Antitussive effect of the optical isomers of mu, kappa and sigma opiate agonists/antagonists in the cat.

The optical isomer of mu and kappa opiates, when given i.v., inhibited the cough reflex in the lightly anesthetized cat, the levoisomers being, in general, 2 to 14 times more potent than the dextro-isomers. The optical isomers of the sigma agonist, SKF 10,047, did not show any antitussive activity up to near lethal or lethal doses (5 mg/kg i.v.). Naloxone (1 mg/kg i.v.) did not block or reverse the antitussive effects of (-)- and (+)-codeine but completely antagonized the effects of an ED84 of (-)-, (+)-morphine, (-)-, (+)-methadone, levomethorphan and dextromethorphan. The cough suppressant effects of the kappa opiates were partially blocked by naloxone, (+/-)-ketocyclazocine being more sensitive to the effect of naloxone than (-)-cyclazocine. (-)-SKF 10,047 at 3.0 mg/kg i.v. and the ED16 of (-)-cyclazocine did not inhibit the antitussive effect of codeine but blocked that of morphine, behaving like naloxone. (+)-SKF 10,047 and (+)-cyclazocine did not show in vivo antagonistic effect vs. codeine or morphine. The ED16 of ketocyclazocine partially antagonized codeine but not morphine. The optical isomers of opiates showed good correlation between the in vivo antitussive potencies and their in vitro inhibitory potencies against (-)-codeine binding in homogenates of the guinea-pig medulla. The data confirm the hypothesis that the cough suppressant effects of opiates are mediated by receptors which are less stereoselective and less naloxone-sensitive than the analgesic receptors. The possible involvement of mu and kappa sites as well as their interactions are discussed.