Gpr151, an orphan G protein-coupled receptor, is involved in multiple biological processes. It has been associated with pain modulation, glucose metabolism, and may play a role in social behaviors. It is expressed in various tissues such as the habenula complex, spinal cord neurons, dorsal root ganglia, and the liver [1,2,5,6]. It is also sensitive to acidic conditions [3].

In nociceptive sensory neurons, conditional knockout of Gpr151 in adult mice alleviated chronic constriction injury-induced neuropathic pain-like behavior without affecting basal nociception. Gpr151 was required for chronic constriction injury-induced neuronal hyperexcitability and upregulation of colony-stimulating factor 1 (CSF1), which is necessary for microglial activation in the spinal cord after nerve injury. Mechanistically, it coupled with P2X3 ion channels and promoted their functional activities [1]. In trigeminal neuropathic pain, global mutation or knockdown of Gpr151 in the trigeminal ganglion attenuated partial infraorbital nerve transection-induced mechanical allodynia. Gpr151 bound to Gαi protein and activated the extracellular signal-regulated kinase (ERK) through Gβγ, inducing ERK-dependent neuroinflammation [4].

In the context of glucose metabolism, Gpr151 ablation in mice led to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production, and restoration of its levels reversed this effect [2]. In social behavior studies, Gpr151 knockout mice showed reduced social preference compared to wild-type mice [6].

In conclusion, Gpr151 plays a key role in pain-related processes, glucose metabolism, and social behaviors. The use of gene knockout (KO) and conditional knockout (CKO) mouse models has been crucial in revealing its functions in neuropathic pain, trigeminal neuropathic pain, glucose metabolism, and social reward. These findings suggest that Gpr151 could be a potential target for treating neuropathic pain and may have implications for understanding glucose metabolism-related disorders and social behavior-related conditions [1,2,4,6].