Nociceptin inhibits airway microvascular leakage induced by HCl intra-oesophageal instillation.
1. Gastro-oesophageal acid reflux may cause airway responses such as cough, bronchoconstriction and inflammation in asthmatic patients. Our previous results suggest that microvascular leakage induced, in the guinea-pig airways, by intra-oesophageal hydrochloric acid (HCl) infusion was mainly dependent on the release of tachykinins. Nociceptin, an endogenous ligand of the opioid receptor NOP, has been shown to inhibit bronchoconstriction and cough in guinea-pig or cat by inhibiting tachykinin release. 2. The purpose of this study was to investigate the effects of nociceptin on the intra-oesophageal HCl-induced airway microvascular leakage evaluated by Evans blue dye extravasation measurement in anaesthetised guinea-pigs pretreated with propranolol, atropine and phosphoramidon. 3. Infusion of intra-oesophageal HCl led to a significant increase in plasma extravasation in the main bronchi and trachea. This increase was abolished when animals underwent a bilateral vagotomy. 4. Airway microvascular leakage was inhibited by nociceptin (3-30 microg x kg(-1) i.v.) in a dose-dependent manner (maximal inhibition at the dose of 30 microg x kg(-1): 19.76+/-1.13 vs 90.92+/-14.00 ng x mg(-1) tissue for nociceptin and HCl infusion, respectively, in the main bronchi, P<0.01). The NOP receptor agonist [Arg(14),Lys(15)]N/OFQ mimicked the inhibitory effect of nociceptin, but at a 10-fold lower dose (3 microg x kg(-1) i.v). The NOP receptor antagonist J-113397 had no effect on plasma protein extravasation by itself, but was able to block the inhibitory effect of nociceptin. 5. Morphine (1 mg x kg(-1)) had a similar inhibitory effect as that of nociceptin. Naloxone pretreatment abolished the effect of morphine, but was enable to block the inhibitory effect of nociceptin. 6. Under similar conditions, nociceptin, in the previous range of concentration, was unable to counteract the airway microvascular leakage induced by substance P (SP). 7. These results suggest that airway plasma extravasation induced by intra-oesophageal HCl instillation might be inhibited by specific stimulation of the NOP receptor with nociceptin. Nociceptin is likely to act at a pre-junctional level, by inhibiting tachykinin release, since it was unable to prevent SP-induced airway plasma extravasation.
UPRES EA220 - Pharmacology, University of Versailles and UFR Biomédicale des Saints Pères, 45 rue des Saints Pères, F-75006 Paris, France.
Céline
C
Rouget
Yong Yao
YY
Cui
Bruno
B
D'Agostino
Christophe
C
Faisy
Emmanuel
E
Naline
Marc
M
Bardou
Charles
C
Advenier
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001980:Bronchi / Q000098:blood supply / Q000294:innervation; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D005764:Gastroesophageal Reflux / Q000139:chemically induced / Q000503:physiopathology*; D006168:Guinea Pigs; D006851:Hydrochloric Acid / Q000037:antagonists & inhibitors; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone; D009292:Narcotic Antagonists; D009294:Narcotics / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013373:Substance P; D014132:Trachea / Q000098:blood supply / Q000294:innervation; D014628:Vagotomy; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097629:Nociceptin
D001562:Benzimidazoles; D006851:Hydrochloric Acid; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D009294:Narcotics; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D013373:Substance P; D014665:Vasodilator Agents; D000097629:Nociceptin; C402921:J 113397