2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and Cough

1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.

Topics: Animals; Antitussive Agents; Brain; Cough; Dextromethorphan; Dose-Response Relationship, Drug; Ethylenediamines; Guinea Pigs; Male; Phenazocine; Protein Binding; Receptors, sigma; Sigma-1 Receptor

The effects of selective sigma-ligands on the capsaicin-induced cough reflex in rats were studied. Intraperitoneal injection of (+)-N-allylnormetazocine ((+)-SKF-10,047) and N,N'-di(ortho-tolyl)guanidine (DTG) in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs dose dependently. The antitussive effects of these sigma-ligands were significantly attenuated by pretreatment with haloperidol. Pretreatment with haloperidol also markedly reduced the antitussive effects of (+/-)-pentazocine and dextromethorphan. These results suggest that haloperidol-sensitive sigma-sites may be involved in the regulation of coughs.

Topics: Animals; Antitussive Agents; Capsaicin; Cough; Dose-Response Relationship, Drug; Drug Interactions; Guanidines; Haloperidol; Injections, Intraperitoneal; Male; Phenazocine; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stereoisomerism