KAPPA-OPIOID RECEPTOR AGONISTS INCREASE LOCOMOTOR-ACTIVITY IN THE MONOAMINE-DEPLETED RAT MODEL OF PARKINSONISM

Excessive glutamate transmission in the basal ganglia is a major facto r in the neural mechanisms underlying parkinsonian akinesia. Activatio n of kappa opioid receptors causes a presynaptic reduction in glutamat e release. kappa opioid receptors are concentrated in those regions of the basal ganglia associated with increased glutamate transmission in parkinsonism, In this study, we use the alpha-methyl-p-tyrosine and r eserpine-treated rat model of parkinsonism to investigate whether syst emic administration of the kappa opioid agonists enadoline (CI-977) an d U69,593 fan alleviate the symptoms of parkinsonism either alone or i n conjunction with dopamine replacement therapy, We report that, when administered alone, both enadoline and U69,593 can increase locomotion in monoamine-depleted rats. No increase in locomotor activity was see n after kappa opioid agonist administration in non-parkinsonian rats. The responses to kappa opioid agonists were blocked by co-administrati on of either the nonspecific opioid receptor antagonist naloxone or th e selective kappa opioid receptor antagonist nor-binaltorphimine (nor- BNI). An important finding is that when enadoline and L-dopa are admin istered together, their anti-akinetic properties are synergistic. Thus , the doses of enadoline and L-dopa required to alleviate akinesia whe n administered together are lower than either administered alone. Thes e data illustrate the importance of kappa opioid receptors in the neur al mechanisms controlling voluntary movement and suggest that kappa op ioid agonists may have a role as adjuncts to dopamine replacement In t he management of Parkinson's disease.