Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Comparison of tolerance development and ethanol reversal of various opioid compounds ED 50 values and 95% confidence limits were calculated under acute, chronic, and chronic + ethanol conditions in mice. All opioids tested produced antinociceptive tolerance when repeatedly administered subcutaneously. Oxycodone and hydrocodone were also evaluated for oral antinociceptive potencies and tolerance development. Only oral oxycodone produced significant tolerance to itself after repeated administration.

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Produced

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Ethanol reversal of oxycodone and hydrocodone tolerance. Ethanol (1 g/kg, i.p.) fully reversed both oxycodone (A) and hydrocodone (B) tolerance. Each data point is represented by a minimum of five mice and presented as the mean ± S.E.M. Animals were injected once hourly with either saline or an ED80 dose of oxycodone or hydrocodone s.c. for 6 hours, followed by an i.p. injection of ethanol (1 g/kg) or saline 1 hour later. Thirty minutes later, various challenge doses of oxycodone or hydrocodone were injected s.c. to construct dose-response curves and generate ED50 values.

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Injection, Construct

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Intraperitoneal and oral ethanol reversed antinociceptive tolerance to subcutaneous oxycodone. Mice were chronically injected with oxycodone (1.25 mg/kg, s.c.) or saline hourly for 6 hours and treated with saline, i.p. ethanol (1 g/kg), or PO ethanol (2 g/kg) prior to receiving a challenge injection of oxycodone (1.25 mg/kg, s.c.). Antinociception was assessed using the tail-immersion assay, where significant tolerance was displayed in mice chronically treated with oxycodone and no ethanol, compared with the acute oxycodone treatment group (*P < 0.05, one-way ANOVA). Two additional groups of mice were treated with repeated injections of oxycodone, but received either an injection of ethanol (1 g/kg, i.p.) or a gavage of ethanol (2 g/kg, PO) 30 minutes prior to receiving an oxycodone challenge injection. Ethanol treatment in these mice reversed tolerance development to oxycodone as seen by a restored response to the antinociceptive effects of oxycodone. Chronic oxycodone–treated mice given either i.p. ethanol (†P < 0.01) or oral ethanol (‡P < 0.05) displayed significantly greater antinociceptive effects in response to a challenge injection of oxycodone compared with chronic oxycodone mice given saline prior to an oxycodone challenge (one-way ANOVA). All groups are represented by a minimum of five mice with data shown as the mean ± S.E.M.

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Injection, Immersion Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Oral oxycodone time course: antinociception and brain concentration. After a single administration of oxycodone (16 mg/kg, PO), brain oxycodone concentrations were plotted against oxycodone’s antinociceptive effect in the warm-water tail-withdrawal assay at various time points ranging from 5 to 480 minutes. All data points represent the mean ± S.E.M. from a minimum of five mice. Brain oxycodone concentrations increased during the first 20 minutes, where a plateau was observed until 30 minutes. Antinociception was slower to reach 100%MPE, which was not observed until 30 minutes and persisted until 60 minutes. Brain oxycodone concentrations at 60 minutes were much lower, measuring closer to the 5-minute time point, despite maximum antinociception. Significant observations for brain oxycodone concentrations were only noted at 120- (†P < 0.05) and 480-minute (‡P < 0.001) time points (one-way ANOVA), where concentrations were lower than all other time points. Antinociception was significantly higher at 20 (*P < 0.05), 30, and 60 minutes (***P < 0.001) compared with 5 minutes. Antinociception at 30 and 60 minutes was significantly higher compared with 240 (P < 0.001) and 480 minutes (P < 0.0001).

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Concentration Assay

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Brain oxycodone concentrations do not correlate with antinociceptive effects of oxycodone. Mice were injected or gavaged with the respective ED80 dose of oxycodone (1.25 mg/kg, s.c. and 16 mg/kg, PO). Both doses produced equal antinociception in mice; however, brain oxycodone concentrations significantly differed, with much higher concentrations detected after subcutaneous administration (****P < 0.0001, Student’s unpaired two-tailed t test). A minimum of five mice were used for each dose tested, with bars representing means ± S.E.M.

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Injection, Produced, Two Tailed Test

Journal: The Journal of Pharmacology and Experimental Therapeutics

Article Title: Ethanol Reversal of Tolerance to the Antinociceptive Effects of Oxycodone and Hydrocodone

doi: 10.1124/jpet.117.241083

Figure Lengend Snippet: Acute and chronic oxycodone brain concentrations. (A) Oxycodone brain concentrations 20 minutes following a challenge gavage of oxycodone (16 mg/kg) in mice either naïve to oxycodone or chronically treated with oxycodone (64 mg/kg, PO) twice a day for 4 days. Acute concentrations represent the mean ± S.E.M. of 10 mice, whereas chronic concentrations represent the mean ± S.E.M. of 13 mice. Brain oxycodone concentrations detected 20 minutes following the oxycodone challenge were significantly lower in mice chronically treated with oxycodone compared with that of acutely treated mice (****P < 0.001, Student’s two-tailed unpaired t test). (B) The effects of ethanol (2 g/kg, PO) were assessed against acute oxycodone brain concentrations. Each bar represents the mean ± S.E.M. of at least 10 mice. Ethanol did not have a significant effect (P > 0.05, Student’s unpaired two-tailed t test), and both groups displayed similar brain oxycodone concentrations. (C) The effects of ethanol (2 g/kg, PO) were assessed against chronic oxycodone brain concentrations. Ethanol did not have a significant effect (P > 0.05, Student’s unpaired two tailed t test), and both groups displayed similar brain oxycodone concentrations in response to a challenge oxycodone gavage (16 mg/kg) following chronic oxycodone treatment. Each bar represents the mean ± S.E.M. of at least eight mice.

Article Snippet: The primary reference materials oxycodone and oxycodone-d 6 were purchased from Cerilliant Corporation (Round Rock, TX) as metabolic solutions.

Techniques: Two Tailed Test