Löscher W, Hönack D
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1993 Jul 20;238(2-3):191-200. doi: 10.1016/0014-2999(93)90847-b.
The anticonvulsant and adverse effects of dextromethorphan, a non-opioid antitussive, and its metabolite dextrorphan were examined in amygdala-kindled rats. Both drugs have repeatedly been proposed to be functional non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, but they also exert effects distinct from antagonism at NMDA receptors, such as blockade of voltage-gated calcium channels and sigma-site mediated actions. Since recent data have demonstrated that kindled rats are more susceptible to the adverse effects of NMDA receptor antagonists than non-kindled rats, the time course, characteristics and severity of adverse effects of dextromethorphan and dextrorphan were also determined in non-kindled animals. Dextromethorphan dose dependently increased the focal seizure threshold (i.e. the threshold for induction of afterdischarges recorded from the amygdala) in fully kindled rats. This anticonvulsant effect was found at relatively low doses (7.5-15 mg/kg i.p.) which were almost free of any adverse effects. At higher doses, dextromethorphan induced motor impairment and seizures, but no phenyclidine (PCP)-like adverse effects, such as hyperlocomotion or stereotypies. In contrast, such adverse effects were seen after dextrorphan, although only infrequently. Dextrorphan was less potent in inducing anticonvulsant but more potent in inducing motor impairing effects than dextromethorphan in kindled rats. In non-kindled rats, the motor impairment induced by dextrorphan was significantly less severe than in kindled rats, whereas no marked differences between kindled and non-kindled rats were found for dextromethorphan. The data indicate that dextromethorphan and dextrorphan differ in their mechanisms of action. Only dextrorphan exerts effects which are characteristic for NMDA receptor antagonism, whereas the potent anticonvulsant effect of dextromethorphan in presumably unrelated to the NMDA receptor complex.
在杏仁核点燃大鼠中研究了非阿片类镇咳药右美沙芬及其代谢产物右啡烷的抗惊厥作用和不良反应。这两种药物多次被认为是功能性非竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，但它们也发挥着与NMDA受体拮抗作用不同的效应，如阻断电压门控钙通道和西格玛位点介导的作用。由于最近的数据表明，点燃大鼠比未点燃大鼠对NMDA受体拮抗剂的不良反应更敏感，因此还在未点燃动物中确定了右美沙芬和右啡烷不良反应的时间进程、特征和严重程度。右美沙芬剂量依赖性地提高了完全点燃大鼠的局灶性癫痫发作阈值（即从杏仁核记录到的后放电诱导阈值）。这种抗惊厥作用在相对低剂量（腹腔注射7.5-15mg/kg）时就已出现，且几乎没有任何不良反应。在较高剂量时，右美沙芬会引起运动障碍和癫痫发作，但没有苯环己哌啶（PCP）样的不良反应，如运动亢进或刻板行为。相比之下，右啡烷虽只是偶尔出现此类不良反应，但也会出现。在点燃大鼠中，右啡烷诱导抗惊厥作用的效力较低，但诱导运动障碍作用的效力比右美沙芬更强。在未点燃大鼠中，右啡烷诱导的运动障碍明显不如点燃大鼠严重，而右美沙芬在点燃和未点燃大鼠之间未发现明显差异。数据表明，右美沙芬和右啡烷的作用机制不同。只有右啡烷发挥出NMDA受体拮抗作用的特征性效应，而右美沙芬的强效抗惊厥作用可能与NMDA受体复合物无关。
