive pain perception are different in male and female mice, in male and female non-human primates, and in male and female humans. »
The findings suggest a new way to approach the treatment of painful conditions, many of which are predominantly female. Migraine and fibromyalgia, for example, have female-to-male ratios of 3:1 and 8 or 9:1, respectively.
Future Directions in Pain Research
Porreca believes that preventing prolactin-induced nociceptor sensitization in women could represent a viable approach to the treatment of female-predominant pain disorders, while targeting orexin B-induced sensitization could improve treatment. painful conditions associated with nociceptor activation in men.
In the future, Porreca and his team will continue to look for other sexually dimorphic pain mechanisms while building on this study to look for viable ways to prevent nociceptor sensitization in women and men. He is encouraged by his recent discovery of an antibody against prolactin, which may prove useful in women, and by the availability of orexin antagonists already approved by the Food and Drug Administration for the treatment of brain disorders. sleep.
“We are applying the concept of precision medicine – taking into account a patient’s genetics to design a therapy – to the treatment of pain,” Porreca said. “The most fundamental genetic difference is: is the patient male or female? Perhaps this should be the first consideration when it comes to treating pain.
The research was funded by the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke and the U.S. Department of Defense.
Porreca University of Arizona Health Sciences co-authors include Associate Professor Edita Navratilova, PhD; assistant professor Laurent Martin, PhD; Grace Lee, PhD, postdoctoral research associate; doctoral student Mahdi Dolatyari; Stefanie Mitchell, research program manager; researcher Xu Yue and former doctoral student Harrison Stratton, PhD; all members of the Tucson College of Medicine – Department of Pharmacology; and Mohab Ibrahim, MD, PhD, professor in the School of Medicine – Department of Anesthesiology in Tucson and medical director of the Comprehensive Center for Pain & Addiction. Other co-authors include assistant professor Aubin Moutal, PhD, research assistant professor Liberty François-Moutal, PhD, doctoral student Nicolas Dumaire, and graduate research assistant Lyuba Salih, all of Saint Louis University; and Andre Ghetti and Tamara Cotta of Anabios in San Diego.
