Gpr83, a class A G protein-coupled receptor, has been implicated in multiple physiological processes. It is considered a novel therapeutic target due to its roles in regulating feeding, reward, anxiety-related behaviors, and pain [1,2,3,4,5]. It has been suggested to be involved in the reward pathway, stress/anxiety responses, learning and memory, and metabolism in the brain, and its expression in the immune system is regulated by Foxp3 in T-regulatory cells [4].

Some studies used gene-knockdown models to explore Gpr83 function. Silencing Gpr83 expression in murine dorsal root ganglia (DRG) downregulated neuronal and behavioral nociception, and alleviated pathologic pain in hind paw inflammation and chemotherapy-induced peripheral neuropathy, suggesting its role in tuning peripheral pain sensitivity [2]. In anxiety-related behaviors, global knockdown of Gpr83 in male mice decreased such behaviors, while local knockdown in the basolateral amygdala of female mice led to more anxiety-related behaviors, indicating a region-and sex-dependent role of Gpr83 [5].

In conclusion, Gpr83 plays essential roles in regulating pain sensitivity and anxiety-related behaviors, as revealed by loss-of-function models. These findings contribute to understanding the underlying mechanisms of pain-related and anxiety-related disorders, potentially providing new therapeutic targets for these conditions.

References:

1. Mack, Seshat M, Gomes, Ivone, Devi, Lakshmi A. 2019. Neuropeptide PEN and Its Receptor GPR83: Distribution, Signaling, and Regulation. In ACS chemical neuroscience, 10, 1884-1891. doi:10.1021/acschemneuro.8b00559. https://pubmed.ncbi.nlm.nih.gov/30726666/

2. Kim, Yerin, Kim, Chaeeun, Lee, Hojin, Choi, Jungmin, Hwang, Sun Wook. 2022. Gpr83 Tunes Nociceptor Function, Controlling Pain. In Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 20, 325-337. doi:10.1007/s13311-022-01327-3. https://pubmed.ncbi.nlm.nih.gov/36352334/

3. Mack, Seshat M, Gomes, Ivone, Fakira, Amanda K, Fricker, Lloyd, Devi, Lakshmi A. 2022. GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling. In Molecular pharmacology, 102, 29-38. doi:10.1124/molpharm.122.000487. https://pubmed.ncbi.nlm.nih.gov/35605991/

4. Lueptow, Lindsay M, Devi, Lakshmi A, Fakira, Amanda K. 2018. Targeting the Recently Deorphanized Receptor GPR83 for the Treatment of Immunological, Neuroendocrine and Neuropsychiatric Disorders. In Progress in molecular biology and translational science, 159, 1-25. doi:10.1016/bs.pmbts.2018.07.002. https://pubmed.ncbi.nlm.nih.gov/30340784/

5. Fakira, Amanda K, Lueptow, Lindsay M, Trimbake, Nikita A, Devi, Lakshmi A. 2021. PEN Receptor GPR83 in Anxiety-Like Behaviors: Differential Regulation in Global vs Amygdalar Knockdown. In Frontiers in neuroscience, 15, 675769. doi:10.3389/fnins.2021.675769. https://pubmed.ncbi.nlm.nih.gov/34512237/