title: Clocinnamox dose-dependently antagonizes morphine-analgesia and [3H]DAMGO binding in rats.
abstract: Clocinnamox is a long-lasting, nonequilibrium, mu-opioid receptor antagonist in mice and monkeys. The present studies examined the in vivo and ex vivo effects of clocinnamox in rats. Under control conditions, morphine dose-dependently increased tail-withdrawal latencies from 50 degrees C water, with a mean ED50 of 7.3 +/- 1.1 mg/kg. Clocinnamox antagonized the antinociceptive effects of morphine. 1.0 mg/kg clocinnamox displaced the morphine dose-response curve 4-fold to the right of the control curve and 10 mg/kg clocinnamox eliminated morphine's antinociceptive effects at doses up to 1000 mg/kg for at least seven days. There was a gradual recovery of the antinociceptive response to morphine; however, the morphine dose-response curve did not return to its original position by five weeks after 10 mg/kg clocinnamox. Whole brain membranes were prepared from separate groups of rats for determination of binding parameters of [3H][D-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO). Clocinnamox dose-dependently decreased [3H]DAMGO binding ex vivo and the decreased binding was a result of changes in Bmax. The control Bmax for [3H]DAMGO was 234 +/- 8 fmol/mg protein; in membranes prepared from rats pretreated with 10 mg/kg clocinnamox, the Bmax value for [3H]DAMGO was 54 +/- 2 fmol/mg protein. The Bmax values for [3H]DAMGO binding after an injection of 10 mg/kg clocinnamox returned towards control values gradually, four weeks after clocinnamox the Bmax was 178 +/- 10 fmol/mg protein. These results suggest that clocinnamox is a long-lasting, nonequilibrium mu-opioid receptor antagonist in rats.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Paronis
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors*; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism*; D005260:Female; D007700:Kinetics; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000037:antagonists & inhibitors*; D009022:Morphine Derivatives / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D002934:Cinnamates; D004745:Enkephalins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C076806:clocinnamox; D009020:Morphine