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

Fu, Weisia; Nelson, Tyler S.b,c,d; Santos, Diogo F.b; Doolen, Suzanneb; Gutierrez, Javier J.P.b; Ye, Nae; Zhou, Jiae; K. Taylor, Bradleya,b,c,*

doi: 10.1097/j.pain.0000000000001557
Research Paper
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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; and (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 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 2 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.

Two signaling pathways drive latent sensitization after inflammation: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. Both are tonically suppressed by spinal NPY-Y1R.

aDepartment of Physiology, University of Kentucky Medical Center, Lexington, KY, United States

bDepartment of Anesthesiology and Perioperative Medicine, Pittsburgh Center for Pain Research, and Pittsburgh Project to End Opioid Misuse, University of Pittsburgh, Pittsburgh, PA, United States

cCenter for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States

dCenter for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, United States

eDepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States

Corresponding author. Address: Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, 200 Lothrop St, Pittsburgh PA 15213, United States. Tel.: 412-624-2092. E-mail address: bkt@pitt.edu (B. Taylor).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received August 11, 2018

Received in revised form February 12, 2019

Accepted March 04, 2019

Online date: March 8, 2019

© 2019 International Association for the Study of Pain
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