The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females.

Hormonal pain modulation: Men and women experience pain differently. However, the mechanisms mediating this difference are unclear. The short isoform of the prolactin (PRL) receptor (PRLR-S), but not the long isoform (PRLR-L), has been shown to regulate the excitability of sensory neurons in female rodents. Here, Chen et al. studied opioid-induced hyperalgesia (OIH) and reported that opioid administration, but not trauma-induced nerve injury, augmented PRL and decreased PRLR-L in female animals, promoting the activation of PRLR-S and the development of OIH. PRL inhibition prevented the occurrence of OIH in female animals. The results suggest that targeting PRL signaling might be an effective therapy for preventing OIH in women. Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner. [ABSTRACT FROM AUTHOR]