Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice.
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.
Department of Pharmacology, University of Michigan, Ann Arbor.
T F
TF
Burke
J H
JH
Woods
J W
JW
Lewis
F
F
Medzihradsky
D000698:Analgesia; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000494:pharmacology*; D009271:Naltrexone / Q000378:metabolism; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism
D001562:Benzimidazoles; D002934:Cinnamates; D004745:Enkephalins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C076806:clocinnamox; D009271:Naltrexone; C084835:etonitazene