Ca. Paronis et Jh. Woods, CLOCINNAMOX DOSE-DEPENDENTLY ANTAGONIZES MORPHINE-ANALGESIA AND [H-3]DAMGO BINDING IN RATS, European journal of pharmacology, 337(1), 1997, pp. 27-34
Clocinnamox is a long-lasting, nonequilibrium, mu-opioid receptor anta
gonist in mice and monkeys. The present studies examined the in vive a
nd ex vivo effects of clocinnamox in rats. Under control conditions, m
orphine dose-dependently increased tail-withdrawal latencies from 50 d
egrees C water, with a mean ED50 of 7.3 +/- 1.1 mg/kg. Clocinnamox ant
agonized the antinociceptive effects of morphine. 1.0 mg/kg clocinnamo
x displaced the morphine dose-response curve 4-fold to the right of th
e control curve and 10 mg/kg clocinnamox eliminated morphine's antinoc
iceptive effects at doses up to 1000 mg/kg for at least seven days. Th
ere was a gradual recovery of the antinociceptive response to morphine
; however, the morphine dose-response curve did not return to its orig
inal position by five weeks after 10 mg/kg clocinnamox. Whole brain me
mbranes were prepared from separate groups of rats for determination o
f binding parameters of [H-3][D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephal
in (DAMGO). Clscinnamox dose-dependently decreased [H-3]DAMGO binding
ex vivo and the decreased binding was a result of changes in B-max. Th
e control B-max for [H-3]DAMGO was 234 +/- 8 fmol/mg protein; in membr
anes prepared from the rats pretreated with 10 mg/kg clocinnamox, the
B-max value for [H-3]DAMGO was 54 +/- fmol/mg protein. The B-max value
s for [3H]DAMGO binding after an injection of 10 mg/kg clocinnamox ret
urned towards control values gradually, four after clocinnamox the B-m
ax was 178 +/- 10 fmol/mg protein. These results suggest that clocinna
mox is a long-lasting, mat nonequilibrium mu-opioid receptor antagonis
t in rats. (C) 1097 Elsevier Science B.V.