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


OBJECTIVE
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.


RESULTS
Nociceptin (3 mg/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 microM, approximately 80% reduction). The inhibitory effect of 5-iodo-resiniferatoxin on acid-induced increases in calcium was mimicked by nociceptin (0.1 microM). 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.


CONCLUSIONS
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.
Lee
Min-Goo
MG
Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Undem
Bradley J
BJ
Brown
Claire
C
Carr
Michael J
MJ
D000818:Animals; D001016:Aortic Bodies / Q000187:drug effects; D002211:Capsaicin; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000517:prevention & control*; D005924:Glomus Jugulare / Q000187:drug effects; D006168:Guinea Pigs; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects; D018847:Opioid Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D011957:Receptors, Opioid / Q000819:agonists*; D012137:Respiratory System / Q000187:drug effects* / Q000294:innervation; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D002211:Capsaicin; D019343:Citric Acid; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin