Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine.

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

doi:10.1038/npp.2015.201

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.

Highlights

Overdose is the most common cause of accidental death for opiate dependent users, especially if the drugs are injected (Mathers et al, 2013; Pierce et al, 2015)
As the experiments were performed in 5% CO2 in air, it is not possible to tell if the decrease in minute volume induced by morphine is due to an action on respiratory rate generation or on chemoreflexes
Morphine-induced respiratory depression, antinociception, and reward result from activation of MOPr as these behaviors are not observed in the MOPr knockout mouse (Matthes et al, 1996; Romberg et al, 2003)

Summary

Introduction

Overdose is the most common cause of accidental death for opiate dependent users, especially if the drugs are injected (Mathers et al, 2013; Pierce et al, 2015). Chronic opioid use results in the development of tolerance such that larger doses are required by an opioid addict to obtain their effects. Levels of heroin and its metabolites in overdose victims are often lower than that expected in highly tolerant individuals (Darke et al, 2002). This has been interpreted as the victims having taken their normal dose of heroin during a period of reduced tolerance, such as that occurring after incarceration or detoxification, with the drug inducing greater respiratory depression than expected (White and Irvine, 1999)

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