Junzo Kamei1, Kayo Morita, Shigeo Miyata, Kenji Onodera. 1. Department of Pathophysiology & Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, 142-8501, Tokyo, Japan.
Abstract
RATIONALE: Little information is available about the interaction between dihydrocodeine and second-generation antihistamine drugs such as cetirizine and ebastine, with particular reference to the rewarding effect of dihydrocodeine. OBJECTIVE: The effects of second generation histamine H(1) antagonists, such as cetirizine and ebastine on the antitussive and rewarding effect of dihydrocodeine were examined in mice. METHODS: Mice were exposed to a nebulized solution of capsaicin (30 micromol/l) under conscious and identical conditions, using a body plethysmograph. The coughs produced during a 3-min exposure period were counted. Effects of H(1) antagonists on the reinforcing effect of dihydrocodeine were assessed by using the conditioned place preference procedure in mice. RESULTS: The antitussive effect of dihydrocodeine was enhanced by the simultaneous administration of either cetirizine or ebastine. There was no statistical difference between the ED(50) of dihydrocodeine in combination with ebastine and that of dihydrocodeine in combination with cetirizine. Concurrent dosing of dihydrocodeine and ebastine produced a significant place preference. This behavioral potentiation was antagonized by SCH23390, a dopamine D(1) antagonist. Moreover, ebastine enhanced the central dopamine turnover ratio, but cetirizine could not, in this study. CONCLUSION: Taken together, the potentiation of place preference of dihydrocodeine with ebastine may be due, at least in part, to stimulation of the central dopaminergic system via D(1) receptors. However, combination of dihydrocodeine with cetirizine does not potentiate place preference at all, nor does it potentiate the central dopaminergic system. Thus, it is likely that cetirizine may be a useful constituent in opioid-containing, antitussive preparations that would not potentiate the development of psychological dependence.
RATIONALE: Little information is available about the interaction between dihydrocodeine and second-generation antihistamine drugs such as cetirizine and ebastine, with particular reference to the rewarding effect of dihydrocodeine. OBJECTIVE: The effects of second generation histamineH(1) antagonists, such as cetirizine and ebastine on the antitussive and rewarding effect of dihydrocodeine were examined in mice. METHODS:Mice were exposed to a nebulized solution of capsaicin (30 micromol/l) under conscious and identical conditions, using a body plethysmograph. The coughs produced during a 3-min exposure period were counted. Effects of H(1) antagonists on the reinforcing effect of dihydrocodeine were assessed by using the conditioned place preference procedure in mice. RESULTS: The antitussive effect of dihydrocodeine was enhanced by the simultaneous administration of either cetirizine or ebastine. There was no statistical difference between the ED(50) of dihydrocodeine in combination with ebastine and that of dihydrocodeine in combination with cetirizine. Concurrent dosing of dihydrocodeine and ebastine produced a significant place preference. This behavioral potentiation was antagonized by SCH23390, a dopamine D(1) antagonist. Moreover, ebastine enhanced the central dopamine turnover ratio, but cetirizine could not, in this study. CONCLUSION: Taken together, the potentiation of place preference of dihydrocodeine with ebastine may be due, at least in part, to stimulation of the central dopaminergic system via D(1) receptors. However, combination of dihydrocodeine with cetirizine does not potentiate place preference at all, nor does it potentiate the central dopaminergic system. Thus, it is likely that cetirizine may be a useful constituent in opioid-containing, antitussive preparations that would not potentiate the development of psychological dependence.