Vol. 288, Issue 2, 438-445, February 1999

Opioid Receptor Selectivity of Heroin Given Intracerebroventricularly Differs in Six Strains of Inbred Mice

Jodie J. Rady, Gregory I. Elmer and James M. Fujimoto

Department of Pharmacology and Toxicology, Medical College of Wisconsin and Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin (J.J.R., J.M.F.); and Behavioral Pharmacology and Genetics Section, Division of Intramural Research/National Institute on Drug Abuse/National Institutes of Health, Baltimore, Maryland (G.I.E.)

Heroin administered i.c.v. acts on supraspinal µ opioid receptors in ICR mice but on  receptors in Swiss Webster mice. The purpose of this study was to determine the degree to which genotype plays a role in the opioid receptor selectivity of heroin across a range of fully inbred strains of mice. Six inbred strains were given heroin i.c.v. 10 min before the tail-flick test. Differences in the descending neurotransmitter systems involved in supraspinal opioid-induced analgesia were evaluated as the first step. Antagonism by bicuculline given intrathecally indicated the involvement of supraspinal  receptors in activating spinal -aminobutyric acid (GABA) receptors; antagonism by intrathecal methysergide indicated either µ or  receptor involvement. Antagonism by intrathecal yohimbine implicated µ and eliminated  receptor involvement. Intracerbroventricular opioid antagonists (-funaltrexamine, 7-benzylidenenaltrexone, naltriben, or nor-binaltorphimine) provided further differentiation. Based on these initial results, receptor selectivity was determined by more extensive ED₅₀ experiments with i.c.v. administration of heroin with opioid antagonists, -funaltrexamine (for µ), naltrindole (for ), and nor-binaltorphimine (for ). The combined results indicated that heroin analgesia was predominantly mediated in C57BL/6J by , in DBA/2J and CBA/J by µ, and in BALB/cByJ and AKR/J by  receptors. The response in C3H/HeJ appeared to involve µ receptors. The results indicate that the opioid receptor selectivity of heroin is genotype-dependent. Because these genotypes are fully inbred, the genetically determined molecular and neurochemical substrate mediating the different opioid receptor selectivities of heroin can be studied further.