Opioid peptides in Parkinson's disease: effects of dopamine repletion

Neurotransmitters other than dopamine, including neuropeptides, could have important pathophysiologic and therapeutic roles in Parkinson's disease. Both Met-enkephalin, the main transmitter of the striatopallidal pathway, and dynorphin, one of the co-transmitters of the striatonigral pathway display complex anatomic and biochemical interactions with the basal ganglionic dopamine system. In this study, the cerebrospinal fluid content of a proenkephalin derivative, Met5 enkephalin-Arg6-Gly7-Leu8 (MERGL), was found in significantly low concentrations in parkinsonian patients following overnight withdrawal of all medications compared with control subjects, and failed to change after at least 16 h of steady-state, optimal doses of levodopa infusion intravenously. MERGL levels increased with advancing age among normal individuals but not among patients with Parkinson's disease. In contrast dynorphin A(1-8) levels were not different between the two study groups, did not change with levodopa therapy, and failed to correlate with age or any indices of disease progression. These observations, consistent with post-mortem studies on Parkinson brains and contrary to findings in animal models of Parkinsonism, suggest that abnormality of the enkephalin system in this disease is due to involvement of these striatal neurons in the primary pathologic process.