title: 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.
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Hill
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Abi
authors.initials: A
authors.lastname: Lyndon
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Withey
authors.affiliation: School of Engineering and Built Environment, Glasgow Caledonian University, Glasgow, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Roberts
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kershaw
authors.affiliation: School of Engineering and Built Environment, Glasgow Caledonian University, Glasgow, UK.
authors.forename: John
authors.initials: J
authors.lastname: MacLachlan
authors.affiliation: Division of Brain Sciences, Centre for Neuropsychopharmacology, Imperial College, London, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Lingford-Hughes
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Kelly
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hickman
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Henderson
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002047:Buprenorphine / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D006358:Hot Temperature; D008297:Male; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D009020:Morphine / Q000493:pharmacokinetics / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D059226:Nociceptive Pain / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D010991:Plethysmography; D012119:Respiration; D019141:Respiratory System Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D013990:Tidal Volume / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D019141:Respiratory System Agents; D000431:Ethanol; D002047:Buprenorphine; D009020:Morphine; D008691:Methadone; D003345:Corticosterone