Specificity of in vivo opiate antagonism by chlornaltrexamine

Chlornaltrexamine (CNA) and the fumaramido methyl ester derivative of naltrexone (FNA) appear to be nonequilibrium opiate antagonists (J.Med.Chem. 22:168 (1979); J. Med. Chem., in press). In an initial in vivo study in rats, it was found that tail-flick analgesia following morphine (10 mg/kg, s.c.) could be antagonized by 1-10 μg/rat of CNA administered intracerebroventricularly (i.c.v.) 90 min before testing. In a subsequent study of CNA effects upon exploratory (rearing) behavior and conditioned autoshape behavior, 1, 2.5 or 5 μg/rat i.c.v. given 90 min before the first of 2 daily acquisition sessions, did not affect conditioning, but the two higher doses reduced rearing. Amphetamine (2.5 mg/kg, i.p.) equally suppressed the conditioned behavior and rearing in CNA and vehicle controls 48-72 hr after CNA. Morphine (15 mg/kg, i.p.) given 48-72 hr after CNA, suppressed the conditioned behavior significantly more in the vehicle group. The data show that the in vivo actions of CNA are long-lasting and opiate specific. In another experiment, FNA (5 mg/kg, i.p.), a more selective nonequilibrium antagonist, was found to have no effect upon autoshaped behavior or rearing. We are currently examining the capacity of FNA to selectively antagonize the suppressant action of morphine.