Opioid receptor selectivity of heroin given intracerebroventricularly differs in six strains of inbred mice.

Heroin administered i.c.v. acts on supraspinal mu opioid receptors in ICR mice but on delta 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 delta receptors in activating spinal gamma-aminobutyric acid (GABA) receptors; antagonism by intrathecal methysergide indicated either mu or kappa receptor involvement. Antagonism by intrathecal yohimbine implicated mu and eliminated kappa receptor involvement. Intracerbroventricular opioid antagonists (beta-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, beta-funaltrexamine (for mu), naltrindole (for delta), and nor-binaltorphimine (for kappa). The combined results indicated that heroin analgesia was predominantly mediated in C57BL/6J by delta, in DBA/2J and CBA/J by mu, and in BALB/cByJ and AKR/J by kappa receptors. The response in C3H/HeJ appeared to involve mu 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.