Ethanol and opioid receptor signalling

Abstract

Ethanol may modulate endogenous opioid systems by disrupting opioid receptor signalling. Low concentrations of ethanol slightly potentiate μ-opioid receptor binding by increasing receptor B_max, and, in some cases, chronic ethanol exposure decreases the density or affinity of the μ-opioid receptors. By contrast, high concentrations of ethanol acutely decrease λ-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 λ-opioid receptors. In the neuronal cell line NG108-15, ethanol does not up-regulate the λ-opioid receptor by blocking receptor degradation or endocytosis, but protein synthesis is required for this response. Up-regulation of the λ-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 Gα_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 λ-opioid receptor, little heterologous desensitization of adenylyl cyclase, and no changes in Gα_s or Gα_i. By contrast, ethanol-treated N1E-115 cells show the largest up-regulation of the λ-opioid receptor, the most heterologous desensitization of adenylyl cyclase, and concentration-dependent decreases in Gα_s and increases in Gα_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.