Kelatorphan, a potent enkephalinases inhibitor, presents opposite properties when injected intracerebroventricularly or into the nucleus accumbens on intracranial self-stimulation.

The ventral tegmental area contains a high density of dopaminergic perikaryon which present ascending axonal projections notably to the nucleus accumbens. This system, referred as the mesolimbic dopamine system has been demonstrated to display moderate to high density of enkephalin-containing fibers. This topographical analogy led us to evaluate the properties of kelatorphan, a new potent inhibitor of multiple enkephalin-degrading enzymes, on this mesolimbic system. Intracranial self-stimulation behavior served to estimate this mesolimbic dopaminergic function. Kelatorphan was injected either into the lateral ventricle or into the nucleus accumbens. Kelatorphan elicited opposite behavioral profiles, i.e. an intracranial self-stimulation increase when intracerebroventricularly injected (70 nmol) and a decreased self-stimulation behavior when directly administered into the nucleus accumbens (35 nmol). The results thus suggest that kelatorphan which protects endogenous enkephalins against enzymatic degradation seemed to act on the regulation of the mesolimbic dopamine system.