naloxone-benzoylhydrazone and norbinaltorphimine

Buprenorphine is widely used as an analgesic drug and it is also increasingly considered for maintenance and detoxification of heroin addicts. It is a potent micro -receptor partial agonist with a long duration of action. An inverted U-shaped dose-effect curve for buprenorphine conditioned place preference (CPP) has been shown previously.. We re-evaluated the CPP effects of buprenorphine by taking into account the particular kinetic properties of the drug in the design of the experiments.. An unbiased CPP procedure with different wash-out periods was used to investigate a possible influence of the long duration of action of buprenorphine on the outcome of the experiment.. Following a standard procedure (drug and vehicle conditioning on alternating days), the inverted U-shaped dose-effect curve was reproduced (no CPP at 0.01 mg/kg, significant CPP at 0.1 and 1.0 mg/kg, and no CPP at 3.16 and 10 mg/kg, IP). However, when there was a 48 h interval between drug and vehicle conditioning, there was a clear tendency towards CPP for the two highest doses, and when there was a 72-h interval between drug and vehicle conditioning, significant CPP was seen. Naloxone (0.215 mg/kg SC), haloperidol (0.215 mg/kg IP) and U-50488 (1.0 mg/kg SC) blocked buprenorphine (1.0 mg/kg) CPP. Buprenorphine CPP was also blocked by coadministration of naltrindole (3.16 mg/kg IP), nor-binaltorphimine (4.64 mg/kg SC), and naloxonebenzoylhydrazone (0.464 mg/kg SC). However, the data suggest that blockade by the three latter drugs was due to state-dependency effects. Buprenorphine at doses of 1.0 mg/kg and higher also produced locomotor sensitization across the 3 drug conditioning days. The sensitization produced by 1.0 mg/kg buprenorphine was blocked by haloperidol and U-50488, but not by naloxone, naltrindole, nor-binaltorphimine, and naloxonebenzoylhydrazone.. The present results suggest that the reported lack of CPP effects at high doses of buprenorphine may be due to factors in the experimental design, resulting in a carry-over effect from drug- to vehicle conditioning. They also suggest that buprenorphine, like other opiates, produces its CPP effects via micro -receptors, although kappa-antagonistic mechanisms also appear to be involved. The implications of these findings for the safety of buprenorphine for human use are discussed.

Topics: Animals; Buprenorphine; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Motor Activity; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Nociceptin Receptor; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, kappa; Time Factors

The effects of fmol doses of nociceptin/orphanin FQ on scopolamine-induced impairment of learning and/or memory were examined using spontaneous alternation of Y-maze and step-down type passive avoidance tasks. While fmol doses of nociceptin alone had no effect on spontaneous alternation or passive avoidance behavior in normal mice, administration of nociceptin (10 and/or 100 fmol/mouse) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, significantly improved the scopolamine-induced impairment of spontaneous alternation and passive avoidance behavior. This ameliorating effect was not antagonized by nocistatin (0.5 and 5.0 nmol/mouse, i.c.v.), naloxone benzoylhydrazone (2.3, 11.2, and 56.1 micromol/kg, s.c.) or nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). These results indicated that very low doses of nociceptin ameliorate impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that this peptide has bidirectional modulatory effects on learning and memory; impairment at high doses and amelioration at low doses.

Topics: Analgesics, Opioid; Animals; Avoidance Learning; Disease Models, Animal; Dizocilpine Maleate; Learning Disabilities; Male; Maze Learning; Memory Disorders; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Neuroprotective Agents; Nociceptin; Opioid Peptides; Psychomotor Performance; Rats; Scopolamine

On the basis of its in vivo activity and binding affinity, naloxone benzoylhydrazone has been characterized as a kappa 3-opioid receptor agonist and a mu-opioid receptor antagonist. This paper continues its pharmacological characterization with the help of isolated tissue preparations. Naloxone benzoylhydrazone was found to have partial agonist activity in the guinea pig ileum longitudinal muscle/myenteric plexus preparation. As an antagonist, naloxone benzoylhydrazone is similar to naloxone, with pA2 values of 8.8, 7.8, and 7.8 for mu-, delta-, and kappa 1-opioid receptors, respectively. Its agonist activity in the guinea pig ileum preparation was not influenced by beta-funaltrexamine treatment but was reversed by the selective kappa-opioid receptor antagonist nor-binaltorphimine and by the irreversible kappa 1-opioid receptor blocker UPHIT (1S,2S)-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)-cyclohexyl] benzeneacetamide. The presence of kappa 3-opioid receptors could not be demonstrated by [3H]naloxone benzoylhydrazone binding in the guinea pig ileum longitudinal muscle/myenteric plexus preparation. From these studies it is concluded that the partial agonist activity of naloxone benzoylhydrazone in this bioassay is probably due to the activation of the kappa 1-opioid receptors.

Topics: Animals; Benzeneacetamides; Binding, Competitive; Computer Simulation; Cyclohexanes; Guinea Pigs; Ileum; In Vitro Techniques; Male; Muscle, Smooth; Myenteric Plexus; Naloxone; Naltrexone; Narcotic Antagonists; Pyrrolidines; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu