title: Acquired Exchange Protein Directly Activated by Cyclic Adenosine Monophosphate Activity Induced by p38 Mitogen-activated Protein Kinase in Primary Afferent Neurons Contributes to Sustaining Postincisional Nociception.
abstract: The molecular mechanisms responsible for sustained pain after tissue injury are largely unknown. The aim of this study was to clarify the role of exchange protein directly activated by cyclic adenosine monophosphate (EPAC) in sustained postincisional nociception, using tissue injury-induced nociceptor priming, and involvement of p38 mitogen-activated protein kinase (p38MAPK) in EPAC-mediated nociceptor priming.
  
  
  
  Plantar incisions were made in the hind paws of Sprague-Dawley rats (n = 144). Nociceptor priming was confirmed by behavior testing followed by prostaglandin E2 injection 14 to 21 days after the incision. ESI-09, a selective EPAC inhibitor, was administered to assess its effects on nociceptor priming. Expression of two isoforms of EPAC (EPAC1/EPAC2) in dorsal root ganglions from naive rats and those 14 days after the incision was detected by immunohistochemistry and Western blotting. Separately, FR167653, a selective p38MAPK inhibitor, was administered to assess its effect on EPAC1/EPAC2 expression and the development of nociceptor priming.
  
  
  
  Prostaglandin E2 injection 14 to 21 days after the plantar incision induced persistent mechanical hyperalgesia for 7 days. EPAC1/EPAC2 expression in dorsal root ganglion neurons was trivial in naive rats (7.7 ± 4.8% for EPAC1; 6.3 ± 4.1% for EPAC2) but markedly increased 14 days after the incision (21.0 ± 9.4% and 20.1 ± 3.8%, respectively). ESI-09 treatment inhibited prostaglandin E2-induced persistent mechanical hypersensitivity but had no effect on incision-induced acute nociceptive hypersensitivity. Treatment with FR167653 before the incision inhibited the development of nociceptor priming and incision-induced EPAC1/EPAC2 expression (8.5 ± 5.4% and 7.6 ± 3.3%, respectively).
  
  
  
  Transient inflammatory stimulation causes long-lasting nociceptive hypersensitivity via nociceptor priming during the subacute period after incision. Acquired EPAC activity by p38MAPK in the dorsal root ganglion neurons is a key for this event.
authors.affiliation: From the Department of Anesthesiology (M.M., T.S., F.A.), Research Unit for the Neurobiology of Pain, Department of Anesthesiology (M.M., F.A.), and Department of Biostatistics, Graduate School of Medical Science (I.Y.), Kyoto Prefectural University of Medicine, Kyoto, Japan; United Graduate School of Drug Discovery and Medical Information Sciences, and Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan (K.O.-H.).
authors.forename: Megumi
authors.initials: M
authors.lastname: Matsuda
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oh-Hashi
authors.forename: Isao
authors.initials: I
authors.lastname: Yokota
authors.forename: Teiji
authors.initials: T
authors.lastname: Sawa
authors.forename: Fumimasa
authors.initials: F
authors.lastname: Amaya
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D009475:Neurons, Afferent / Q000378:metabolism*; D059225:Nociception / Q000502:physiology*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases