Endogenous opioid systems and alcohol addiction

Abstract

Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.

Association of the κ-opioid system with alcohol dependence

“…In neither case did [1][2][3] 0.015 CAG TGA SNP [2][3][4] 0.010 AGG GAA SNP [3][4][5] 0.044 GGG AAA SNP [4][5][6] 0.005 GGA AAG SNP [5][6][7] 0.065 GAA AGA* SNP [6][7][8] 0.027 AAC -SNP [7][8][9] 0.062 ACA* -SNP [8][9][10] 0.09 CAT** -SNP [9][10][11] 0.08 --SNP [10][11][12] 0.28 --SNP [11][12][13] 0.37 --SNP [12][13][14] 0.60 --SNP [13][14][15] 0.031 TGC TGT SNP [14][15][16] 0.057 GCA GTA SNP [15][16][17] 0.074 CCT** TAA SNP [16][17][18] 0.30 --Individual overtransmitted haplotypes for alcohol dependence are indicated in bold when P < 0.05; *P = 0.06, and **P < 0.10.…”

“…[1][2][3][4][5] The opioid system appears to play an important role in the reward system by influencing dopamine release in the nucleus accumbens. 6 There are three major groups of endogenous opioid peptides (dynorphins, endorphins and enkephalins) and three corresponding opioid receptors, k-opioid receptor (KOR), m-opioid receptor (MOR) and d-opioid receptor (DOR). 7 Stimulation of MOR and DOR in mouse brain increases the release of dopamine in the nucleus accumbens, whereas stimulation of KOR reduces the release of dopamine and generates aversive states.…”

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…It is well known that the endogenous opioid system plays an important role in the development of ethanol reinforcement through repeated exposures (Herz, 1997). Furthermore, enkephalin is especially known to regulate the hedonic value and positive reinforcing properties of ethanol through the cortico-mesolimbic system.…”

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

“…Knockout of the d-receptor results in a loss of morphine tolerance in mice. 8,9 d-receptor agonists have been found to have analgesic properties, but induce weaker physical dependence. 10,11 In the central nervous system, d-receptor agonists have been shown to modulate m-receptormediated analgesia, suggesting cross-talk between these two kinds of receptors.…”

“…19 Interestingly, these opposing effects are paralleled by an increase (produced by m-and d-receptor agonists) and a decrease (produced by k-receptor agonists) in dopamine release in the nucleus accumbens. 8 Furthermore, antagonists for these receptors produce effects that are opposite to one another. Pharmacological blockage of the endogenous opioid system by m-and d-receptor antagonists prevents ethanol from activating the dopamine system and reduces ethanol craving and consumption.…”