Abstract

Heroin administered i.c.v. acts on supraspinal μ opioid receptors in ICR mice but on δ 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 δ receptors in activating spinal γ-aminobutyric acid (GABA) receptors; antagonism by intrathecal methysergide indicated either μ or κ receptor involvement. Antagonism by intrathecal yohimbine implicated μ and eliminated κ receptor involvement. Intracerbroventricular opioid antagonists (β-funaltrexamine, 7-benzylidenenaltrexone, naltriben, or nor-binaltorphimine) provided further differentiation. Based on these initial results, receptor selectivity was determined by more extensive ED₅₀experiments with i.c.v. administration of heroin with opioid antagonists, β-funaltrexamine (for μ), naltrindole (for δ), and nor-binaltorphimine (for κ). The combined results indicated that heroin analgesia was predominantly mediated in C57BL/6J by δ, in DBA/2J and CBA/J by μ, and in BALB/cByJ and AKR/J by κ 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.