Ethanol reversal of tolerance to the respiratory depressant effects of morphine

Rob Hill, Abi Lyndon, Sarah Withey, Joanne Roberts, Yvonne Kershaw, John MacLachlan, Anne Lingford-Hughes, Eamonn Kelly, Chris Bailey, Matthew Hickman, Graeme Henderson

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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.
Original languageEnglish
Pages (from-to)762-773
Number of pages12
JournalNeuropsychopharmacology
Volume41
Issue number3
Early online date14 Jul 2015
DOIs
Publication statusPublished - 1 Feb 2016

Cite this

Hill, R., Lyndon, A., Withey, S., Roberts, J., Kershaw, Y., MacLachlan, J., ... Henderson, G. (2016). Ethanol reversal of tolerance to the respiratory depressant effects of morphine. Neuropsychopharmacology, 41(3), 762-773. https://doi.org/10.1038/npp.2015.201

Ethanol reversal of tolerance to the respiratory depressant effects of morphine. / Hill, Rob; Lyndon, Abi; Withey, Sarah; Roberts, Joanne; Kershaw, Yvonne; MacLachlan, John; Lingford-Hughes, Anne; Kelly, Eamonn; Bailey, Chris; Hickman, Matthew; Henderson, Graeme.

In: Neuropsychopharmacology, Vol. 41, No. 3, 01.02.2016, p. 762-773.

Research output: Contribution to journalArticle

Hill, R, Lyndon, A, Withey, S, Roberts, J, Kershaw, Y, MacLachlan, J, Lingford-Hughes, A, Kelly, E, Bailey, C, Hickman, M & Henderson, G 2016, 'Ethanol reversal of tolerance to the respiratory depressant effects of morphine', Neuropsychopharmacology, vol. 41, no. 3, pp. 762-773. https://doi.org/10.1038/npp.2015.201
Hill R, Lyndon A, Withey S, Roberts J, Kershaw Y, MacLachlan J et al. Ethanol reversal of tolerance to the respiratory depressant effects of morphine. Neuropsychopharmacology. 2016 Feb 1;41(3):762-773. https://doi.org/10.1038/npp.2015.201
Hill, Rob ; Lyndon, Abi ; Withey, Sarah ; Roberts, Joanne ; Kershaw, Yvonne ; MacLachlan, John ; Lingford-Hughes, Anne ; Kelly, Eamonn ; Bailey, Chris ; Hickman, Matthew ; Henderson, Graeme. / Ethanol reversal of tolerance to the respiratory depressant effects of morphine. In: Neuropsychopharmacology. 2016 ; Vol. 41, No. 3. pp. 762-773.
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