Abstract: |
Studies from our laboratory have shown that analgesia produced by opioid agonists and their metabolites may be mediated via different mu opioid receptor subtypes. For instance, the receptor subtypes that mediate morphine analgesia are different from those mediating the analgesic effect of its metabolite M6G and heroin. The present studies assess and compare the analgesic activity of the heroin analog dihydroheroin (DHH) and its metabolite 6-acetyldihydromorphine (6-ADHM) to heroin and morphine. After systemic administration, DHH and 6-ADHM produced dose-dependent analgesia in the tail flick test with potencies lower than heroin and its metabolite 6-acetylmorphine, but similar to that of morphine. When injected supraspinally, DHH and 6-ADHM had similar potencies, but slower onsets of action than heroin and its metabolite. While the delta antagonist naltrindole did not decrease DHH and 6-ADHM analgesia, the opioid antagonist naltrexone and the mu antagonists beta-FNA and naloxonazine, as well as the M6G/heroin antagonist 3-O-methylnaltrexone did. The classification of these two compounds as mu agonists was also supported by their high affinity for mu binding sites. Finally, DHH and 6-ADHM showed incomplete cross-tolerance to morphine. The results indicate that the analgesic profile of DHH and 6-ADHM resembles that of heroin rather than that of morphine. |