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Papers of the Week

Papers: 9 Mar 2019 - 15 Mar 2019

Animal Studies, Pharmacology/Drug Development

2019 Mar 08


An NPY Y1 receptor antagonist unmasks latent sensitization and reveals the contribution of Protein Kinase A and EPAC to chronic inflammatory pain.



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