Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel.
Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid-like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin-induced bronchoconstriction in isolated guinea-pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea-pig nodose ganglia cells. Capsaicin increased intracellular Ca(2+) concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca(2+) responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 microM). N/OFQ inhibitory effect on the Ca(2+) response in nodose ganglia cells was antagonized by tertiapin (0.5 microM), an inhibitor of inward-rectifier K(+) channels, but not by verapamil, a voltage gated Ca(2+) channel blocker, indicating that an inward-rectifier K(+) channel is involved in N/OFQ inhibitory effect. In isolated guinea-pig bronchus, N/OFQ (1 microM) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 microM) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. Capsaicin (10 microg) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 microM). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin-induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 microM) blocked the capsaicin-induced tachykinin release. These results indicate that N/OFQ-induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward-rectifier K(+) channel activation, accounts for the inhibition of capsaicin-evoked broncoconstriction.
Jia
Yanlin
Y
Allergy, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. yanlin.jia@spcorp.com
Wang
Xin
X
Aponte
Sonia I
SI
Rivelli
Maria A
MA
Yang
Richard
R
Rizzo
Charles A
CA
Corboz
Michel R
MR
Priestley
Tony
T
Hey
John A
JA
D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018847:Opioid Peptides / Q000494:pharmacology / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015320:Tachykinins / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D000097629:Nociceptin
D002211:Capsaicin; D018847:Opioid Peptides; D024661:Potassium Channels, Inwardly Rectifying; D015320:Tachykinins; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000097629:Nociceptin