PT  - JOURNAL ARTICLE
AU  - Hull, L. C.
AU  - Gabra, B. H.
AU  - Bailey, C. P.
AU  - Henderson, G.
AU  - Dewey, W. L.
TI  - Reversal of Morphine Analgesic Tolerance by Ethanol in the Mouse
AID  - 10.1124/jpet.112.202184
DP  - 2013 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 512--519
VI  - 345
IP  - 3
4099  - http://jpet.aspetjournals.org/content/345/3/512.short
4100  - http://jpet.aspetjournals.org/content/345/3/512.full
SO  - J Pharmacol Exp Ther2013 Jun 01; 345
AB  - The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However, chronic opioid use is often made more dangerous by the coconsumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals who died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross-tolerance between [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the gamma receptor blocker bicuculline and by the γ-aminobutyric acid (GABA)B receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABAA antagonist bicuculline but not by the GABAB antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment.