title: Pharmacological actions of a novel mixed opiate agonist/antagonist: naloxone benzoylhydrazone.
abstract: NalBzoH (6-desoxy-6-benzoylhydrazido-N-allyl-14-hydroxydihydronomorphin one) is a novel opiate with potent actions at both mu and kappa receptors. Analgesic studies in mice examining increasing doses of NalBzoH with a fixed dose of morphine revealed a biphasic curve. NalBzoH at doses as low as 1 microgram/kg partially antagonized morphine analgesia. Higher NalBzoH doses continued to inhibit morphine analgesia in a dose-dependent manner, with the 1-mg/kg dose antagonizing completely morphine analgesia. As the NalBzoH dose increased beyond 1 mg/kg analgesia returned. NalBzoH also prduced a similar analgesic response when administered alone in mice and also was active in rats. NalBzoH had excellent p.o. activity, with an analgesic potency in mice equivalent to s.c. administration. Naloxone reversed NalBzoH analgesia far less effectively than morphine analgesia. In contrast, Win44,441 antagonized both morphine and NalBzoH analgesia with a similar potency, consistent with a kappa mechanism for NalBzoH analgesia. Repeated administration of NalBzoH resulted in tolerance. There was no analgesic cross-tolerance between NalBzoH and either morphine or the kappa 1-selective agent U50,488H, implying a selective kappa 3 mechanism of analgesia. In addition to blocking morphine analgesia, low doses of NalBzoH also partially reversed the inhibition of gastrointestinal transit in mice produced by morphine, antagonized completely morphine lethality and precipitated withdrawal in morphine-dependent mice, confirming its antagonist activity in mu receptors. The duration of NalBzoH's kappa and mu actions differed dramatically. In mice, analgesia typically lasted less than 2 hr whereas the same NalBzoH dose antagonized completely morphine analgesia, a mu action, for 16 hr. Full sensitivity to morphine did not return for 32 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Cotzias Laboratory of Neuro-Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: M A
authors.initials: MA
authors.lastname: Gistrak
authors.forename: D
authors.initials: D
authors.lastname: Paul
authors.forename: E F
authors.initials: EF
authors.lastname: Hahn
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000818:Animals; D004361:Drug Tolerance; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
chemical_list: D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C058380:naloxone benzoylhydrazone; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine