Inhibitory activity of nociceptin/orphanin FQ on capsaicin-induced bronchoconstriction in the guinea-pig.
In vivo studies were conducted in the guinea-pig to investigate the activity of the selective ORL1 receptor agonist nociceptin/orphanin FQ against capsaicin-induced bronchoconstriction, a response mediated by the release of tachykinins from pulmonary sensory nerves. Anesthetized guinea-pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph, and pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were monitored. Intravenous administration of nociceptin/orphanin FQ (0.3 mg/kg) inhibited the capsaicin-induced bronchoconstriction. The new nonpeptide ORL1 receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) administered intravenously (1 mg/kg) produced a significant blockade of the inhibitory effect of nociceptin/orphanin FQ (0.3 mg/kg) on capsaicin-induced bronchoconstriction, whereas the nonselective opioid receptor antagonist naloxone (1 mg/kg) had no effect. Nociceptin/orphanin FQ (0.3 mg/kg) did not affect the bronchoconstriction induced exogenously by the tachykinin NK2 receptor agonist [beta-ala8]-neurokinin A (4-10). We conclude that nociceptin inhibits in vivo capsaicin-evoked tachykinin release from sensory nerve terminals in the guinea-pig by a prejunctional mechanism. This inhibitory action does not involve activation of opioid receptors.
Corboz
M R
MR
Allergy, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. michel.corboz@spcorp.com
Fernandez
X
X
Egan
R W
RW
Hey
J A
JA
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008297:Male; D009270:Naloxone / Q000627:therapeutic use; D009479:Neuropeptides / Q000378:metabolism; D018847:Opioid Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D010993:Plethysmography, Whole Body; D011480:Protease Inhibitors / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000819:agonists; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D001562:Benzimidazoles; D016085:Bronchoconstrictor Agents; D002211:Capsaicin; D009270:Naloxone; D009479:Neuropeptides; D018847:Opioid Peptides; D010880:Piperidines; D011480:Protease Inhibitors; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397