Jacob Joanna C, Poklis Justin L, Akbarali Hamid I, Henderson Graeme, Dewey William L
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia- (J.C.J., J.L.P., H.I.A., W.L.D.); and School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom (G.H.).
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia- (J.C.J., J.L.P., H.I.A., W.L.D.); and School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, United Kingdom (G.H.)
J Pharmacol Exp Ther. 2017 Jul;362(1):45-52. doi: 10.1124/jpet.117.241083. Epub 2017 Apr 25.
This study compared the development of tolerance to two orally bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine, and the reversal of this tolerance by ethanol. Oxycodone (s.c.) was significantly more potent in the mouse tail-withdrawal assay than either morphine or hydrocodone. Oxycodone was also significantly more potent in this assay than hydrocodone when administered orally. Tolerance was seen following chronic subcutaneous administration of each of the three drugs and by the chronic administration of oral oxycodone, but not following the chronic oral administration of hydrocodone. Ethanol (1 g/kg i.p.) significantly reversed the tolerance to the subcutaneous administration of each of the three opioids that developed when given 30 minutes prior to challenge doses. It took twice as much ethanol, when given orally, to reverse the tolerance to oxycodone. We investigated whether the observed tolerance to oxycodone and its reversal by ethanol were due to biodispositional changes or reflected a true neuronal tolerance. As expected, a relationship between brain oxycodone concentrations and activity in the tail-immersion test existed following administration of acute oral oxycodone. Following chronic treatment, brain oxycodone concentrations were significantly lower than acute concentrations. Oral ethanol (2 g/kg) reversed the tolerance to chronic oxycodone, but did not alter brain concentrations of either acute or chronic oxycodone. These studies show that there is a metabolic component of tolerance to oxycodone; however, the reversal of that tolerance by ethanol is not due to an alteration of the biodisposition of oxycodone, but rather is neuronal in nature.
本研究比较了对两种口服生物利用度高的处方阿片类药物羟考酮和氢可酮与吗啡的耐受性发展情况，以及乙醇对这种耐受性的逆转作用。在小鼠甩尾试验中，皮下注射的羟考酮比吗啡或氢可酮的效力显著更强。口服给药时，羟考酮在该试验中的效力也比氢可酮显著更强。对三种药物中的每一种进行慢性皮下给药以及对羟考酮进行慢性口服给药后均出现了耐受性，但慢性口服氢可酮后未出现耐受性。在挑战剂量前30分钟给予乙醇（1克/千克腹腔注射）可显著逆转对三种阿片类药物皮下给药所产生的耐受性。口服乙醇时，逆转对羟考酮的耐受性所需剂量是前者的两倍。我们研究了观察到的对羟考酮的耐受性及其被乙醇逆转是由于生物处置变化还是反映了真正的神经元耐受性。正如预期的那样，急性口服羟考酮后，脑内羟考酮浓度与尾浸试验中的活性之间存在关联。慢性治疗后，脑内羟考酮浓度显著低于急性给药后的浓度。口服乙醇（2克/千克）可逆转对慢性羟考酮的耐受性，但未改变急性或慢性羟考酮的脑内浓度。这些研究表明，对羟考酮的耐受性存在代谢成分；然而，乙醇对该耐受性的逆转并非由于羟考酮生物处置的改变，而是本质上属于神经元性的。
