Nociceptin inhibits airway microvascular leakage induced by HCl intra‐oesophageal instillation

Abstract

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 HClinduced 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. Lys 15 ]N/OFQ mimicked the inhibitory effect of nociceptin, but at a 10-fold lower dose (3 mg kg À1 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 kg À1 ) 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.

Activation of the nociceptin/orphanin FQ receptor reduces bronchoconstriction and microvascular leakage in a rabbit model of gastroesophageal reflux

“…HCl infusion. In addition to our previous findings in the guinea-pig (Rouget et al, 2004), we have shown that HCl induced plasma extravasation but also bronchoconstriction were significantly reduced by a pretreatment with N/OFQ (Okada et al, 2000;Rizzi et al, 2002). We have also shown that the effects of both agonists were abolished by the selective NOP receptor antagonist UFP-101 , suggesting that their preventive actions on vascular leakage and bronchoconstriction are exclusively due to NOP receptor activation and share common mechanisms.…”

“…These results are in agreement with several lines of evidence indicating inhibitory actions of N/OFQ on sensory nerves in the guinea-pig, such as inhibition of the contraction of the isolated bronchus induced by EFS , of capsaicin-induced bronchoconstriction of isolated lung (Corboz et al, 2000), of airway microvascular leakage induced by i.oe. HCl (Rouget et al, 2004), or in human isolated bronchi, inhibition of airway hyperresponsiveness induced by beta2-adrenoceptor agonists (Faisy et al, 2003). In addition, in this study, we also showed that N/OFQ and [Arg 14 ,Lys 15 ]N/OFQ did not inhibit SP-induced bronchoconstriction and microvascular leakage in airways, suggesting that NOP agonists do not interact with postsynaptic neurokinin receptors, but exert their inhibitory effects on sensory nerves at presynaptic sites.…”

“…In vivo studies have shown that N/OFQ inhibits bronchoconstriction and cough induced by capsaicin in guinea-pigs Jia et al, 2002) or by mechanical stimulation of intrathoracic airways in the cat (Bolser et al, 2001). Finally, N/OFQ inhibits guineapig airway inflammation induced by esophageal hydrochloric acid (HCl) instillation (Rouget et al, 2004). Collectively, these studies demonstrate that N/OFQ may influence airway physiology by modulating cholinergic and/or tachykininergic neurotransmission.…”

Recent advances towards the discovery of ORL-1 receptor agonists and antagonists

“…In vitro, nociceptin inhibits bronchoconstriction and the release of pro-inflammatory molecules in isolated bronchi from guinea-pigs [101,102]. Nociceptin inhibited the microvascular leakage induced by hydrochloric acid (HCl) infusion in the oesophagus of anaesthetised guinea-pigs and this effect was reversed by J-113397 [103]. This result suggests that ORL-1 agonists might have utility in cough, bronchoconstriction, and inflammation resulting from gastro-oesophageal acid reflux.…”

Relaxin Receptors - New Drug Targets for Multiple Disease States

“…In the brain, there are dense NOP receptors in the medullar nucleus tractus solitarius [11], where pulmonary and extrapulmonary afferent fibers terminate and provide polysynaptic inputs to second-order neurons which modulate the respiratory neuron activities [186]. Recently, N/OFQ was found to inhibit airway microvascular leakage induced by intra-esophageal acid instillation [188]. The inhibitory effect of N/OFQ on acidinduced cough in guinea pigs may result from a decrease of peripheral C-fiber activity through an inhibition of the vallinoid receptor on airway-specific capsaicin-sensitive jugular ganglia [189].…”