Folia Pharmacologica Japonica

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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-HT₁ 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 μ₁-opioid receptor antagonist, had no effect on the antitussive effects associated with i.c.v. DAMGO. These results indicate that μ₂- rather than μ₁-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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Transgenic animals are a very important tool not only for basic science but also for the pharmaceutical industry. The use of genetically engineered farm animals are suitable as a disease model. Production of a therapeutic protein such as human clotting factors by transgenic animals will reduce the risk of infection with human immunodeficiency virus and hepatitis virus. The efficiency of transgenic animal production, however, has been low and thus limited its application. We improved the efficiency using a green fluorescent protein (GFP) as a marker of gene integration. Using this method, we obtained 12 fetuses, and Southern blot analysis showed eight of them were transgenic, indicating transgenic embryos were successfully selected at the preimplantation stage. We also observed similar GFP expression in rat and bovine blastocysts. Application of this GFP selection method should improve the efficiency of transgenic livestock production.

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