There is considerable evidence in the literature that deaths due to the simultaneous abuse of ethanol with opioids such as heroin or prescription opioids leads to lower blood levels of the opioid upon autopsy than is observed following death due to the opioid alone. We have carried out an extensive study which has shown that either ethanol or diazepam at doses that do not alter the acute effects of morphine reversed the antinociceptive tolerance produced by chronic morphine. The mechanism of the reversal produced by the two drugs differed in that inhibitors of either GABAA or GABAB receptors alone did not reverse the effect of alcohol but blocking both type GABA receptors completely reversed the effect of ethanol on morphine tolerance. Conversely the inhibition of morphine tolerance produced by diazepam was completely reversed by a GABAA inhibitor alone but not by the GABAB inhibitor. The overall objective of the work described in this proposal is to elucidate the cellular mechanisms by which opioid tolerance is reversed by the concomitant administration of ethanol and other agents affecting the central nervous system. Using genetically altered mice and a number of molecular techniques we will elucidate further the role of GABA receptors and the signaling mechanisms involved in these effects. In the second specific aim we propose to elucidate whether ethanol and diazepam reverses the tolerance to opioids such as buprenorphine and methadone which are used in maintenance therapy and oxycodone and other prescription opioids with a history of abuse. We and others have reported differences in the mechanism of tolerance development for various opioids. For instance, protein kinase A and protein kinase C inhibitors but not GIRK inhibitors reversed tolerance to morphine and other moderately efficacious opioids but not to the high efficacy DAMGO. GIRK inhibitors revered the tolerance to DAMGO but not the other opioids. These differences in the mechanism of tolerance development to various opioids cause us to investigate whether ethanol and/or diazepam will reverse the tolerance to opioids of various efficacies. Obviously, we will elucidate the differing mechanisms if the opioids are affected differently by ethanol or diazepam. In the third specific aim we will investigate whether ethanol and diazepam also reverse tolerance to a peripheral effect of opioids. We and others have found certain differences between the mechanisms of opioid tolerance in the brain and the gastrointestinal tract and now we propose to determine whether ethanol and/or diazepam reverses opioid tolerance in the gastrointestinal tract. The information gained from these experiments will provide important information as we and others continue to elucidate the mechanism of opioid tolerance.

Public Health Relevance

It is clear from the literature that the vast majority of individuals who use opiates chronically also consume alcohol or other central nervous system depressants. It also has been reported that the consumption of alcohol potentiates the lethal and other effects of opioids and that blood levels of morphine and other opioids are lower in autopsy of individuals who have consumed alcohol than in people who die from the opioid alone. The overall goal of the work described in this proposal is to elucidate the mechanisms underlying these events.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Purohit, Vishnudutt
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Virginia Commonwealth University
Schools of Medicine
United States
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Gade, Aravind R; Kang, Minho; Khan, Fayez et al. (2016) Enhanced Sensitivity of α3β4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation. J Pharmacol Exp Ther 357:520-8
Zhang, Yan; Williams, Dwight A; Zaidi, Saheem A et al. (2016) 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(4'-pyridylcarboxamido)morphinan (NAP) Modulating the Mu Opioid Receptor in a Biased Fashion. ACS Chem Neurosci 7:297-304
Hill, Rob; Lyndon, Abi; Withey, Sarah et al. (2016) Ethanol Reversal of Tolerance to the Respiratory Depressant Effects of Morphine. Neuropsychopharmacology 41:762-73
Williams, Dwight A; Zheng, Yi; David, Bethany G et al. (2016) 6β-N-Heterocyclic Substituted Naltrexamine Derivative BNAP: A Peripherally Selective Mixed MOR/KOR Ligand. ACS Chem Neurosci 7:1120-9
Akbarali, H I; Inkisar, A; Dewey, W L (2014) Site and mechanism of morphine tolerance in the gastrointestinal tract. Neurogastroenterol Motil 26:1361-7