Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine.

The 6-bis(2)chloroethyl)amino derivatives of oxymorphone and naltrexone, chloroxymorphamine (COA) and chlornaltrexamine (CNA), respectively, produce an irreversible inhibition of [3H]naltrexone binding to mouse brain homogenates. Intracerebroventricular (i.c.v.) injection of COA (4 nmol/mouse) elicits analgesia which lasts 4 times longer than analgesia produced by equimolar and equieffective dose of oxymorphone. The analgesia induced by COA can be reversed and blocked by naloxone. Injections of both COA and CNA i.c.v. antagonize morphine-induced analgesia for 3 days. Similarly, when [3H]naltrexone binding is measured in brains from mice pretreated i.c.v. with COA or CNA, there is a significant decrease in total specific binding for 3 days after pretreatment. These data suggest that CNA and COA alkylate the opioid receptors to produce antagonist and agonist-antagonist effects, respectively. The implications of these findings are discussed with respect to their effect on our perception of the opioid receptor-narcotic agonist interaction and the mechanisms of tolerance and dependence.