The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice

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Abstract
There is theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct from angiotensin converting enzyme (ACE)3-6, might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the CNS is suggested by parallel regional and subcellular distribution as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogs, and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, a potent and specific enkephalinase inhibitor was designed. Thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after intracerebroventricular or systemic administration. Thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.