[Enkephalin catabolism inhibitors and antalgics of the future: from preclinical research to clinical trials].

It is now well accepted that the pain suppression effect of morphine is related to the interaction of this alkaloid with binding sites located in the central nervous system. The wide distribution of opioid receptors probably accounts for the multiplicity of pharmacological responses elicited by morphine administration, as in addition to its strong analgesic potency morphine induces side effects. Therefore, there is a critical need for new analgesics able to fulfil the gap existing between opioid analgesics and antalgics. These new analgesics could be of major interest in a number of severe pain syndromes. The discovery that the endogenous morphine-like peptides enkephalins are degraded by well-defined metabolic pathways represents a promising outlook for the development of new analgesics. The complete inhibitors of enkephalin catabolism produce their physiological effects by increasing the extracellular levels of endogenous opioid peptides released either tonically or following stimuli-evoked depolarization. Under these conditions, their effects will depend upon the magnitude and duration of the enkephalin release evoked by a particular stimulus, which probably varies in the different enkephalinergic pathways. It is expected that increasing the levels of endogenous opioid peptides would avoid serious drawbacks inasmuch as they appear related to a ubiquitous overstimulation of brain opioid receptors. Some mixed inhibitors of enkephalin degrading enzymes are now undergoing preclinical trials.