IRREVERSIBLE OPIOID ANTAGONIST EFFECTS OF CLOCINNAMOX ON OPIOID ANALGESIA AND MU-RECEPTOR BINDING IN MICE

The effects of the systemically active irreversible opioid receptor an tagonist clocinnamox (C-CAM; 14 rocinnamoyl-amino)-7,8-dihydro-N-cyclo propylmethyl normorphinone mesylate) on mu receptor binding to cerebra l membranes and on mu opioid analgesia were assessed using mice. After systemic administration, C-CAM produced a dose-dependent decrease in the B-max values of both [H-3]DAMGO ([D-Ala(2), N-MePhe(4), Gly(5)-ol] [tyrosyl-3,5-H-3]enkephalin) and [H-3]naltrexone without affecting the K-d value of either ligand. After administration of 3.2 mg/kg of C-CA M, [H-3]DAMGO binding recovered gradually, returning to control levels by 8 days. This time course of recovery was similar to that observed with 3.2 mg/kg of C-CAM against morphine analgesia in the warm-water t ail-withdrawal assay. The analgesic effect of the mu agonist etonitaze ne also was assessed in the assay. C-CAM produced dose-dependent right ward and slight downward shifts of the etonitazene dose-effect curve. The analgesic activity of etonitazene had still not returned to base-l ine levels 12 days after administration of 32 mg/kg of C-CAM, a time a t which [H-3]DAMGO binding had returned to control levels. In addition , the apparent pA(2) values of etonitazene with naltrexone in the tail -withdrawal assay were assessed at 4, 8 and 12 days after the administ ration of 32 mg/kg of C-CAM, and none were found to be different from the control pA(2) value. These results support the notion that C-CAM i s an irreversible mu receptor antagonist and suggest that post-treatme nt, perhaps newly synthesized, mu receptors are similar to mu receptor s in control membranes.