title: Activation of TRPV1 by capsaicin induces functional kinin B(1) receptor in rat spinal cord microglia.
abstract: BACKGROUND
  The kinin B(1) receptor (B(1)R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B(1)R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B(1)R expression in the spinal cord dorsal horn, and the underlying mechanism.
  
  
  METHODS
  B(1)R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B(1)R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B(1)R agonist (des-Arg(9)-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B(1)R agonist, [Nα-bodipy]-des-Arg(9)-BK. The effect of i.t. capsaicin (1 μg/site) was also investigated.
  
  
  RESULTS
  Capsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B(1)R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 μg/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 μg/site, i.t.). Increases of B(1)R mRNA were correlated with IL-1β mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 μg/site) also enhanced B(1)R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days) prevented B(1)R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg(9)-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg(9)-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B(1)R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 μg/site, i.t.), substance P NK-1 receptor (RP-67580, 10 μg/site, i.t.) and nitric oxide synthase (L-NNA, 10 μg/site, i.t.). The B(1)R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats.
  
  
  CONCLUSIONS
  This study highlights a new mechanism for B(1)R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.
authors.affiliation: Department of Physiology, Faculty of Medicine, Université de Montréal, C,P, 6128, Succursale Centre-ville, Montréal, H3C 3J7, Québec, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Talbot
authors.forename: Jenny Pena
authors.initials: JP
authors.lastname: Dias
authors.forename: Karim
authors.initials: K
authors.lastname: Lahjouji
authors.forename: Maurício Reis
authors.initials: MR
authors.lastname: Bogo
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Campos
authors.forename: Pierrette
authors.initials: P
authors.lastname: Gaudreau
authors.forename: Réjean
authors.initials: R
authors.lastname: Couture
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001345:Autoradiography; D001920:Bradykinin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008297:Male; D017628:Microglia / Q000187:drug effects*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology*; D013481:Superoxides / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D000813:Anilides; D000975:Antioxidants; D065169:Bradykinin B1 Receptor Antagonists; D002934:Cinnamates; D007456:Iodine Isotopes; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C120984:R 715; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D044005:Tetrahydroisoquinolines; D013481:Superoxides; C076640:bradykinin, Hyp(3)-Thi(5)-Tic(7)-Oic(8)-desArg(9)-; C071423:capsazepine; D002211:Capsaicin; D001920:Bradykinin; D000111:Acetylcysteine