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

1 The treatment of Parkinson's disease relies predominantly upon dopamine r eplacement therapy, usually with 1-dihydroxyphenylalanine (L-DOPA). However , side-effects of long-term treatment, such as L-DOPA-induced dyskinesias c an 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-adr enoreceptor agonist, clonidine, both alone or in combination, in the reserp ine-treated rat model of Parkinson's disease. 3 Rats were treated with reserpine (3 mg kg(-1)), and experiments carried o ut 18 h later, at which time they exhibited profound akinesia (normal anima ls 1251 +/- 228 mobile counts h(-1), reserpine-treated animals 9 +/- 2 mobi le counts h(-1)). Both enadoline and clonidine increased locomotion in rese rpine-treated rats in a dose-dependent manner. The maximum locomotor-stimul ating 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 do se 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 in volved 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 mechanist ic explanations of the ability of alpha(2)-adrenergic receptor antagonist t o reduce L-DOPA-induced dyskinesia in Parkinson's disease.