Importantly, ethanol has been shown to increase release of endogenous opioids in brain regions key to the rewarding properties of drugs of abuse. This would be expected to increase signal CCG215022 transduction through MOR, in effect signaling the presence of ethanol. By extension, opioid antagonists, such as naltrexone, are thought to decrease ethanol consumption because they block the actions of these endogenously released opioids. On the other hand, chronic ethanol consumption appears to decrease the functional responsiveness of the MOR, suggesting that adaptations can occur during chronic ethanol SNS-314 Mesylate exposure that make the MOR less sensitive to the same dose of opioid. However, the mechanisms that mediate these decreases in the sensitivity of MOR responses are not known. After activation by endogenous opioids, signaling from the MOR is regulated by many processes, including desensitization by G protein coupled receptor kinases and arrestins, endocytosis of the receptor, and recycling and resensitization of the receptor. This cascade of events serves to carefully titrate signal transduction from the receptor and is ideally suited to monitor the presence of ligands, such as the endogenous opioid peptides that are released in a pulsatile manner. Agonist ligands such as morphine that do not promote desensitization/endocytosis/ resensitization of the MOR, have been shown to facilitate homeostatic adaptive responses in signal transduction that manifest as reduced responsiveness to the presence of opioid ligands at the cellular level, and as antinociceptive tolerance at the behavioral level. Here, we found that chronic voluntary consumption of ethanol causes a downregulation of GRK and prevents endocytosis of the MOR in response to opioid peptide ligand. As a consequence, rats consuming ethanol show tolerance to the antinociceptive effects of opioids. As mentioned above, we have previously observed that failure to endocytose the MOR can promote antinociceptive tolerance and see. Thus, we investigated whether ethanol promoted antinociceptive tolerance to opioids by altering the ability of the MOR to endocytose in response to opioid peptide.