Summary: It is known that females are more likely to report chronic pain. However, the reason for higher pain sensitivity in females is poorly understood. One of the new studies shows that male and female pain receptors differ significantly, with female receptors more sensitive to prolactin and male pain receptors more sensitive to orexin B.
A few things are well known but poorly understood, like females are more likely to experience chronic pain. Not only that, they are also more likely to be diagnosed with conditions associated with chronic pain. Thus, females are more likely to develop issues like irritable bowel syndrome, fibromyalgia, and other chronic pain conditions.
Quite often, it is assumed that these gender differences are merely due to sex hormones. This may be partially correct. However, now researchers think that there is more to the story. One new study suggests that pain receptors might differ significantly in males and females. This may be due to numerous factors. This new and emerging theory may completely change an approach to managing pain in males and females.
Pain Receptors in Males and Females Are Functionally Different
One of the latest studies explored the phenomenon of peripheral nociceptor sensitization (pain receptors sensitization) and how it differs between the sexes. Nociceptors, the sensory neurons responsible for detecting painful stimuli, become sensitized under certain conditions, lowering the pain perception threshold. This sensitization is a key factor in various pain conditions. However, the question of whether nociceptor sensitization occurs differently in males and females has not been thoroughly investigated until now.
To address this, researchers in this new study used patch-clamp electrophysiology to assess the excitability of dorsal root ganglion (DRG) neurons from male and female rodents, non-human primates, and humans. The study focused on the effects of prolactin and orexin B, two agents (bioactive compounds or hormones) known to influence pain perception. Previous studies indicated that prolactin selectively promotes pain responses in female rodents. This study confirmed those findings by demonstrating that prolactin sensitizes DRG neurons in female but not male mice. This sex-specific sensitization was also observed in female macaque monkeys and human female DRG neurons, confirming the consistency of these effects across species. Since prolactin is more abundant in females, females are more sensitive to certain pains.
Furthermore, the study found that orexin B (more abundant in males) sensitized DRG neurons in male but not female mice, macaque monkeys, and humans. This male-specific sensitization was linked to higher expression of orexin receptor 2 in male DRG neurons, while female neurons showed increased prolactin receptor expression. Immunohistochemical analyses supported these findings, indicating higher receptor expression corresponding to the respective sensitizing agents in males and females.
These results reveal a fundamental sexual dimorphism/difference in pain receptor sensitization. This is one of the first studies to demonstrate that males and females experience pain through different underlying mechanisms.
This discovery has profound implications for pain management and therapy. Currently, patient sex is not typically considered when choosing pain treatments. However, this study suggests that precision medicine approaches, which tailor treatments based on the patient’s sex, could significantly enhance therapeutic outcomes. For instance, targeting prolactin pathways might be more effective in treating pain in women, while targeting orexin pathways could be more beneficial for men.
The study also highlights the need for sex-specific considerations in the design and analysis of clinical trials for pain therapies. By including balanced proportions of male and female participants and analyzing results by sex, researchers can better understand the efficacy of treatments and potentially uncover reasons for previous trial failures. Revisiting past clinical trials with this new perspective may yield valuable insights and guide the development of more effective, sex-specific pain therapies.
The Bottom Line
This study provides compelling evidence that the sensitization of pain receptors differs significantly between males and females. This difference is seen in many species, including humans. In females, prolactin plays an important role in the sensitization of pain receptors, whereas in males, orexin. This study also highlights the importance of considering patient sex into pain management strategies. The findings advocate for a more personalized approach to pain therapy, ensuring that treatments are specifically tailored to the distinct biological responses of male and female patients.
Source:
Stratton, H., Lee, G., Dolatyari, M., Ghetti, A., Cotta, T., Mitchell, S., Yue, X., Ibrahim, M., Dumaire, N., Salih, L., Moutal, A., François-Moutal, L., Martin, L., Navratilova, E., & Porreca, F. (2024). Nociceptors are functionally male or female: From mouse to monkey to man. Brain, awae179. https://doi.org/10.1093/brain/awae179