Opposite role of delta(1)- and delta(2)-opioid receptors activated by endogenous or exogenous opioid agonists on the endogenous cholecystokinin system: Further evidence for delta-opioid receptor heterogeneity

Using the mouse caudate-putamen, where delta-opioid receptor subtypes have been shown to regulate adenylyl cyclase activity, we show in this study that endogenous enkephalins inhibit enzyme activity through activation of delta(1)- and delta(2)-opioid receptors. Thus, naltriben or 7-benzylidenenaltrexone as well as the delta-selective antagonist naltrindole (mixed delta(1), and delta(2) antagonist) antagonized inhibition of adenylyl cyclase activity induced by methionine- or leucine-enkephalin, while the mu-antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) was without effect. Furthermore, we have previously shown that activation of delta-opioid receptors increases cholecystokinin release in the central nervous system, resulting in a potentiation of mu-opioid antinociceptive responses, and the respective role of delta(1)-and delta(2)-opioid receptors in this facilitatory effect has now been evaluated. Activation of delta(2)-opioid receptors, either by endogenous enkephalins protected from catabolism by the complete enkephalin-degrading enzyme inhibitor N-((R,S)-2-benzyl-3((S)(2-amino-4-methyl-thio) butyldithio)-1-oxopropyl)-L-phenyl-alanine benzyl ester (RB 101), or by the delta(2)-selective agonist Tyr-D-Ser(O-tert-butyl)-Gly-Phe-Leu-Thr(O-tert-butyl) (BUBU), potentiated mu-opioid antinociceptive responses in the hot-plate test in mice. This effect was antagonized by a selective cholecystokinin-A antagonist. Activation of delta(1)-opioid receptors by endogenous opioid peptides decreased the mu-opioid responses. These results suggest that stimulation of delta(2)-opioid receptors potentiates mu-opioid analgesia in the hot-plate test in mice through an increase in endogenous cholecystokinin release, while activation of delta(1)-opioid receptors could decrease it. Thus, the pre-existing physiological balance between opioid and cholecystokinin systems seems to be modulated in opposite directions depending on whether delta(1)- or delta(2)-opioid receptors are selectively activated. This is the first demonstration that endogenous enkephalins, methionine- and leucine-enkephalin, are the natural ligands of delta-opioid receptor subtypes, and that delta(2)-opioid receptor activation may facilitate the endogenous cholecystokinin-related modulation of mu-opioid analgesia, while the delta(1)-opioid receptors may have an inhibitory role. These results could have important applications for the characterization of opioid delta(1) and delta(2) as subtypes or subsites and in pain alleviation. Copyright (C) 1996 IBRO.