The dopaminergic mesolimbic system plays a key role in the mechanisms of reinforcement elicited by alcohol (ethanol) and other drugs of abuse. Numerous lines of evidence indicate that ethanol reinforcement mechanisms involve, at least partially, the ethanol-induced activation of the endogenous opioid system. Ethanol may alter opioidergic transmission at different levels, including the biosynthesis, release, and degradation of opioid peptides, as well as binding of endogenous ligands to opioid receptors. Several studies suggest that mu and delta opioid receptors play a major role in ethanol reinforcement and dependence. These studies implicate enkephalins and beta-endorphin as physiological mediators of ethanol's actions in the brain. In this review we describe the pharmacological characteristics of opioid receptors and their distribution in brain, as well as the major functions of their endogenous ligands. Thereafter, we present evidence supporting the participation of mu and delta opioid receptors in ethanol reinforcement mechanisms and high alcohol drinking behaviour. The use of opioid receptor agonists and antagonists, as well as ethanol-preferring selected rodents and knockout mice, has contributed to understand the role of mu and delta receptors in these processes. The effects of ethanol on binding of selective ligands to opioid receptors in different experimental models are also reviewed. The relevance of opioid receptors in human alcoholism is further evidenced by the association of mu receptor polymorphisms with ethanol dependence. The clinical implication of these findings is discussed regarding the differential responses observed in some alcoholic patients to treatment with opioid receptor antagonists such as naltrexone.
The G protein-coupled receptor constitutes a large family of plasma membrane receptors, representing 1% of the total genome, and are implicated in a diverse variety of cellular functions (1-3). The understanding of how the expression of these receptors are regulated should provide a better comprehension regarding agonist function.Until now, most studies have reported on the effects of desensitization, receptor coupling, and second messenger stimulation of G protein-coupled receptors (4, 5). To elucidate these mechanisms, experiments were carried out on agonist-deprived cultured cells and then triggered with a rapid burst of high agonist concentrations. Under these conditions, cells would remain desensitized for long periods of time (6, 7). However, in vivo, cells are constantly surrounded by agonists, each possessing a characteristic basal level. In the stimulated state, receptors are triggered by "waves" of agonist such as the hormones released into the blood circulation, and the neurotransmitters released into the synaptic cleft, which are more or less intense or frequent.The complete desensitization of a cell would have grave consequences in vivo, because the cell's triggering mechanisms would be essentially inoperable for long periods of time. Rather it would seem required that the cell's machinery would provide a means to remain sensitized to agonist during standard stimulated conditions. By examining the long term effect of agonist exposure on high affinity neurotensin receptor (NTR) 1 expression, we were able to clarify a potential mechanism responsible for maintain of cell sensitization to neurotensin (NT) agonist.
Our results indicate that enkephalin expression in regions of the rat mesocorticolimbic system is differentially altered by acute ethanol treatment and suggest that enkephalins may play a key role in ethanol reinforcement mechanisms.
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