Journal Article

GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents

Guo, Chun, Harada, Caron M., Samson, Willis K., Yosten, Gina L.C., Giancotti, Luigino Antonio, Patel, Ryan, Doyle, Timothy M., Dickenson, Anthony H., Kolar, Grant R., Salvemini, Daniela, Haddock, Chris, Chen, Zhoumou, Zhang, Jinsong

2020

Overview

Treating neuropathic pain is challenging and novel non-opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

• Publisher: American Society for Clinical Investigation
• Subject: Addictions / Amphetamines / Analysis / Animals / Biomedical research / Cell Line / Central nervous system agents / Cocaine / Cocaine- and amphetamine-regulated transcript protein / Cold / Concise Communication / Cyclic adenosine monophosphate / Cyclic AMP response element-binding protein / Diseases / Dorsal horn / Female / Fluorescent antibody technique / G protein-coupled receptors / Humans / Hybridization / Hypersensitivity / Immunofluorescence / Information processing / Ligands / Male / Mice / Narcotics / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neuralgia / Neuralgia - etiology / Neuralgia - genetics / Neuralgia - physiopathology / Novels / Opioids / Pain / PC12 Cells / Peptides / Phosphorylation / Protein binding / Rats / Receptors, G-Protein-Coupled - antagonists & inhibitors / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - physiology / Reinforcement / RNA, Small Interfering - genetics / Rodents / Sciatic Nerve - injuries / Sciatic Nerve - physiopathology / Sensory integration / Sensory perception / Signal Transduction / Spinal cord / Spinal Cord - metabolism / Spinal cord injuries / Thalamus / Therapeutic applications / Transcription / Up-Regulation