Protection of endogenous enkephalin catabolism as natural approach to novel analgesic and antidepressant drugs.

The most efficient drugs to alleviate severe pain are opioid compounds. However, their chronic use could be associated with serious drawbacks, such as tolerance, respiratory depression and constipation. Therefore, there is a need for compounds able to efficiently alleviate inflammatory and neurogenic pain following chronic treatment. The discovery that the endogenous opioid peptides, enkephalins, are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by synthetic dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of morphine side effects. These dual inhibitors also have antidepressant-like properties through enkephalin-related activation of delta-opioid receptors. This is expected to reduce the emotional component of pain in humans. This article reviews the promising data obtained for future development of a new class of analgesic that could be of major interest in a number of severe and chronic pain syndromes.