Abstract
Excessive glutamate transmission in the basal ganglia is a major factor in the neural mechanisms underlying parkinsonian akinesia. Activation of K opioid receptors causes a presynaptic reduction in glutamate release. K opioid receptors are concentrated in those regions of the basal ganglia associated with increased glutamate transmission in parkinsonism. In this study, we use the α‐methyl‐p‐tyrosine and reserpine‐treated rat model of parkinsonism to investigate whether systemic administration of the K opioid agonists enadoline (CI‐977) and U69,593 can alleviate the symptoms of parkinsonism either alone or in 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 seen after K opioid agonist administration in non‐parkinsonian rats. The responses to K opioid agonists were blocked by co‐administration of either the nonspecific opioid receptor antagonist naloxone or the selective K opioid receptor antagonist nor‐binaltorphimine (nor‐BNI). An important finding is that when enadoline and L‐dopa administered togethe, their anti‐akinetic properties are synergistic. Thus, the doses of enadoline and L‐dopa required to alleviate akinesia when administered together are lower than either administered alone. These data illustrate the importance of K opioid receptors in the neural mechanisms controlling voluntary movement and suggest that K opioid agonists may have a role as adjuncts to dopamine replacement in the management of Parkinson's disease.