Future medication in the management of pain: complete inhibitors of enkephalin catabolism

It is now well accepted that the pain suppression effect of morphine is rel ated 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 morp hine administration, as in addition to its strong analgesic potency morphin e induces side effects. Therefore, there is a critical need for new analges ics able to fulfil the gap existing between opioid analgesics and antalgics . These new analgesics could be of major interest in a number of severe pai n syndromes. The discovery that the endogenous morphine-like peptides enkep halins are degraded by well-defined metabolic pathways represents a promisi ng outlook for the development of new analgesics. The complete inhibitors o f enkephalin catabolism produce their physiological effects by increasing t he extracellular levels of endogenous opioid peptides released either tonic ally or following stimuli-evoked depolarization. Under these conditions, th eir effects will depend upon the magnitude and duration of the enkephalin r elease evoked by a particular stimulus, which probably varies in the differ ent enkephalinergic pathways. It is expected that increasing the levels of endogenous opioid peptides would avoid serious drawbacks inasmuch as they a ppear related to a ubiquitous overstimulation of brain opioid receptors. So me mixed inhibitors of enkephalin degrading enzymes are now undergoing prec linical trials.