Nociceptin inhibits capsaicin-induced bronchoconstriction in isolated guinea pig lung.
The isolated perfused guinea pig lung was used to investigate the effect of nociceptin against bronchoconstriction elicited by endogenous and exogenous tachykinins. The opioid receptor-like 1 (ORL1) receptor agonist, nociceptin/orphanin FQ (0.001-1 microM) produced a dose-related inhibition of the capsaicin-induced bronchoconstriction (10(-5)-10(3) microg) in isolated guinea pig lung (P<0.05), a response mediated by the release of endogenous tachykinins from lung sensory nerves. The new ORL1 receptor antagonist 1-[(3R, 4R)-1-Cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397) (0.3 microM) significantly blocked the inhibitory effect of nociceptin/orphanin FQ (0.01 microM) on capsaicin-induced bronchoconstriction, whereas the non-selective opioid receptor antagonist naloxone (1 microM) had no effect. Nociceptin/orphanin FQ (1 microM) did not affect the bronchoconstriction induced exogenously by the tachykinin NK2 receptor agonist neurokinin A. In conclusion, the present data provide evidence that nociceptin inhibits capsaicin-evoked tachykinin release from sensory nerve terminals in guinea pig lung by a prejunctional mechanism. This inhibitory action occurs independently from activation of opioid receptors. The present study also indicates that J-113397 is a potent ORL1 receptor antagonist.
Allergy, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. michel.corboz@spcorp.com
M R
MR
Corboz
M A
MA
Rivelli
R W
RW
Egan
D
D
Tulshian
J
J
Matasi
A B
AB
Fawzi
L
L
Benbow
A
A
Smith-Torhan
H
H
Zhang
J A
JA
Hey
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects*; D016466:CHO Cells; D002211:Capsaicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013462:Sulfur Radioisotopes; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D001562:Benzimidazoles; D002211:Capsaicin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D013462:Sulfur Radioisotopes; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397