The adrenergic receptor agonist, clonidine, potentiates the anti-parkinsonian action of the selective κ-opioid receptor agonist, enadoline, in the monoamine-depleted rat

被引:29
作者
Hill, MP [1 ]
Brotchie, JM [1 ]
机构
[1] Univ Manchester, Sch Biol Sci, Div Neurosci 1 124, Manchester Movement Disorder Lab, Manchester M13 9PT, Lancs, England
关键词
Parkinson's disease; kappa-opioid; alpha-adrenoreceptor; reserpine; L-DOPA-induced dyskinesia;
D O I
10.1038/sj.bjp.0702943
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The treatment of Parkinson's disease relies predominantly upon dopamine replacement therapy, usually with 1-dihydroxyphenylalanine (L-DOPA). However, side-effects of long-term treatment, such as L-DOPA-induced dyskinesias can be more debilitating than the disease itself. Non-dopaminergic treatment strategies might therefore be advantageous. 2 The aim of this study was to investigate the potential anti-parkinsonian efficacy of the kappa-opioid receptor agonist, enadoline, and the alpha-adrenoreceptor agonist, clonidine, both alone or in combination, in the reserpine-treated rat model of Parkinson's disease. 3 Rats were treated with reserpine (3 mg kg(-1)), and experiments carried out 18 h later, at which time they exhibited profound akinesia (normal animals 1251 +/- 228 mobile counts h(-1), reserpine-treated animals 9 +/- 2 mobile counts h(-1)). Both enadoline and clonidine increased locomotion in reserpine-treated rats in a dose-dependent manner. The maximum locomotor-stimulating effect of enadoline alone was seen at a dose of 0.2 mg kg(-1) (208 +/- 63 mobile counts h(-1)). The maximum effect of clonidine was seen at a dose of 2 mg kg(-1) (536 +/- 184 mobile counts h(-1)). 4 Co-administration of enadoline (0.1 mg kg(-1)) and clonidine (0.01 - 0.1 mg kg(-1)) at subthreshold doses, synergistically increased locomotion. 5 The synergistic stimulation of locomotion in the reserpine-treated rat involved activation of kappa-opioid receptors and a combination of both alpha(1) and alpha(2)-adrenoreceptors. 6 The results presented suggest a need for further studies on the potential of stimulating kappa-opioid and/or alpha-adrenoreceptors as a therapy for Parkinson's disease. Furthermore, the studies may offer potential mechanistic explanations of the ability of alpha(2)-adrenergic receptor antagonist to reduce L-DOPA-induced dyskinesia in Parkinson's disease.
引用
收藏
页码:1577 / 1585
页数:9
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