An NPY Y1 receptor antagonist unmasks latent sensitization and reveals the contribution of protein kinase A and Epac to chronic inflammatory pain
In: Pain, Jg. 160 (2019-03-08), S. 1754-1765
Online
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Zugriff:
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.
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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
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Autor/in / Beteiligte Person: | Santos, Diogo F. ; Nelson, Tyler S. ; Ye, Na ; Fu, Weisi ; Javier J. Polania Gutierrez ; Taylor, Bradley K. ; Doolen, Suzanne ; Zhou, Jia |
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Zeitschrift: | Pain, Jg. 160 (2019-03-08), S. 1754-1765 |
Veröffentlichung: | Ovid Technologies (Wolters Kluwer Health), 2019 |
Medientyp: | unknown |
ISSN: | 1872-6623 (print) ; 0304-3959 (print) |
DOI: | 10.1097/j.pain.0000000000001557 |
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