Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 271; no. 2; p. 715
• Main Authors: Burke, T F, Woods, J H, Lewis, J W, Medzihradsky, F
• Format: Journal Article
• Language: English
• Published: United States 01-11-1994
• Subjects: Analgesia; Animals; Benzimidazoles - pharmacology; Cinnamates - pharmacology; Enkephalin, Ala-MePhe-Gly; Enkephalins - metabolism; Male; Mice; Morphine Derivatives - pharmacology; Naltrexone - metabolism; Narcotic Antagonists - pharmacology; Receptors, Opioid, mu - antagonists & inhibitors; Receptors, Opioid, mu - drug effects; Receptors, Opioid, mu - metabolism
• ISSN: 0022-3565

The effects of the systemically active irreversible opioid receptor antagonist clocinnamox (C-CAM; 14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N- cyclopropylmethyl normorphinone mesylate) on mu receptor binding to cerebral membranes and on mu opioid analgesia were assessed using mice. After systemic administration, C-CAM produced a dose-dependent decrease in the Bmax values of both [3H]DAMGO ([D-Ala2, N-MePhe4, Gly5-ol][tyrosyl-3,5-3H]enkephalin) and [3H]naltrexone without affecting the Kd value of either ligand. After administration of 3.2 mg/kg of C-CAM, [3H]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 tail-withdrawal assay. The analgesic effect of the mu agonist etonitazene also was assessed in the assay. C-CAM produced dose-dependent rightward and slight downward shifts of the etonitazene dose-effect curve. The analgesic activity of etonitazene had still not returned to base-line levels 12 days after administration of 32 mg/kg of C-CAM, a time at which [3H]DAMGO binding had returned to control levels. In addition, the apparent pA2 values of etonitazene with naltrexone in the tail-withdrawal assay were assessed at 4, 8 and 12 days after the administration of 32 mg/kg of C-CAM, and none were found to be different from the control pA2 value. These results support the notion that C-CAM is an irreversible mu receptor antagonist and suggest that post-treatment, perhaps newly synthesized, mu receptors are similar to mu receptors in control membranes.