Protease-activated receptor 2 activation is sufficient to induce the transition to a chronic pain state.

Abstract

Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is sufficient to induce a chronic pain state through extracellular signal-regulated kinase (ERK) signaling to protein synthesis machinery. We have further tested whether the maintenance of this chronic pain state involves a brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (trkB)/atypical protein kinase C (aPKC) signaling axis. We observed that intraplantar injection of the novel highly specific PAR2 agonist, 2-aminothiazol-4-yl-LIGRL-NH2 (2-at), evokes a long-lasting acute mechanical hypersensitivity (median effective dose ∼12 pmoles), facial grimacing, and causes robust hyperalgesic priming as revealed by a subsequent mechanical hypersensitivity and facial grimacing to prostaglandin E2 (PGE2) injection. The promechanical hypersensitivity effect of 2-at is completely absent in PAR2(-/-) mice as is hyperalgesic priming. Intraplantar injection of the upstream ERK inhibitor, U0126, and the eukaryotic initiation factor (eIF) 4F complex inhibitor, 4EGI-1, prevented the development of acute mechanical hypersensitivity and hyperalgesic priming after 2-at injection. Systemic injection of the trkB antagonist ANA-12 similarly inhibited PAR2-mediated mechanical hypersensitivity, grimacing, and hyperalgesic priming. Inhibition of aPKC (intrathecal delivery of ZIP) or trkB (systemic administration of ANA-12) after the resolution of 2-at-induced mechanical hypersensitivity reversed the maintenance of hyperalgesic priming. Hence, PAR2 activation is sufficient to induce neuronal plasticity leading to a chronic pain state, the maintenance of which is dependent on a BDNF/trkB/aPKC signaling axis.

• Authors: Dipti V Tillu, Shayne N Hassler, Carolina C Burgos-Vega, Tammie L Quinn, Robert E Sorge, Gregory Dussor, Scott Boitano, Josef Vagner, Theodore J Price
• Journal: Pain (Pain) Vol. 156 Issue 5 Pg. 859-867 (May 2015) ISSN: 1872-6623 [Electronic] United States
• PMID: 25734998 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4EGI-1 compound
• ANA 12 compound
• Azepines
• Benzamides
• Brain-Derived Neurotrophic Factor
• Butadienes
• Hydrazones
• Nitriles
• Receptor, PAR-2
• Thiazoles
• U 0126
• Receptor, trkB
• PKC-3 protein
• Protein Kinase C
• Dinoprostone

Topics

• Animals
• Azepines (pharmacology)
• Behavior, Animal (drug effects)
• Benzamides (pharmacology)
• Brain-Derived Neurotrophic Factor (antagonists & inhibitors, metabolism)
• Butadienes (pharmacology)
• Chronic Pain (chemically induced, drug therapy, metabolism, psychology)
• Dinoprostone (pharmacology)
• Disease Models, Animal
• Facial Expression
• Hydrazones (pharmacology)
• Hyperalgesia (chemically induced, drug therapy, metabolism, psychology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Knockout
• Nitriles (pharmacology)
• Protein Kinase C (antagonists & inhibitors)
• Receptor, PAR-2 (agonists, antagonists & inhibitors, deficiency, metabolism)
• Receptor, trkB (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)