Irreversible opiate agonists and antagonists. IV. Analgesic actions of 14-hydroxydihydromorphinone hydrazones.
Several phenylhydrazone derivatives of oxymorphone [phenylhydrazone and p-nitrophenylhydrazone (OxyPNPH)] as well as oxymorphonazine produce a wash-resistant inhibition of radiolabeled opioid binding, suggesting nonequilibrium binding to opiate receptors. All are agonists and, in an effort to correlate their prolonged inhibition of binding with their pharmacology, we examined their analgesic actions in vivo. Dose-response curves at 1 hr revealed similar potencies of oxymorphone and the derivatives, with the exception of OxyPNPH which was significantly less potent. After 10 hr, oxymorphone at doses up to 50 mg/kg did not demonstrate any effect. In contrast, OxyPNPH at 25 mg/kg elevated tail-flick latencies from 2 to over 8 sec after 10 hr. The 50-mg/kg dose elevated latencies to approximately 5 sec after 24 hr. Oxymorphonazine and oxymorphone phenylhydrazone also produced a prolonged analgesia, although not as effectively as OxyPNPH. The prolonged analgesic actions of OxyPNPH were highly dependent upon a critical period of 2 to 3 h immediately after injection. Blockade of receptors during this period with naloxone prevented analgesia at all time points examined. If the long duration of action of OxyPNPH resulted simply from a long half-life and persistent-free compound within the brain, analgesia should have returned by 8 hr, at which time naloxone has been eliminated. The absence of analgesia 8 hr after both OxyPNPH and naloxone argues against simple pharmacokinetic mechanisms for the prolonged analgesia and is consistent with persistent receptor occupation. OxyPNPH (25 mg/kg) administered in vivo lowered radiolabeled opioid binding effectively in brain membranes despite extensive washing. OxyPNPH lowered mu1 binding by approximately 60% and mu2 binding by 35% whereas delta binding was not lowered significantly.
D000698:Analgesia; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology; D004091:Hydromorphone / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D010111:Oxymorphone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D013997:Time Factors
D004745:Enkephalins; D006835:Hydrazones; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C055730:oxymorphone phenylhydrazone; C055731:oxymorphone 4-nitrophenylhydrazone; D009270:Naloxone; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C034640:oxymorphazone; D010111:Oxymorphone; D004091:Hydromorphone