Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine

Abstract

Opioids are the most common drugs associated with unintentional drug overdose. Death results from respiratory depression. Prolonged use of opioids results in the development of tolerance but the degree of tolerance is thought to vary between different effects of the drugs. Many opioid addicts regularly consume alcohol (ethanol), and post-mortem analyses of opioid overdose deaths have revealed an inverse correlation between blood morphine and ethanol levels. In the present study, we determined whether ethanol reduced tolerance to the respiratory depressant effects of opioids. Mice were treated with opioids (morphine, methadone, or buprenorphine) for up to 6 days. Respiration was measured in freely moving animals breathing 5% CO2 in air in plethysmograph chambers. Antinociception (analgesia) was measured as the latency to remove the tail from a thermal stimulus. Opioid tolerance was assessed by measuring the response to a challenge dose of morphine (10 mg/kg i.p.). Tolerance developed to the respiratory depressant effect of morphine but at a slower rate than tolerance to its antinociceptive effect. A low dose of ethanol (0.3 mg/kg) alone did not depress respiration but in prolonged morphine-treated animals respiratory depression was observed when ethanol was co-administered with the morphine challenge. Ethanol did not alter the brain levels of morphine. In contrast, in methadone- or buprenorphine-treated animals no respiratory depression was observed when ethanol was co-administered along with the morphine challenge. As heroin is converted to morphine in man, selective reversal of morphine tolerance by ethanol may be a contributory factor in heroin overdose deaths.

Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice

“…We have reported previously that tolerance to the respiratory-depressant effects of morphine could be reversed by acute administration of a low dose of ethanol, whereas that to methadone was unaffected (Hill et al, 2016). This may indicate that different cellular mechanisms underlie the tolerance to these two opioid ligands.…”

“…Respiration was measured in freely moving mice using plethysmography chambers (EMKA Technologies, Paris, France) supplied with a 5% CO 2 in air mixture (BOC Gas Supplies, Manchester, UK), as described previously (Hill et al, 2016). Rate and depth of respiration were recorded and converted to minute volume.…”

“…In mice, prolonged exposure to opioid drugs, such as morphine and methadone, results in the development of tolerance to their respiratory-depressant effects, but the tolerance to respiratory depression develops more slowly than that to antinociception (Hill et al, 2016). We have reported previously that tolerance to the respiratory-depressant effects of morphine could be reversed by acute administration of a low dose of ethanol, whereas that to methadone was unaffected (Hill et al, 2016).…”

“…We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al, 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK).…”

Commentary on Cousins et al. (2016): Accumulating evidence on risk of mortality on and off opioid substitution treatment

“…There is good evidence from multiple studies that patients have better outcomes, including a reduced risk of mortality during opioid substitution treatment (OST) [4][5][6][7][8]. Heroin and other opioid use, especially if injected, are inherently risky, and the risk of mortality is heightened at specific times-such as in periods of low tolerance to the effect of opioids immediately after prison release or treatment discharge, or when taken in combination with alcohol, benzodiazepines and other drugs [6,[9][10][11][12].…”