buprenorphine and dezocine

Opioid dependence is a major public health issue without optimal therapeutics. This study investigates the potential therapeutic effect of dezocine, a nonaddictive opioid, in opioid dependence in rat models.. Dezocine was administered intraperitoneally to a morphine-dependent rat model to investigate its effect on withdrawal and conditioned place preference (CPP). Effect of dezocine on morphine withdrawal syndrome and CPP was analyzed using 2-way analysis of variance (ANOVA) followed by Tukey's post hoc test. Buprenorphine and vehicle solution containing 20% (v/v) dimethyl sulfoxide were used for positive and negative control, respectively. The astrocytes activation in nucleus accumbens was assessed by immunofluorescence assay of glial fibrillary acidic protein. Effect of dezocine and buprenorphine on the internalization of κ opioid receptor (KOR) was investigated using Neuro2A expressing KOR fused to red fluorescent protein tdTomato (KOR-tdT). Buprenorphine and dezocine were screened against 44 G-protein-coupled receptors, ion channels, and transporter proteins using radioligand-binding assay to compare the molecular targets.. The mean withdrawal score was reduced in rats treated with 1.25 mg·kg dezocine compared to vehicle-treated control animals starting from the day 1 (mean difference: 7.8; 95% confidence interval [CI], 6.35-9.25; P < .0001 by 2-way ANOVA). Significance was observed at all treatment days, including day 7 (mean difference: 2.13; 95% CI, 0.68-3.58; P < .001 by 2-way ANOVA). Furthermore, dezocine inhibited the reinstatement of morphine-induced CPP (mean difference: 314; 95% CI, 197.9-430.1; P < .0001 by 2-way ANOVA) compared to the control group. Chronic morphine administration induced astrocytes activation in nucleus accumbens, which was attenuated by dezocine. Dezocine blocked the agonist-induced KOR internalization in vitro, 1 of the mechanisms involved in the downstream signaling and development of opioid dependence. Dezocine had affinity to norepinephrine and serotonin transporters and sigma-1 receptor, whereas buprenorphine showed no activity against these targets.. Dezocine could potentially be used to alleviate opioid dependence. Due to the unique molecular target profile different from buprenorphine, it might have important value in studying the mechanisms of morphine dependence and developing novel therapeutic approaches.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Astrocytes; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Cell Line; Dose-Response Relationship, Drug; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Male; Morphine; Morphine Dependence; Narcotic Antagonists; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Tetrahydronaphthalenes

Recent experimental data suggest that metabotropic glutamate receptor (mGluR) antagonists with selectivity for mGluR1 and mGluR2/3 enhance morphine-induced antinociception.. The present study addressed the hypothesis that mGluR antagonists enhance opioid antinociception by increasing opioid efficacy.. The antinociceptive effects of the partial mu-opioid receptor agonists buprenorphine and dezocine were first assessed in a hot-plate procedure under conditions of low (53 degrees C) and high (56 degrees C) stimulus intensity. Under conditions in which buprenorphine and dezocine produced submaximal antinociceptive effects, these drugs were assessed after pretreatment with the mGluR1 antagonist JNJ16259685, the mGluR5 antagonist MPEP, the mGluR2/3 antagonist LY341495, and for comparison, the N-methyl-D-aspartate (NMDA) receptor antagonist LY235959.. Buprenorphine (0.032-3.2 mg/kg) and dezocine (0.1-10 mg/kg) were fully efficacious at 53 degrees C and produced submaximal antinociceptive effects at 56 degrees C (i.e., their effects did not exceed 50% of the maximum possible effect). Pretreatment with JNJ16259685 (1.0-3.2 mg/kg), LY341495 (1.0-3.2 mg/kg), and LY235959 (0.32-1.0 mg/kg) enhanced the antinociceptive effects of buprenorphine and dezocine at 56 degrees C, as revealed by significant increases in the peak effects of both drugs to approximately 100% maximum possible effect. In contrast, pretreatment with MPEP (1.0-3.2 mg/kg) did not modulate the antinociceptive effects of buprenorphine and dezocine.. These results suggest that, similar to the NMDA receptor antagonist LY235959, the mGluR1 antagonist JNJ16259685 and the mGluR2/3 antagonist LY341495 increase the antinociceptive efficacy of buprenorphine and dezocine.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hot Temperature; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Morphine; Narcotic Antagonists; Pain Measurement; Receptors, Metabotropic Glutamate; Receptors, Opioid, mu; Tetrahydronaphthalenes

The influence of sex in determining responses to opioid analgesics has been well established in rodents and monkeys in assays of short-lasting, phasic pain. The purpose of this investigation was to use a capsaicin model of tonic pain to evaluate sex differences in hyperalgesia and mu-opioid-induced antihyperalgesia in Fischer 344 (F344) rats. Capsaicin injected into the tail produced a dose-dependent thermal hyperalgesia in males and females, with the dose required to produce a comparable level of hyperalgesia being 3.0-fold higher in males than in females. These sex differences were modulated by gonadal hormones, inasmuch as gonadectomy increased the potency of capsaicin in males and decreased its potency in females. Morphine, buprenorphine, and dezocine administered by various routes [systemic (s.c.), local (in the tail), and central (i.c.v.)] generally produced marked antihyperalgesic effects in males and females. Although in most instances these opioids were equally potent and effective in males and females, selected doses of local and i.c.v. administered buprenorphine produced greater effects in females. When administered locally, the antihyperalgesic effects of morphine were mediated by peripheral opioid receptors in both males and females, since this effect was not reversed by i.c.v. naloxone methiodide. These data contrast with the finding that mu-opioids are more potent in male rodents in assays of phasic pain, thus suggesting that distinct mechanisms underlie male and female sensitivity to opioid antinociception in phasic and tonic pain models. These findings emphasize the need to test male and female rodents in tonic pain assays that may have greater relevance for human pain conditions.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Capsaicin; Clinical Trials as Topic; Cycloparaffins; Disease Models, Animal; Female; Humans; Hyperalgesia; Male; Morphine; Pain Measurement; Rats; Rats, Inbred F344; Receptors, Opioid, mu; Tetrahydronaphthalenes

Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys.. To evaluate the influence of sex, nociceptive stimulus intensity and an opioid's relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception.. Antinociceptive testing was conducted using a rat warm-water (50-56 degrees C) tail-withdrawal procedure. Dose-response and time-course determinations were performed with various opioids.. Across the nociceptive stimulus intensities tested, the high-efficacy mu opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy mu opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females.. That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid's relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of mu opioids as antinociceptive agents is greater in male than female rats.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Dose-Response Relationship, Drug; Etorphine; Female; Genotype; Levorphanol; Male; Morphine; Nalbuphine; Rats; Rats, Inbred F344; Rats, Inbred Lew; Reaction Time; Receptors, Opioid, mu; Sex Factors; Species Specificity; Tetrahydronaphthalenes

We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids.. Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Topics: Analgesics, Opioid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Dose-Response Relationship, Drug; Drug Combinations; Levorphanol; Morphine; Nalbuphine; Narcotics; Nociceptors; Pain; Physical Stimulation; Rats; Rats, Long-Evans; Receptors, Opioid, mu; Tetrahydronaphthalenes

Responding in patas monkeys was maintained under a multiple schedule of food presentation. One component of the multiple schedule was a repeated-acquisition task in which the discriminative stimuli for left- and right-key responses changed each session (learning). In the other component, the discriminative stimuli were the same each session (performance). The mixed agonist-antagonists dezocine, GPA 1657 and nalbuphine each produced dose-related decreases in the overall rate of responding in each component of the multiple schedule. In general each drug produced greater rate-decreasing effects in the learning than in the performance component, although this differential effect between components was less apparent with dezocine. In the learning component low doses of nalbuphine and GPA 1657 produced small increases in percentage of errors but had little or no effect on response rate. A similar effect was obtained with dezocine in only one of four subjects tested. At doses which produced comparable rate-decreasing effects dezocine also exerted the least disruptive effect on the within-session pattern of acquisition. High doses of each drug disrupted accuracy in each component of the multiple schedule. In contrast to the other drugs tested, buprenorphine had virtually no effect on response rate or percentage of errors in either component of the multiple schedule across a wide range of doses (0.01-3.2 mg/kg). The results suggest that, among the mixed agonist-antagonist, buprenorphine is unique in that it does not disrupt the acquisition or performance of complex discrimination in patas monkeys.

Topics: Animals; Benzomorphans; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Conditioning, Operant; Cycloparaffins; Discrimination Learning; Erythrocebus patas; Female; Male; Nalbuphine; Narcotic Antagonists; Narcotics; Reinforcement, Psychology; Tetrahydronaphthalenes

Nine mixed agonist-antagonist opioids were evaluated in macaque monkeys for their ability to serve as positive reinforcers and for their discriminative stimulus similarity to etorphine and ethylketazocine. For tests of reinforcing properties, various doses of each drug were substituted for codeine under a fixed-ratio 30 time-out 600 sec schedule of i.v. delivery. Discriminative properties were assessed in separate groups of monkeys for which etorphine and saline, or ethylketazocine and saline, were established as discriminative stimuli for responses maintained under a fixed-ratio 20 schedule of food delivery. Two patterns of reinforcing and discriminative stimulus properties were observed. Buprenorphine, butorphanol, GPA 1657, nalbuphine, propiram and WY 16225 (dezocine) functioned as positive reinforcers and occasioned etorphine-appropriate but not ethylketazocine-appropriate responses. dl-Profadol also functioned as a positive reinforcer; its stereoisomers occasioned etorphine-appropriate but not, in general, ethylketazocine-appropriate responses. In contrast, levallorphan and oxilorphan did not function as positive reinforcers and occasioned ethylketazocine-appropriate but no more than 30% etorphine-appropriate responses. Under these experimental conditions, the reinforcing and discriminative stimulus profiles of the mixed agonist-antagonist opioids paralleled those of etorphine-like (mu) or ethylketazocine-like (kappa) opioid agonists.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Buprenorphine; Butorphanol; Cycloparaffins; Discrimination Learning; Female; Levallorphan; Macaca mulatta; Male; Morphinans; Nalbuphine; Narcotic Antagonists; Narcotics; Pyridines; Pyrrolidines; Reinforcement, Psychology; Tetrahydronaphthalenes