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Comparison of Opioid Antagonist Modulation of Buprenorphine‐Induced Neurochemical Changes
Author(s) -
Eyerman David,
Li WenI,
Cunningham Jacobi,
Dean Reginald,
Deaver Daniel
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.929.8
Subject(s) - microdialysis , homovanillic acid , nucleus accumbens , chemistry , pharmacology , neurochemical , opioid , naltrexone , dopamine , dopaminergic , buprenorphine , endocrinology , medicine , serotonin , receptor , biochemistry
Objective Evaluate differences in onset and duration of action of µ‐opioid antagonists on buprenorphine (BUP)‐induced elevations of nucleus accumbens shell (NAc‐sh) neurotransmitters. Methods: Studies utilized male Wistar rats (275 ‐ 375g) with microdialysis probes inserted into the NAc‐sh (A/P +1.70; M/L ±0.8; D/V ‐7.8 from bregma). Bioanalytical analyses of dopamine (DA) and its metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were performed using HPLC‐EC. Data were converted to percent change from baseline and analyzed using a repeated measures two‐way ANOVA and mechanistic pharmacodynamic modeling. Results: BUP (0.1 mg/kg) elevated extracellular concentrations of DA, DOPAC and HVA in the NAc‐sh for approximately 20 hours after subcutaneous administration. Co‐administration of either samidorphan (SAM) or naltrexone (NTX) (0.3 ‐ 3.0 mg/kg) dose dependently attenuated BUP‐induced dopaminergic activity. However, the temporal pattern of this attenuation was different for NTX and SAM. NTX displayed a rapid K on and K off resulting in an immediate but short‐lived (~4 hours) attenuation of BUP's effects. SAM displayed a longer K on and K off resulting in a protracted but longer‐lasting (~8‐10 hours) attenuation of BUP's effects. Conclusions Differences observed between SAM and NTX in onset and duration of action were not predicted by in‐vitro pharmacology or pharmacokinetic profiles. Importantly, the duration of action reported previously in humans for both antagonists is much longer than in rats. These data illustrate the importance of understanding the duration of action when assessing the activity of different opioid antagonists in nonclinical models.