NEUROANATOMICAL AND BIOCHEMICAL STUDIES OF MULTIPLE OPIATE RECEPTORS (EMKEPHALINERGIC, DOPAMINERGIC)
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Neurochemical, behavioral, and pharmacological evidence indicates the existence of multiple opiate receptors and multiple opioid peptides of the central nervous system. Light microscopy auto-radiography studies have established that these receptors have different neuro-anatomical distribution patterns.;First, a comparative study of K receptors in guinea pig and rat brain was carried out. K opiate receptors were labeled using the K ligand ('3)H EKC in the presence of the synthetic peptides DAGO and DADLE. Equilibrium binding was achieved by 40 minutes, after which these sites underwent a time-dependent increase in binding affinity. To test the hypothesis that the altered affinity was due to a conformational change, receptor preparations were reacted with the sulfhydryl reagent N-ethylmaleimide (NEM) at different times. Findings suggest that there is an apparent conformational change in guinea pig brain K receptors with increased time of incubation. K receptors of rat brain exhibit a similar affinity and density, but do not undergo conformational alteration.;To gain insight into the physiological functions of the receptors, we attempted to determine different topographical organizations with respect to pre and postsynaptic membranes. Our second project focused on the nigrostriatal pathway and suggests the presence of (mu), (delta) and a low density of K receptors on the presynaptic membranes of nigral dopaminergic terminals in the striatum. Quantitative receptor assays using highly specific ('3)H ligands were used to measure the number of (mu), (delta), and K receptors in rat striatum before and after denervation of the dopaminergic terminals projecting from the substantia nigra. Parallel quantitative autoradiography determined the neuroanatomical distribution patterns of each receptor type in lesioned and nonlesioned brain. 15 - 21 days after the lesion, the density of (mu) receptors was 60 (+OR-) 6% lower on the lesioned side of the striatum relative to striatal tissue from control animals. (delta) receptors showed 49 (+OR-) 9% decrease of the receptor density in lesioned vs. control striatum. By contrast, K receptors exhibited only a 19 (+OR-) 7% decrease in receptor density. Autoradiographic studies demonstrated that the opiate receptor density in other areas of the brain did not change. These findings demonstrate that the loss of nigral innervation results in decreased numbers of multiple opiate receptors in the striatum. The profile and the percentage of receptor density changes suggest that a high percentage of (mu) and (delta) receptors in the striatum are located on the nigral dopaminergic terminals, whereas there is only a low density of K receptors on these nerve endings. Together these findings provide evidence for the presynaptic localization of (mu), (delta), and to a lesser extent K receptors, and support the concept of a neuromodulatory role for (mu) and (delta) opioid peptides in the nigrostriatal dopaminergic pathway. (Abstract shortened with permission of author.).