Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat.

Quaternary derivatives of naloxone and naltrexone, methyl naloxonium chloride(ORG 10908) and naltrexone methobromide ( MRZ 2663BR ), respectively, were compared with the parent compounds for their ability to antagonize the reinforcing properties of heroin as measured in an operant, i.v., self-administration paradigm. As expected, lower doses (up to 0.2 mg/kg) of naloxone and naltrexone produced dose-dependent increases in heroin self-administration, but at higher doses (10-30 mg/kg) these drugs produced transient decreases (20-100 min) in self-administration followed by recovery. Naltrexone was approximately 1.5 times more potent than naloxone in increasing heroin self-administration at the lower doses (up to 0.2 mg/kg) and had a slightly longer duration of action. The quaternary derivatives were ineffective as antagonists of heroin self-administration in doses 200 times greater than the effective antagonist dose of naloxone or naltrexone. These results support the hypothesis that the acute reinforcing properties of i.v. opiates associated with the sensation of the "rush" involve opiate receptors located within the central nervous system and do not involve peripheral opiate receptors.