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 μ M ). N/OFQ inhibitory effect on the Ca 2+ response in nodose ganglia cells was antagonized by tertiapin (0.5 μ M ), 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 μM) inhibited capsaicin‐induced airway contraction. Tertiapin (0.5 μ M ) abolished the N/OFQ inhibition of capsaicin‐induced bronchial contraction. Capsaicin (10 μg) increased pulmonary inflation pressure in the isolated perfused guinea‐pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 μ M ). 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 μ M ) 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.British Journal of Pharmacology (2002) 135 , 764–770; doi: 10.1038/sj.bjp.0704515