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 m ice 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 r eceptor selectivity of heroin across a range of fully inbred strains of mic e. Six inbred strains were given heroin i.c.v. 10 min before the tail-flick test. Differences in the descending neurotransmitter systems involved in s upraspinal opioid-induced analgesia were evaluated as the first step. Antag onism by bicuculline given intrathecally indicated the involvement of supra spinal delta receptors in activating spinal gamma-aminobutyric acid (GABA) receptors; antagonism by intrathecal methysergide indicated either mu or ka ppa receptor involvement. Antagonism by intrathecal yohimbine implicated mu and eliminated kappa receptor involvement. Intracerbroventricular opioid a ntagonists (beta-funaltrexamine, 7-benzylidenenaltrexone, naltriben, or nor -binaltorphimine) provided further differentiation. Based on these initial results, receptor selectivity was determined by more extensive ED50 experim ents with i.c.v. administration of heroin with opioid antagonists, beta-fun altrexamine (for mu), naltrindole (for delta), and nor-binaltorphimine (for kappa). The combined results indicated that heroin analgesia was predomina ntly 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 invo lve 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 furth er.