Spinal-level activation of GPR37 in TRPV1-expressing sensory neurons erases nociceptive system sensitization in murine models

Intense injury induces long-term changes in the spinal nociceptive system, which increases pain in magnitude and duration. We investigated whether activation of G protein-coupled receptor 37 (GPR37) at the spinal level can erase this nociceptive system sensitization and resolve long-lasting, enhanced pain using two animal models: the capsaicin model and the hyperalgesic priming model. Without altering normal mechanical and heat nociception, a single intrathecal (i.th.) administration of two GPR37 agonists, TX14A and protectin D1 (PD1), dose-dependently inhibited capsaicin-induced increase in nociception not only acutely but also long-term. In the hyperalgesic priming model, a single i.th. injection of either GPR37 agonist after an initial injury-induced priming dose-dependently prevented increased nociception following a subsequent inflammatory insult, indicating an unpriming effect. Global GPR37 knockout or conditional knockout of GPR37 in TRPV1-lineage sensory neurons abolished the long-term inhibitory effect and unpriming effect of i.th. TX14A, confirming that GPR37 in this specific cellular population mediates these effects. Ex vivo Ca²⁺ imaging revealed that i.th. TX14A, given in vivo to the capsaicin model a week before imaging, had rescued dorsal horn excitatory and inhibitory interneurons from long-term potentiation and depression of responsiveness to afferent inputs, respectively, suggesting the erasure of capsaicin-induced nociceptive system sensitization. Conditioned place preference tests indicated no obvious abuse liability for centrally administered GPR37 agonists. These findings suggest that spinally targeting GPR37 in TRPV1-expressing sensory neurons represents a promising therapeutic strategy for resolving persistent pain by erasing nociceptive system sensitization. PERSPECTIVE: This article presents preclinical evidence that spinal-level activation of GPR37 normalizes injury-induced long-term changes in the spinal nociceptive system, thereby resolving long-lasting pain hypersensitivity without affecting normal nociception or causing apparent abuse liability. These findings support spinal-level GPR37, specifically the receptor in TRPV1-positive sensory neuronal cell bodies and/or central terminals, as a promising target for novel pain therapeutics.