GPR183 Activation in the Peripheral Nervous System Induces Behavioral Hypersensitivities in Rats

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 385; p. 7
• Main Authors: Oberkrom, Kyle, Braden, Kathryn, Chen, Zhoumou, Giancotti, Luigi A., Arnatt, Christopher K., Salvemini, Daniela
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.06.2023
• ISSN: 0022-3565
• DOI: 10.1124/jpet.122.252030

Abstract ID 25203 Poster Board 7 Neuropathic pain is a global health concern. Neuropathic pain is poorly managed; current pharmacological therapies have limited efficacy and multiple side effects. Novel therapeutic approaches are needed. Our group has identified the G-protein coupled receptor (GPCR), GPR183, as a non-opioid based target for therapeutic intervention with selective GPR183 antagonists. GPR183 is expressed in a number of immune cells known to be involved in neuropathic pain states such as T cells, as well as in glia and neurons. Interestingly, this expression in the nervous system correlates with key areas of the pain neuroaxis including in human spinal cord and dorsal root ganglia. We have recently reported that GPR183 plays a role in central sensitization. However, the role of GPR183 in peripheral sensitization is not known and was the subject of our investigation. In rats, intraplantar injection of 7α,25-dihydroxycholesterol (7α,25-OHC), the most potent ligand for GPR183, induced behavioral hypersensitivities associated with neuropathic pain states (i.e. thermal hyperalgesia and mechano-allodynia). These effects were blocked by an inhibitor of GPR183, SAE14. At the molecular level, we found that GPR183 induced hypersensitivities were driven by the mitogen activated protein kinase, ERK. Indeed, U0126, a well characterized MEK/ERK inhibitor blocked 7α,25-OHC-induced behavioral hypersensitivities. Our results provide the first evidence implicating GPR183 signaling in the development of peripheral sensitization and first mechanistic insight on molecular pathways engaged downstream, of this GPCR opening the doors for future investigations into this novel pathway. Supported by start-up funds of Dr. Salvemini and Dr. Arnatt, the National Institutes of Health (NIH) Grant R01NS128004, and the NIH Training Grant T32 GM141602-01 A1 (KDO)