PMID- 25734998
OWN - NLM
STAT- MEDLINE
DCOM- 20160126
LR  - 20221005
IS  - 1872-6623 (Electronic)
IS  - 0304-3959 (Print)
IS  - 0304-3959 (Linking)
VI  - 156
IP  - 5
DP  - 2015 May
TI  - Protease-activated receptor 2 activation is sufficient to induce the transition 
      to a chronic pain state.
PG  - 859-867
LID - 10.1097/j.pain.0000000000000125 [doi]
AB  - 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  approximately 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.
FAU - Tillu, Dipti V
AU  - Tillu DV
AD  - 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.
FAU - Hassler, Shayne N
AU  - Hassler SN
FAU - Burgos-Vega, Carolina C
AU  - Burgos-Vega CC
FAU - Quinn, Tammie L
AU  - Quinn TL
FAU - Sorge, Robert E
AU  - Sorge RE
FAU - Dussor, Gregory
AU  - Dussor G
FAU - Boitano, Scott
AU  - Boitano S
FAU - Vagner, Josef
AU  - Vagner J
FAU - Price, Theodore J
AU  - Price TJ
LA  - eng
GR  - R01 NS073664/NS/NINDS NIH HHS/United States
GR  - R01 NS065926/NS/NINDS NIH HHS/United States
GR  - R01NS073664/NS/NINDS NIH HHS/United States
GR  - R01NS065926/NS/NINDS NIH HHS/United States
GR  - R01 GM102575/GM/NIGMS NIH HHS/United States
GR  - R01GM102575/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pain
JT  - Pain
JID - 7508686
RN  - 0 (4EGI-1 compound)
RN  - 0 (ANA 12 compound)
RN  - 0 (Azepines)
RN  - 0 (Benzamides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Butadienes)
RN  - 0 (Hydrazones)
RN  - 0 (Nitriles)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Thiazoles)
RN  - 0 (U 0126)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.13 (PKC-3 protein)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - K7Q1JQR04M (Dinoprostone)
SB  - IM
MH  - Animals
MH  - Azepines/pharmacology
MH  - Behavior, Animal/drug effects
MH  - Benzamides/pharmacology
MH  - Brain-Derived Neurotrophic Factor/antagonists & inhibitors/metabolism
MH  - Butadienes/pharmacology
MH  - Chronic Pain/chemically induced/drug therapy/*metabolism/psychology
MH  - Dinoprostone/pharmacology
MH  - Disease Models, Animal
MH  - Facial Expression
MH  - Hydrazones/pharmacology
MH  - Hyperalgesia/chemically induced/drug therapy/*metabolism/psychology
MH  - MAP Kinase Signaling System/drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred ICR
MH  - Mice, Knockout
MH  - Nitriles/pharmacology
MH  - Protein Kinase C/antagonists & inhibitors
MH  - Receptor, PAR-2/*agonists/*antagonists & inhibitors/deficiency/*metabolism
MH  - Receptor, trkB/antagonists & inhibitors
MH  - Signal Transduction/*drug effects
MH  - Thiazoles/pharmacology
PMC - PMC4589228
MID - NIHMS660864
COIS- The authors declare no conflicts of interest.
EDAT- 2015/03/04 06:00
MHDA- 2016/01/27 06:00
PMCR- 2016/05/01
CRDT- 2015/03/04 06:00
PHST- 2015/03/04 06:00 [entrez]
PHST- 2015/03/04 06:00 [pubmed]
PHST- 2016/01/27 06:00 [medline]
PHST- 2016/05/01 00:00 [pmc-release]
AID - 00006396-201505000-00013 [pii]
AID - 10.1097/j.pain.0000000000000125 [doi]
PST - ppublish
SO  - Pain. 2015 May;156(5):859-867. doi: 10.1097/j.pain.0000000000000125.