title: Nociceptin inhibits vanilloid TRPV-1-mediated neurosensitization induced by fenoterol in human isolated bronchi.
abstract: Chronic exposure to beta(2)-adrenoceptor agonists, especially fenoterol, has been shown to increase smooth muscle contraction to endothelin-1 in human bronchi partly through tachykinin-mediated pathways. The purpose of this work was to further investigate the role of sensory nerves in fenoterol-induced sensitization of human airways and the effect of nociceptin, a nociceptin/orphanin FQ (NOP) receptor agonist, on the increase in contraction after fenoterol exposure. Human bronchi from 62 patients were sensitized to endothelin-1 by prolonged incubation with fenoterol (0.1 microM, 15 h). The sensitizing effect of fenoterol was inhibited by high concentration of capsaicin (10 microM, 30 min before fenoterol sensitization), which induces depletion of mediators from sensory nerves, or co-incubation of fenoterol and capsazepine (1 microM), a vanilloid TRPV-1 receptor antagonist. Moreover, short pretreatment of bronchi with capsaicin (10 microM) or capsazepine (1 microM) after sensitization by fenoterol decreased the rise in smooth muscle contraction to endothelin-1. Nociceptin (1 microM) also inhibited the increased contraction in fenoterol-sensitized bronchi. Tertiapin (10 microM), an inhibitor of the inward-rectifier K(+) channels, but not naloxone (0.1 microM), a DOP/KOP/MOP receptor antagonist, prevented the inhibitory effect of nociceptin. In conclusion, fenoterol induces sensitization of human isolated bronchi to endothelin-1 in part through the stimulation of the vanilloid TRPV-1 receptor on tachykininergic sensory nerves. Nociceptin inhibits airway hyperresponsiveness via NOP receptor activation. This effect involves inward-rectifier K(+) channels.
authors.affiliation: Unité de Recherche de l'Enseignement Supérieur, Equipe d'Accueil 220, Faculté de Médecine Paris-Ile de France-Ouest, Unité de Formation et de Recherche Biomédicale des Saint-Pères, 45 rue des Saint-Pères, 75006, Paris, France. christophe.faisy@wanadoo.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.forename: Céline
authors.initials: C
authors.lastname: Rouget
authors.forename: Paul-André
authors.initials: PA
authors.lastname: Risse
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guerot
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Fagon
authors.forename: Thierry
authors.initials: T
authors.lastname: Chinet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Roche
authors.forename: Charles
authors.initials: C
authors.lastname: Advenier
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D005280:Fenoterol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D018847:Opioid Peptides / Q000494:pharmacology*; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D050916:TRPV Cation Channels; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097629:Nociceptin
chemical_list: D000318:Adrenergic beta-Agonists; D002211:Capsaicin; D019332:Endothelin-1; D005280:Fenoterol; D007473:Ion Channels; D018847:Opioid Peptides; D011955:Receptors, Drug; D050916:TRPV Cation Channels; D014665:Vasodilator Agents; D000097629:Nociceptin; C494482:TRPV1 protein, human; C071423:capsazepine