beta-funaltrexamine and dezocine

Dezocine is an opioid with low efficacy at μ-opioid and κ-opioid receptors. It also inhibits the reuptake of norepinephrine and serotonin. Dezocine is an effective analgesic against various clinical painful conditions and is widely used in many Asian countries. Given the unique pharmacology of dezocine, the drug may also have antidepressant-like properties. However, no published preclinical study has explored this possibility. This study examined the potential antidepressant-like activity of dezocine in mice. Male ICR mice were used in the forced swimming test, the tail suspension test, the warm water tail withdrawal test and locomotor activity test to test the effects of dezocine (0.3-3.0 mg/kg). The 5-HT1A receptor antagonist WAY-100635 (1 mg/kg), the μ-opioid receptor antagonist β-funaltrexamine (2 mg/kg) and the κ-opioid receptor agonist U50488 (1 mg/kg) were also studied in combination with dezocine. Dezocine produced a dose-dependent decrease in the immobility time in the forced swimming test and tail suspension test at doses that did not alter the motoric activity as determined in the locomotion test. WAY-100635 and U50488 but not β-funaltrexamine pretreatment significantly blocked the effects of dezocine. Dezocine dose-dependently increased the latency in the tail withdrawal test which was blocked by WAY-100635 and β-funaltrexamine. Combined, these results suggest that dezocine may have antidepressant-like effects. Considering the well-documented analgesic property of dezocine, it may be useful to treat pain and depression comorbidity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Antidepressive Agents; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Mice; Naltrexone; Piperazines; Pyridines; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin 5-HT1 Receptor Antagonists; Tetrahydronaphthalenes; Treatment Outcome

The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl >[-]-cyclazocine >buprenorphine = butorphanol >l-methadone >nalbuphine >[-]-metazocine >morphine). (-)-N-allylnormetazocine and (+)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 - 10 mg/kg) antagonized the stimulus effects of dezocine, (+)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl's rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (+)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist beta-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, beta-funaltrexamine failed to antagonize dezocine's rate-decreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine's stimulus or rate-decreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Columbidae; Cycloparaffins; Discrimination Learning; Female; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta; Receptors, Opioid, mu; Tetrahydronaphthalenes