Oxycodone-induced tolerance to respiratory depression: reversal by ethanol, pregabalin and protein kinase C inhibition

Abstract

Background and Purpose: Oxycodone, a prescription opioid, is a major drug of abuse, especially in the USA, and contributes significantly to opioid overdose deaths each year. Overdose deaths result primarily from respiratory depression. We have studied respiratory depression by oxycodone and have characterized how tolerance develops on prolonged exposure to the drug. We have investigated the role of PKC in maintaining tolerance and have examined whether ethanol or pregabalin reverses oxycodone-induced tolerance. Experimental Approach: Respiration was measured in male CD-1 mice by whole-body plethysmography. Mice were preinjected with oxycodone then implanted with mini-pumps (s.c.) delivering 20, 45 or 120 mg·kg −1 ·day −1 oxycodone for 6 days and subsequently challenged with oxycodone (3 mg·kg −1 , i.p.) or morphine (10 mg·kg −1 , i.p.) to assess the level of tolerance. Key Results: Oxycodone-treated mice developed tolerance to oxycodone and cross tolerance to morphine-induced respiratory depression. Tolerance was less with 20 mg·kg −1 ·day −1 than with 45 or 120 mg·kg −1 ·day −1 oxycodone treatment. At doses that do not depress respiration, ethanol (0.3 g·kg −1 ), pregabalin (20 mg·kg −1 ) and calphostin C (45 μg·kg −1 ) all reversed oxycodone-induced tolerance resulting in significant respiratory depression. Reversal of tolerance was less in mice treated with oxycodone (120 mg·kg −1 ·day −1 ). In mice receiving ethanol and calphostin C or ethanol and pregabalin, there was no greater reversal of tolerance than seen with either drug alone. Conclusion and Implications: These data suggest that oxycodone-induced tolerance is mediated by PKC and that reversal of tolerance by ethanol or pregabalin may be a contributory factor in oxycodone overdose deaths.