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. 2019 Jun;128(6):1328-1335.
doi: 10.1213/ANE.0000000000003365.

Dezocine Alleviates Morphine-Induced Dependence in Rats

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Free PMC article

Dezocine Alleviates Morphine-Induced Dependence in Rats

Fei-Xiang Wu et al. Anesth Analg. .
Free PMC article

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Dezocine alleviates morphine withdrawal syndrome comparable to that of buprenorphine. Data represented as mean ± standard deviation (n = 15 in each group). P < .0001 in both dezocine versus dimethyl sulfoxide (DMSO) and buprenorphine versus DMSO groups by 2-way analysis of variance with Tukey’s post hoc test.
Figure 2
Figure 2
Dezocine treatment alleviates morphine withdrawal syndrome with various doses. The morphine withdrawal syndrome decreased with the elevation of the dosage of dezocine on day 1 (A) and day 7 (B). Each data point represents mean ± standard error of the mean (n = 10). **P < .01 and P < .0001, a significant difference from the dimethyl sulfoxide (DMSO) group in both (A) and (B). #P < .01 and ##P < .0001, a significant difference from the naive group by 1-way analysis of variance with Tukey’s post hoc test.
Figure 3
Figure 3
Dezocine treatment reduced reinstatement of morphine-induced conditioned place preference (CPP). The CPP score was expressed as time spent in the drug-associated compartment during a period of 15 min. Results are presented as the mean ± standard deviation from experiments conducted on 10 mice per group. P < .0001 and ***P < .001, a significant difference from the naive group; #P < .0001 a significant difference from the dimethyl sulfoxide (DMSO) group according to 2-way analysis of variance (ANOVA) with Tukey’s post hoc test.
Figure 4
Figure 4
Dezocine inhibits morphine-induced astrocytes activation in nucleus accumbens. A, Immunofluorescence staining for glial fibrillary acidic protein (GFAP) in the nucleus accumbens slices of rats in treatment groups. No GFAP overexpression was detected in the naive group. However, the number of GFAP-positive cells was significantly increased in the vehicle control group of the morphine-dependent model compared with those in the naive group. GFAP expression was reduced after 3 d of dezocine and buprenorphine administration. B, Summary plot of the effect of drugs on fluorescence showing the significant decrease of astrocytes activation in dezocine- and buprenorphine-administered animal models compared to the vehicle control. Data represented as the ratio of mean pixel intensity of each group (arbitrary units [AU]) to the naive group and shown as mean ± standard error of the mean, n = 6; *P < .05, **P < .01.
Figure 5
Figure 5
Dezocine inhibits agonist-induced κ opioid receptor (KOR) internalization. KOR internalization was visualized by fluorescence microscopy in control cells either untreated or treated with salvinorin A (A) and in cells pretreated for 30 min with buprenorphine (B) or dezocine (C) at indicated doses for 30 min before stimulation with salvinorin A.

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