Effect of nociceptin in acid-evoked cough and airway sensory nerve activation in guinea pigs

Rationale: Nociceptin/orphanin FQ has been reported to inhibit capsaicin- and mechanically provoked cough in animal models, but the mechanism of this effect has not been elucidated. Objectives: The objectives of this study were to determine whether nociceptin inhibits acid-evoked cough in conscious animals and to evaluate the mechanism of this effect. Methods: We tested the effect of nociceptin on acid-induced cough in conscious guinea pigs and acid-induced nerve activation in airway-specific vagal sensory neurons using calcium imaging techniques and the gramicidin-perforated patch clamp technique. Measurements and Main Results: Nociceptin (3mg/kg, intraperitoneal) effectively inhibited acid-evoked cough in guinea pigs by nearly 70%. Acid (pH 5) increased intracellular free calcium in acutely dissociated vagal jugular ganglionic neurons. The acid-induced increase in intracellular calcium was inhibited by a selective transient receptor potential vanilloid-1 antagonist, 5-iodo-resiniferatoxin (1 μM, ∼ 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acidinduced increases in calcium wasmimicked by nociceptin (0.1 μM). In gramicidin-perforated patch clamp recordings on airway-specific capsaicin-sensitive jugular ganglion neurons, acid (pH 5) induced two distinct inward currents. A transient current was evoked that was inhibited by amiloride and a sustained current was evoked that was inhibited by 5-iodo-resiniferatoxin. Nociceptin selectively inhibited only the sustained component of acid-induced inward current. Conclusion: These results indicate that the inhibitory effect of nociceptin on acid-induced cough may result from a direct inhibitory effect on peripheral C-fiber activity caused by the selective inhibition of acid-induced transient receptor potential vanilloid-1 activation.