LONG-TERM CHANGES IN STRIATAL OPIOID SYSTEMS AFTER 6-HYDROXYDOPAMINE LESION OF RAT SUBSTANTIA-NIGRA

The effects of unilateral 6-hydroxydopamine lesion of the nigrostriata l pathway on striatal opioid peptides and receptors were determined at different time-intervals, from three days up to 24 weeks, post-lesion . Mu, delta and kappa opioid binding site densities in the ipsilateral caudate-putamen were decreased by 25-50% in rats which exhibited a gr eater than 90% loss of dopamine uptake sites. Differentiation of radio ligand binding to kappa, and kappa, subtypes demonstrated a selective loss of kappa2 sites post-lesion. The onset of significant 6-hydroxydo pamine lesion-induced changes in striatal opioid binding sites was del ayed with respect to the loss of dopamine uptake sites. Furthermore, m aximal loss of dopamine uptake sites was apparent within seven days po st-lesion, but not until two to four weeks for mu, delta and kappa sit es. In animals which exhibited an incomplete loss of dopamine uptake s ites (less than 80%) there was no significant change in opioid binding site density. Striatal proenkephalin and prodynorphin messenger RNA l evels were increased and decreased, respectively, after complete 6-hyd roxydopamine lesion. Modulation of peptide messenger RNA levels was ap parent within seven days and was maintained up to 24 weeks post-lesion . In contrast, proenkephalin and prodynorphin messenger RNA levels wer e unchanged in animals which exhibited an incomplete loss of striatal dopamine uptake sites. Taken together, these observations suggest that the majority of mu, delta and kappa, opioid binding sites are localiz ed on non-dopaminergic elements in the caudate-putamen, but that subst antia nigra innervation plays a role in the control of striatal opioid receptor expression. The 6-hydroxydopamine lesion-induced decreases i n striatal opioid binding site density may, in part, be a function of agonist-induced receptor downregulation. Alternatively, both opioid re ceptor and peptide expression in the caudate-putamen may be directly, but independently, regulated by ventral mesencephalic neurons.