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Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

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Original languageEnglish
Pages (from-to)45-52
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Early online date1 Jun 2017
DateAccepted/In press - 20 Apr 2017
DateE-pub ahead of print - 1 Jun 2017
DatePublished (current) - Jul 2017


This study compared the development of tolerance and its reversal by ethanol of two orally-bioavailable prescription opioids, oxycodone and hydrocodone, to that of morphine. 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 that developed to the subcutaneous administration of each of the three opioids 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 tolerance observed to oxycodone and its reversal by ethanol were due to bio-dispositional changes or were reflecting 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 bio-disposition of oxycodone, but rather is neuronal in nature.

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