Functional Sexual Dimorphism in Human Nociceptors

  1. Harrison Stratton
  2. Mahdi Dolatyari
  3. Nicolas Dumaire
  4. Aubin Moutal
  5. Andre Ghetti
  6. Tamara Cotta
  7. Stefanie Mitchell
  8. Xu Yue
  9. Edita Navratilova
  10. Frank Porreca

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Abstract

The recent demonstration of differences in transcript expression in human post-mortem sensory neurons suggests the possibility of sexually dimorphic pain mechanisms. To date, however, the concept of “male” and “female” nociceptors has not been demonstrated at a functional level. We now report sensitization of female, but not male, human nociceptors by prolactin revealing a female-selective mechanism that can be exploited to improve the treatment of pain in women.

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  1. Arcadia Science

    Wenow report sensitization of female, but not male, human nociceptors by prolactin revealing a female-selective mechanism that can be exploited to improve the treatment of pain in women.

    Thanks for sharing these results! It's awesome to see how clinical reporting of differences in pain between males and females can help drive an understanding of the molecular mechanisms associated with those differences. The implication of this finding is especially interesting when we consider how prolactin levels in females increase during pregnancy and breastfeeding!

    Summary: Evidence of differences in RNA transcripts between male and female human DRG neurons and of an increase in receptivity of trigeminal nociceptors in the presence of prolactin led this team to provide functional evidence to support or refute the hypothesis that prolactin may differentially sensitize DRG neurons. Using PrlrCre/+;Ai6 transgenic mice and patch clamp recording of cultured mouse DRG cells, an increase in firing frequency was found in female DRG neurons when exogenous mouse prolactin was introduced. Male DRG neurons did not display the same relative increase in firing. Further, immunostaining revealed higher expression levels of prolactin receptors in female human DRG tissue samples in comparison to male human DRG tissue samples. Cultured and PRLR-stained human neurons displayed differential expression of prolactin receptors between male and female samples. Finally, patch clamp recording was used on human DRG cultures in order to compare sex-based action potential differences in the presence of prolactin. As in mice, a notable increase in firing frequency was found in female human DRG neurons in the presence of prolactin but not for male human DRG neurons.

  4. Arcadia Science

    while sex differences inprolactin receptor transcripts have not been reported in human nociceptors, sexual dimorphism likelyoccurs at the protein level

    Have you considered exploring the potential relationship between prolactin and the top 25 pain-associated genes in the female cohort from the “RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain” study? Even though prolactin receptor transcripts weren’t reported, is there a possible relationship between the genes that were and the impact of prolactin?

    Do you have additional experiments in mind that could further explore the role of prolactin in human nociceptors despite the limited availability of human cells? It would be interesting to compare the spatial organization of prolactin receptor expressing neurons in mouse and human DRG tissues considering the probability that the organization of the DRG is likely different?

  5. Arcadia Science

    It shouldbe noted that we observed mPRL-induced reduced rheobase in rodent, but not human studies.

    Your data seems to suggest the opposite, the p-value for the female human vehicle versus prolactin DRG rheobase is 0.0105 while the male and female rodent p-values are both well-above 0.05.

  6. Version published to 10.1101/2023.06.14.545010v1 on bioRxiv