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 replacement therapy, usually with l-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 sub-threshold 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 alpha1 and alpha2-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 alpha2-adrenergic receptor antagonist to reduce L-DOPA-induced dyskinesia in Parkinson's disease.
Hill
M P
MP
Manchester Movement Disorder Laboratory, 1.124 Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, M13 9PT. m.hill@man.ac.uk
Brotchie
J M
JM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D012110:Reserpine / Q000633:toxicity; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000978:Antiparkinson Agents; D001572:Benzofurans; D015306:Biogenic Monoamines; D004338:Drug Combinations; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D015016:Yohimbine; C051844:norbinaltorphimine; D009271:Naltrexone; D012110:Reserpine; C067110:enadoline; D003000:Clonidine; D011224:Prazosin