This paper provides an overview of our current understanding of the central mechanisms of cough and antitussives. Systemic administration of 8-OH-DPAT at doses of 0.1 and 0.3 mg/kg, i.p. markedly reduced the number of coughs in rats in a dose-dependent manner. The antitussive effect of 8-OH-DPAT, dihydrocodeine and dextromethorphan significantly was reduced by pretreatment with methysergide, but not ketanserin. Therefore, it is possible to speculate that the 5-HT
1 receptors, in particular the 5-HT
1A receptors, may be more important than others with respect to the effect of antitussive drugs. DAMGO, a selective μ-opioid receptor agonist, and U-50, 488H, a highly selective κ-opioid receptor agonist, have potent antitussive effects when administered either i.c. or i.p. However, we did not observe a cough-depressant effect of DPDPE, a selective δ-opioid receptor agonist. These results indicate that the antitussive effects of opioids are mediated predominantly by μ- and κ-opioid receptors. On the other hand, naloxonazine, a selective μ
1-opioid receptor antagonist, had no effect on the antitussive effects associated with i.c.v. DAMGO. These results indicate that μ
2- rather than μ
1-opioid receptors are involved in μ-opioid receptor-induced antitussive effects. Antitussive effects of dextromethorphan and noscapine were significantly and dosedependently reduced by pretreatment with rimcazole, a specific antagonist of σ sites. However, rimcazole did not have a significant effect on the antitussive effect of morphine. These results suggest that σ sites may be involved in the antitussive mechanism of non-narcotic antitussive drugs.
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