Enhancement of the effects of a complete inhibitor of enkephalin-catabolizing enzymes, RB 101, by a cholecystokinin-B receptor antagonist in diabeticrats

1 RB 101, a complete inhibitor of enkephalin-catabolizing enzymes, has been previously shown to produce antinociception in normal rats after systemic administration. Moreover, its coadministration with a cholecystokinin-B (CC K-B) receptor antagonist has been shown to strongly enhance its antinocicep tive effect in normal rats. In this work, we determined whether RE 101 was able to reduce hyperalgesia and allodynia in diabetic rats, a model of neur opathic pain. The type of opioid receptors (mu or delta) involved was deter mined using naloxone and naltrindole, respectively, and the interactions be tween endogenous enkephalins and CCK on nociception control was investigate d using coadministration of RE 101 and the CCK-B receptor antagonist CI-988 . 2 RB 101 suppressed mechanical hyperalgesia (paw pressure-induced vocalizat ion test), partially alleviated mechanical allodynia (von Frey hair test), and was ineffective in thermal allodynia (tail immersion test). The analges ic effect was completely cancelled by naloxone or naltrindole, suggesting t hat is requires the availability of mu- and/or delta -opioid receptors. 3 The combination of an inactive dose of CI-988 with the lowest effective d ose of RE 101 resulted in a stronger increase in the vocalization threshold comparatively to RE 101 alone. 4 The present study demonstrates that the antinociception generated by RE 1 01 induced by elevation of extracellular levels of endogenous enkephalins, can be extended to neuropathic pain in diabetic rats and that blockade of C CK-B receptors potentiated antinociceptive effects elicited by RB 101.