3-Methoxynaltrexone, a selective heroin/morphine-6β-glucuronide antagonist

Abstract 

Recent work has suggested that heroin and morphine-6β-glucuronide (M6G) both act through a novel mu opioid receptor subtype distinct from those mediating morphine's actions. This very high affinity ³H-M6G site is selectively competed by 3-methoxynaltrexone. In vivo, 3-methoxynaltrexone (2.5 ng, i.c.v.) selectively antagonizes the analgesic actions of heroin and M6G without interfering with mu (morphine and [d-Ala²,MePhe⁴,Gly(ol)⁵]enkephalin), delta ([d-Pen²,d-Pen⁵]enkephalin), kappa₁ (U50,488H) or kappa₃ (naloxone benzoylhydrazone) analgesia. In dose–response studies, 3-methoxynaltrexone (2.5 ng, i.c.v.) significantly shifted the ED₅₀ values for heroin and its active metabolite, 6-acetylmorphine, without affecting the morphine curve. These results indicate that 3-methoxynaltrexone selectively blocks a novel ³H-M6G binding site which is responsible for the analgesic actions of heroin and M6G. This ability to selectively antagonize heroin actions opens new possibilities in the development of therapeutics for the treatment of opioid abuse.

Keywords:  Opioid , Morphine , Opioid receptor , Analgesia , Mu receptor