Role of Acetaldehyde in Ethanol Reversal of Tolerance to Morphine-Induced Respiratory Depression in Mice.

Rob Hill,Graeme Henderson,Eamonn Kelly,William Dewey,Alexandra Conibear

doi:10.3389/adar.2021.10143

Rob Hill, Graeme Henderson + Show 3 more

Open Access

https://doi.org/10.3389/adar.2021.10143

Copy DOI

Abstract

BackgroundOpioid users regularly consume other drugs such as alcohol (ethanol). Acute administration of ethanol rapidly reverses tolerance to morphine-induced respiratory depression. However, recent research has suggested that the primary metabolite of ethanol, acetaldehyde, may play a key role in mediating the CNS effects seen after ethanol consumption. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression.MethodsTolerance was induced in mice by 6-days implantation of a 75 mg morphine pellet with control mice implanted with a placebo pellet. Tolerance was assessed by acute morphine administration on day 6 and respiration measured by plethysmography. Levels of acetaldehyde were inhibited or enhanced by pre-treatments with the acetaldehyde chelator D-penicillamine and the inhibitor of acetaldehyde dehydrogenase disulfiram respectively.ResultsMorphine pellet implanted mice displayed tolerance to an acute dose of morphine compared to placebo pellet implanted controls. Acute acetaldehyde administration dose-dependently reversed tolerance to morphine respiratory depression. As previously demonstrated, ethanol reversed morphine tolerance, and this was inhibited by D-penicillamine pre-treatment. An acute, low dose of ethanol that did not significantly reverse morphine tolerance was able to do so following disulfiram pre-treatment.ConclusionThese data suggest that acetaldehyde, the primary metabolite of ethanol, is responsible for the reversal of morphine tolerance observed following ethanol administration.

Highlights

Heroin users are notorious poly drug users, often taking other drugs such as alcohol, benzodiazepines, cocaine, gabapentinoids, other illicit drugs as well as other opioids [1,2,3,4,5,6,7]
We have previously described the induction of tolerance to morphine respiratory depression by subcutaneous implantation of a 75 mg morphine pellet (MP) for 6 days [16]
Whilst acute morphine depressed respiration in placebo pellet implanted mice, in morphine pellet implanted mice there was little or no depression of respiration indicating the development of tolerance to the respiratory depressant effect of morphine

Summary

Introduction

Heroin users are notorious poly drug users, often taking other drugs such as alcohol (ethanol), benzodiazepines, cocaine, gabapentinoids, other illicit drugs as well as other opioids [1,2,3,4,5,6,7]. In a study of overdose deaths involving both ethanol and heroin [10] reported that high blood ethanol levels were associated with intermittent heroin use and this could reflect additivity. They reported a number of deaths in which blood ethanol and morphine were not high (ethanol < 1,000 mg/L and morphine < 0.5 mg/L). Others have reported that blood alcohol levels in fatal heroin overdoses are not typically high [1, 11,12,13,14], suggesting another interaction between heroin and ethanol, beyond simple additivity, may be occurring [15]. This research investigated the role of acetaldehyde in ethanol reversal of tolerance to morphine-induced respiratory depression

Methods

Results

Discussion

Conclusion