GPR37 activation erases spinal pain memory and resolves increased nociception in murine models

Intense nociceptor inputs from injury induce long-term changes in the spinal nociceptive system - referred to as spinal pain memory - that increase pain in magnitude and duration. We investigated whether activation of G protein-coupled receptor 37 (GPR37) at the spinal level can erase this memory 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, administered after an initial injury-induced priming, dose-dependently prevented increased nociception following a subsequent inflammatory insult, indicating an unpriming effect. Global GPR37 knockout abolished the long-term inhibitory effect and unpriming effect of i.th. TX14A, confirming the receptor at the spinal level as the molecule mediating the 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 spinal pain memory. Conditioned place preference tests indicated no obvious abuse liability for centrally-administered GPR37 agonists. These findings suggest that spinally targeted GPR37 agonism represents a promising therapeutic strategy for resolving persistent pain by erasing spinal pain memory.