Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel

1 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 Ca2+ concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca2+ responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 muM). 2 N/OFQ inhibitory effect on the Ca2+ response in nodose ganglia cells was antagonized by tertiapin (0.5 muM), an inhibitor of inward-rectifier K+ channels. but not by verapamil, a voltage gated Ca2+ channel blocker, indicating that an inward-rectifier K+ channel is involved in N/OFQ inhibitory effect. 3 In isolated guinea-pig bronchus, N/OFQ (1 muM) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 muM) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. 4 Capsaicin (10 mug) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 muM). 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 muM) blocked the capsaicin-induced tachykinin release. 5 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.