Morphine tolerance in mice changes response of heroin from μ to δ opioid receptors

Heroin produced antinociception in the tail flick test through μ receptors in the brain of ICR and CD-1 mice, a response inhibited by 3-O- methylnaltrexone. Tolerance to morphine was produced by subcutaneous morphine pellet implantation. By the third day, the heroin response was produced through δ opioid receptors. The response was inhibited by simultaneous intracerebroventricular (i.c.v.) administration of naltrindole, a δ opioid receptor antagonist. More specifically, δ₁ rather than δ₂ receptors were involved because 7-benzylidenenaltrexone, a δ₁ receptor antagonist, inhibited but naltriben, a δ₂ antagonist, did not. Also, antinociception produced by i.c.v. heroin was inhibited by intrathecal administration of bicuculline and picrotoxin consistent with the concept that δ₁ receptors in the brain mediated the antinociceptive response through descending neuronal pathways to the spinal cord to activate GABA(A) and GABA(B) receptors rather than spinal α₂-adrenergic and serotonergic receptors activated originally by the μ agonist action in naive mice. The μ response of 6- monoacetylmorphine, a metabolite of heroin, was changed by morphine pellet implantation to a δ₂ response (inhibited by naltriben but not 7- benzylidenenaltrexone). The agonist action of morphine in these morphine- tolerant mice remained μ. Thus, the opioid receptor selectivity of heroin and 6-monoacetylmorphine in the brain is changed by production of tolerance to morphine. Such a change explains how morphine tolerant mice are not cross- tolerant to heroin.