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

Abstract

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.

• Authors: Yanxia Chen, Aubin Moutal, Edita Navratilova, Caroline Kopruszinski, Xu Yue, Megumi Ikegami, Michele Chow, Iori Kanazawa, Shreya Sai Bellampalli, Jennifer Xie, Amol Patwardhan, Kenner Rice, Howard Fields, Armen Akopian, Volker Neugebauer, David Dodick, Rajesh Khanna, Frank Porreca
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 529 (02 05 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32024801 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Analgesics, Opioid
• Protein Isoforms
• Receptors, Prolactin
• Prolactin

Topics

• Analgesics, Opioid
• Animals
• Female
• Hyperalgesia (chemically induced)
• Mice
• Nociceptors
• Prolactin
• Protein Isoforms
• Receptors, Prolactin