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

Jodie J. Rady, Blythe B. Holmes, Philip S. Portoghese, James M. Fujimoto

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)93-101
Number of pages9
JournalProceedings of the Society for Experimental Biology and Medicine
Issue number2
StatePublished - Jun 2000


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