Effects of talipexole on emesis-related changes in abdominal afferent vagal activity and ileal serotonin metabolism in rats.
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.
Minami
M
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Science University of Hokkaido, Ishikari-Tobetsu, Japan.
Nemoto
M
M
Endo
T
T
Hamaue
N
N
Kohno
Y
Y
D000005:Abdomen / Q000294:innervation*; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism; D001971:Bromocriptine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology; D014839:Vomiting / Q000378:metabolism*
D001381:Azepines; D015306:Biogenic Monoamines; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D012701:Serotonin; D001971:Bromocriptine; C024763:talipexole; D014365:Tryptophan Hydroxylase; D008995:Monoamine Oxidase