Association of enkephalin catabolism inhibitors and CCKB antagonists: A potential use in the management of pain and opioid addiction

The overlapping distribution of opioid and cholecystokinin (CCK) peptides and their receptors (μ and δ opioid receptors; CCK-A and CCK-B receptors) in the central nervous system have led to a large number of studies aimed at clarifying the functional relationships between these two neuropeptides. Most of the pharmacological studies devoted to the role of CCK and enkephalins have been focused on the control of pain. Recently the existence of regulatory mechanisms between both systems have been proposed, and the physiological antagonism between CCK and endogenous opioid systems has been definitely demonstrated by coadministration of CCK-B selective antagonists with RB 101, a systemically active inhibitor, which fully protects enkephalins from their degradation. Several studies have also been done to investigate the functional relationships between both systems in development of opioid side-effects and in behavioral responses. This article will review the experimental pharmacology of association of enkephalin-degrading enzyme inhibitors and CCK-B antagonists to demonstrate the interest of these molecules in the management of both pain and opioid addiction. Special issue dedicated to Dr. Eric J. Simon.