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

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.