An NPY Y1 receptor antagonist unmasks latent sensitization and reveals the contribution of protein kinase A and Epac to chronic inflammatory pain

摘要: Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons, that is, masked by tonic inhibitory controls. We explored mechanisms with an established four-step approach: (1) induction inflammation; (2) allow pain hypersensitivity to resolve; (3) interrogate channel blocker, mutant mouse, or receptor antagonist; and (4) disrupt compensatory inhibition antagonist so as reinstate hypersensitivity. found the neuropeptide Y Y1 BIBO3304 reinstated hypersensitivity, indicative unmasking sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice prevented intrathecal co-administration pharmacological blocker N-methyl-D-aspartate (NMDAR), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), transient potential cation A1 (TRPA1), V1 (TRPV1), exchange activated cAMP (Epac1 Epac2). PKA activator evoked both touch-evoked pERK expression dorsal horn; former TRPA1 TRPV1 blocker. An Epac also expression. conclude are sufficient maintain horn neurons is kept remission NPY-Y1 system. Furthermore, we have identified characterized 2 novel molecular signaling pathways drive setting chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 NMDAR→AC1→Epac1/2. New treatments for might either increase endogenous NPY analgesia inhibit AC1, PKA, Epac.