3-METHOXYNALTREXONE, A SELECTIVE HEROIN MORPHINE-6-BETA-GLUCURONIDE ANTAGONIST/

Recent work has suggested that heroin and morphine-6 beta-glucuronide (M6G) both act through a novel mu opioid receptor subtype distinct fro m those mediating morphine's actions, This very high affinity H-3-M6G site is selectively competed by 3-methoxynaltrexone. In vivo, 3-methox ynaltrexone (2.5 ng, i.c.v.) selectively antagonizes the analgesic act ions of heroin and M6G without interfering with mu (morphine and [D-Al a(2),MePhe(4),Gly(ol)(5)]enkephalin), delta ([D-Pen(2),D-Pen(5)]enkeph alin), kappa(1) (U50,488H) or kappa(3) (naloxone benzoylhydrazone) ana lgesia. In dose-response studies, 3-methoxynaltrexone (2.5 ng, i.c.v.) significantly shifted the ED50 values for heroin and its active metab olite, 6-acetylmorphine, without affecting the morphine curve, These r esults indicate that 3-methoxynaltrexone selectively blocks a novel H- 3-M6G binding site which is responsible for the analgesic actions of h eroin and M6G. This ability to selectively antagonize heroin actions o pens new possibilities in the development of therapeutics for the trea tment of opioid abuse. (C) 1997 Federation of European Biochemical Soc ieties.