Ethanol and opioid receptor signalling.
Ethanol may modulate endogenous opioid systems by disrupting opioid receptor signalling. Low concentrations of ethanol slightly potentiate mu-opioid receptor binding by increasing receptor Bmax, and, in some cases, chronic ethanol exposure decreases the density or affinity of the mu-opioid receptors. By contrast, high concentrations of ethanol acutely decrease delta-opioid receptor binding by decreasing receptor affinity, whereas chronic exposure of animals and neuronal cell lines to lower concentrations of ethanol leads to possibly adaptive increases in the density or affinity of the delta-opioid receptors. In the neuronal cell line NG108-15, ethanol does not up-regulate the delta-opioid receptor by blocking receptor degradation or endocytosis, but protein synthesis is required for this response. Up-regulation of the delta-opioid receptor renders ethanol-treated NG108-15 cells 3.5-fold more sensitive to opioid inhibition of adenylyl cyclase. Long-term treatment with ethanol also increases maximal opioid inhibition in NG108-15 cells, possibly by decreasing levels of G alpha s and its mRNA. Ethanol differentially modulates signal transduction proteins in three additional neuronal cell lines, N18TG2, N4TG1, and N1E-115. Ethanol-treated N18TG2 cells show the least up-regulation of the delta-opioid receptor, little heterologous desensitization of adenylyl cyclase, and no changes in G alpha s or G alpha i. By contrast, ethanol-treated N1E-115 cells show the largest up-regulation of the delta-opioid receptor, the most heterologous desensitization of adenylyl cyclase, and concentration-dependent decreases in G alpha s and increases in G alpha i. Further analysis of these related neuronal cell lines may help to identify the molecular elements that endow some, but not all, neuronal cells with the capacity to adapt to ethanol.
Charness
M E
ME
Department of Neurology, University of California San Francisco 94110.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D011957:Receptors, Opioid; D000431:Ethanol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins