Minami M, Nemoto M, Endo T, Hamaue N, Kohno Y
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tobetsu, Japan.
Res Commun Mol Pathol Pharmacol. 1997 Jan;95(1):67-82.
The involvement of abdominal afferent vagal activity and serotonergic mechanisms were examined following intravenous administration of talipexole, a dopamine D2 receptor agonist used for treatment of Parkinson's disease, in anesthetized rats. Intravenous administration of dopamine receptor agonists including D1/D2 components increased the spontaneous firing of afferent vagal neurons as did 2-methyl-5-hydroxytryptamine. Both talipexole (0.25-1.0 mg/kg) and bromocriptine (1.0-10.0 mg/kg) increased vagal nerve activity in a dose-dependent manner, and the effect of 10 mg/kg of bromocriptine was significantly greater than that noted with 1.0 mg/kg of talipexole. Increasing vagal firing induced by talipexole was prevented by pretreatment with granisetron, but not with metoclopramide or by spinal section, indicating that afferent vagal firing was mediated via stimulation of the 5-HT3 receptors on the neurons and secondarily caused by stimulation of dopamine receptors. On the other hand, bromocriptine at 5 mg/kg increased 5-HIAA concentration in the ileum, and serotonin turnover (5-HIAA/5-HT) was increased approximately 4-fold when compared to the vehicle group. Bromocriptine also increased the activities of tryptophan hydroxylase and monoamine oxidase. Talipexole at 0.5 mg/kg did not affect ileal 5-HT metabolism and the enzymatic activities. These findings suggest that dopamine receptor agonists may induce changes in abdominal afferent vagal activity and ileal 5-HT metabolism similar to those observed with emetic compounds, and that talipexole has a much smaller influence on serotonin-mediated responses than does bromocriptine with equipotent antiparkinsonian doses. One of the possible reason why talipexole showed fewer emetic side effects in patients with Parkinson's disease may be that the emetic responses triggered by D2 receptor stimulation may secondarily cause an increase of abdominal afferent vagal activity, which may be weakened by the 5-HT3 receptor antagonistic property of talipexole.
在麻醉大鼠中，静脉注射用于治疗帕金森病的多巴胺D2受体激动剂泰必利，研究腹部传入迷走神经活动和血清素能机制的参与情况。静脉注射包括D1/D2成分的多巴胺受体激动剂以及2-甲基-5-羟色胺，均可增加传入迷走神经神经元的自发放电。泰必利（0.25 - 1.0毫克/千克）和溴隐亭（1.0 - 10.0毫克/千克）均以剂量依赖性方式增加迷走神经活动，且10毫克/千克溴隐亭的作用明显大于1.0毫克/千克泰必利。预先用格拉司琼处理可阻止泰必利诱导的迷走神经放电增加，但甲氧氯普胺或脊髓横断则不能，这表明传入迷走神经放电是通过刺激神经元上的5-HT3受体介导的，其次是由多巴胺受体刺激引起的。另一方面，5毫克/千克的溴隐亭可增加回肠中5-HIAA的浓度，与溶剂组相比，血清素周转率（5-HIAA/5-HT）增加约4倍。溴隐亭还增加了色氨酸羟化酶和单胺氧化酶的活性。0.5毫克/千克的泰必利不影响回肠5-羟色胺代谢和酶活性。这些发现表明，多巴胺受体激动剂可能诱导腹部传入迷走神经活动和回肠5-羟色胺代谢的变化，类似于催吐化合物所观察到的变化，并且在等效抗帕金森病剂量下，泰必利对血清素介导反应的影响远小于溴隐亭。泰必利在帕金森病患者中催吐副作用较少的一个可能原因可能是，D2受体刺激引发的催吐反应可能继发引起腹部传入迷走神经活动增加，而泰必利的5-HT3受体拮抗特性可能会削弱这种增加。
