Dopamine receptors mediate alterations in striato-nigral dynorphin and substance P pathways.

Peptides derived from prodynorphin, dynorphin A and B, (Leu)-enkephalin and (Leu)enkephalyl-Arg, as well as substance P, were measured in substantia nigra, striatum and globus pallidus, after subacute (5 doses at 6 hr intervals) treatment of rats with a number of dopamine receptor agonists and antagonists. Drugs selective for the dopamine D1 and D2 receptors, respectively, as well as unselective drugs were used. In the substantia nigra, levels of immunoreactive dynorphin A and dynorphin B were increased after treatment with a D2-antagonist (sulpiride) and a D1-agonist (SKF 38393), while a D1-antagonist (SCH 23390) reduced levels. The mixed D1 and D2 antagonist cis-flupenthixol reduced only the level of dynorphin A. A corresponding increase of the levels of (Leu)enkephalin in the nigra was found after treatment with sulpiride. In contrast to dynorphin peptides, the levels of (Leu)enkephalyl-Arg were markedly increased after both D1- and D2 (LY 171555)-stimulation. Substance P tended to be reduced after D1-stimulation and treatment with all the dopamine antagonists; the reduction was significant with sulpiride and cis-flupenthixol. Levels of peptides in striatum and globus pallidus were generally affected in the same direction as levels in the nigra. The results in this study present further evidence that dopamine receptor agents affect dynorphin peptides and substance P, differentially. Effects on (Leu)enkephalin and (Leu)enkephalyl-Arg only partly paralleled the effects on levels of dynorphin. Thus, the D1 and D2 receptors differentially affect levels of different products of prodynorphin, that is, seem to affect certain steps of the processing of prodynorphin selectively.