Adaptation to Ethanol in Cultured Neural Cells and Human Lymphocytes From Alcoholicsa

Gordon, Adrienne S.; Wrubel, Bradley; Collier, Kathleen; Estrin, William J.; Diamond, Ivan

doi:10.1111/j.1749-6632.1987.tb48693.x

Cited by 4 publications

(1 citation statement)

References 14 publications

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“…Ethanol acts on multiple cellular sites without interacting with a predominant or specific receptor (Thibault et al, 2005). It is known that treatment of neuronal cells with ethanol causes distinct changes in cellular biochemical mechanisms, such as cAMP accumulation, function of the cAMP-response elementbinding protein to regulate genes activated by the cAMP pathway, G protein expression, and increased expression of opioid receptors (Gordon et al, 1986(Gordon et al, , 1987Charness et al, 1988Charness et al, , 1993Thibault et al, 2005). Treatment of cells with morphine causes receptor down-regulation and an increase of receptor number in a constitutively active state (Zadina et al, 1993;Wang et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Marczak¹,

Jinsmaa²,

Li³

et al. 2007

J Pharmacol Exp Ther

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ABSTRACT[N-Allyl-Dmt 1 ]-endomorphin-1 and -2 ([N-allyl-Dmt 1 ]-EM-1 and -2) are new selective -opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2Ј,6Ј-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5Ј-O-(3-[35 S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-Allyl- Dmt1 ]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine-and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone-and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.The -opioid receptor (MOP) is a key element in the neuronal reward pathway in the central nervous system, responsible for craving and addiction to various drugs, such as morphine and its derivatives, as well as alcohol and food (Di Chiara et al

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Section: Discussionmentioning

confidence: 99%

[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Marczak¹,

Jinsmaa²,

Li³

et al. 2007

J Pharmacol Exp Ther

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Alcohol, cancer, and immunomodulation

Mufti

Darban

Watson

1989

Critical Reviews in Oncology/Hematology

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The Role of Adenosine and Adenosine Transport in Ethanol‐Induced Cellular Tolerance and Dependence

Diamond

Nagy

Mochly‐Rosen

et al. 1991

Annals of the New York Academy of Sciences

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Acute exposure to ethanol in culture inhibits adenosine uptake into cells, thereby increasing the concentration of extracellular adenosine. Extracellular adenosine then reacts with adenosine A2 receptors to stimulate intracellular cAMP production. During prolonged exposure to ethanol, the increase in cAMP is followed by the development of heterologous desensitization of receptors coupled to adenylyl cyclase via Gs, the stimulatory GTP-binding protein. Ethanol-induced heterologous desensitization appears to be due to a reduction in mRNA and protein for G alpha s, a subunit of Gs. This is an example of cellular dependence on ethanol. The important implication of these findings is that a selective inhibitory effect of ethanol on adenosine uptake can lead to desensitization of diverse receptors coupled to cAMP production. Such changes could contribute to the pleiotropic effects of ethanol in the brain and other organs. Prolonged exposure to ethanol also alters the nucleoside transport system. While ethanol inhibits adenosine uptake into naive cells, ethanol no longer inhibits adenosine uptake into cells that have adapted to ethanol. This resistance to ethanol inhibition appears to be a form of cellular tolerance to ethanol. Thus, there appears to be a synergism between ethanol-induced heterologous desensitization of receptor-stimulated cAMP production (cellular dependence) and resistance to ethanol inhibition of adenosine uptake (cellular tolerance), because both lead to reduced intracellular levels of cAMP. Our studies on cAMP signal transduction in cell culture are directly relevant to the pathophysiology of human alcoholism. Heterologous desensitization of cAMP production is demonstrable in lymphocytes taken from actively drinking alcoholics; this measurement appears to be a biologic marker of active alcohol consumption. In addition, regulation of adenosine receptor-dependent cAMP production may be altered in patients at risk to develop alcoholism because of genetic factors. Thus, lymphocytes from alcoholics cultured many generations in the absence of ethanol show increased adenosine receptor-dependent cAMP production and increased sensitivity to ethanol-induced heterologous desensitization. These persistent phenotypic abnormalities in cell culture could be used as genetic markers for alcoholism. Studies are under way to test this possibility.

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Adaptation to Ethanol in Cultured Neural Cells and Human Lymphocytes From Alcoholicsa

Cited by 4 publications

References 14 publications

[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Alcohol, cancer, and immunomodulation

The Role of Adenosine and Adenosine Transport in Ethanol‐Induced Cellular Tolerance and Dependence

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Adaptation to Ethanol in Cultured Neural Cells and Human Lymphocytes From Alcoholicsa

Cited by 4 publications

References 14 publications

[N-Allyl-Dmt1]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

[N-Allyl-Dmt1]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

Alcohol, cancer, and immunomodulation

The Role of Adenosine and Adenosine Transport in Ethanol‐Induced Cellular Tolerance and Dependence

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Product

Resources

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[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties

[N-Allyl-Dmt¹]-Endomorphins Are μ-Opioid Receptor Antagonists Lacking Inverse Agonist Properties