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The adrenergic receptor agonist, clonidine, potentiates the anti‐parkinsonian action of the selective κ‐opioid receptor agonist, enadoline, in the monoamine‐depleted rat
Author(s) -
Hill M P,
Brotchie J M
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702943
Subject(s) - reserpine , clonidine , agonist , dopaminergic , pharmacology , endocrinology , medicine , opioid , dopamine , stimulation , opioid receptor , chemistry , receptor
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. The aim of this study was to investigate the potential anti‐parkinsonian efficacy of the κ‐opioid receptor agonist, enadoline, and the α‐adrenoreceptor agonist, clonidine, both alone or in combination, in the reserpine‐treated rat model of Parkinson's disease. 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 ). 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. The synergistic stimulation of locomotion in the reserpine‐treated rat involved activation of κ‐opioid receptors and a combination of both α 1 and α 2 ‐adrenoreceptors. The results presented suggest a need for further studies on the potential of stimulating κ‐opioid and/or α‐adrenoreceptors as a therapy for Parkinson's disease. Furthermore, the studies may offer potential mechanistic explanations of the ability of α 2 ‐adrenergic receptor antagonist to reduce L ‐DOPA‐induced dyskinesia in Parkinson's disease.British Journal of Pharmacology (1999) 128 , 1577–1585; doi: 10.1038/sj.bjp.0702943