{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:40:08Z","timestamp":1745469608533,"version":"3.40.4"},"reference-count":15,"publisher":"S. Karger AG","issue":"3","license":[{"start":{"date-parts":[[2004,1,1]],"date-time":"2004-01-01T00:00:00Z","timestamp":1072915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2004,1,1]],"date-time":"2004-01-01T00:00:00Z","timestamp":1072915200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology"],"published-print":{"date-parts":[[2004]]},"abstract":"<jats:p>We have previously shown that N\/OFQ, the endogenous peptide ligand for the \u2018opioid-like\u2019 NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The K&lt;sub&gt;i&lt;\/sub&gt; values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol\/l, respectively. In GTP\u03b3S-binding assays, Ro-64-6198 displayed &gt;900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10\u00a0\u00b5mol\/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca&lt;sup&gt;2+&lt;\/sup&gt; concentration evoked by capsaicin stimulation (1 \u00d7 10&lt;sup&gt;\u20138&lt;\/sup&gt;\u20131 \u00d7 10&lt;sup&gt;\u20136&lt;\/sup&gt; mol\/l). Similar to previously reported data with N\/OFQ, Ro-64-6198 (3 and 10 \u00b5mol\/l) significantly attenuated Ca&lt;sup&gt;2+&lt;\/sup&gt; responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 \u00b5mol\/l) on capsaicin-induced intracellular Ca&lt;sup&gt;2+&lt;\/sup&gt; responses was blocked by the NOP antagonist, J113397 (3 \u00b5mol\/l). In guinea pig in vivo studies, aerosolized capsaicin (10\u2013300 \u00b5mol\/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 \u00b5mol\/l) exposure. In a duration study we found that the maximum antitussive effect (42 \u00b1 8% inhibition) of Ro-64-6198 (3 mg\/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003\u20133.0 mg\/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg\/kg, i.p.) was blocked by J113397 (12\u00a0mg\/kg, i.p.) but not by the classical opioid antagonist naltrexone (10\u00a0mg\/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and\/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approach for the treatment of cough. Moreover, because these drugs do not interact at MOP receptors, they may be devoid of codeine-like side effects such as respiratory depression, sedation, constipation or proclivities for addictive liabilities.<\/jats:p>","DOI":"10.1159\/000077448","type":"journal-article","created":{"date-parts":[[2004,5,28]],"date-time":"2004-05-28T08:45:10Z","timestamp":1085733910000},"page":"143-149","source":"Crossref","is-referenced-by-count":24,"title":["Antitussive Profile of the NOP Agonist Ro-64-6198 in the Guinea Pig"],"prefix":"10.1159","volume":"71","author":[{"given":"Robbie L.","family":"McLeod","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanlin","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiomara","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard E.","family":"Parra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deen B.","family":"Tulshian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugenia J.","family":"Kiselgof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmad B.","family":"Fawzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"April","family":"Smith-Torhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongtao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John A.","family":"Hey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2004,6,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(01)01197-3"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00505-7"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(97)01227-2"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-9781(00)00237-0"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(01)00048-X"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.090514397"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-9781(00)00246-1"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(97)00875-6"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1006\/pupt.2002.0357"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1159\/000028226"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1517\/eotp.13.10.1501.22917"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1038\/377532a0"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)80235-1"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1159\/000054301"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4892(02)00152-2"}],"container-title":["Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/77448","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/77448","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:21:46Z","timestamp":1745468506000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000077448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004]]},"references-count":15,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2004,7,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000077448","archive":["Portico"],"relation":{},"ISSN":["0031-7012","1423-0313"],"issn-type":[{"type":"print","value":"0031-7012"},{"type":"electronic","value":"1423-0313"}],"subject":[],"published":{"date-parts":[[2004]]}}}