Protease-activated receptor 2 activation is sufficient to induce the transition to a chronic pain state.
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.
Department of Pharmacology, University of Arizona University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, USA Department of Psychology, University of Alabama at Birmingham Department of Physiology, University of Arizona University of Arizona, Arizona Respiratory Center University of Arizona, Bio5 Institute.
Dipti V
DV
Tillu
Shayne N
SN
Hassler
Carolina C
CC
Burgos-Vega
Tammie L
TL
Quinn
Robert E
RE
Sorge
Gregory
G
Dussor
Scott
S
Boitano
Josef
J
Vagner
Theodore J
TJ
Price
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D059350:Chronic Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D005149:Facial Expression; D006835:Hydrazones / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology
C517852:4EGI-1 compound; C559317:ANA 12 compound; D001381:Azepines; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D002070:Butadienes; D006835:Hydrazones; D009570:Nitriles; D044464:Receptor, PAR-2; D013844:Thiazoles; C113580:U 0126; D020813:Receptor, trkB; C115015:PKC-3 protein; D011493:Protein Kinase C; D015232:Dinoprostone