Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modulation of alpha 2-adrenergic and opioid neurotransmission may contribute to ethanol intoxication, tolerance, and physical dependence. We showed previously that ethanol increased the expression of functional delta-opioid receptors in NG108-15 cells (Charness, M. E., Querimit, L. A., and Diamond, I. (1986) J. Biol. Chem. 261, 3164-3169). Here we report that long-term (2 days) treatment of NG108-15 cells with ethanol increased the binding of the alpha 2-adrenergic receptor (alpha 2AR) antagonist [3H]rauwolscine and the muscarinic acetylcholine receptor (mAChR) antagonist [3H]quinuclidinyl benzilate by 2.8- and 1.4-fold, respectively. Increased receptor expression was associated with a proportionate increase in the potency of oxymetazoline and carbachol in inhibiting cAMP accumulation. Ethanol did not change the expression of G alpha i2 and reduced levels of G alpha s. Pertussis toxin pretreatment did not prevent the ethanol-induced increase in alpha 2AR, mAChR, and delta-opioid receptor expression. Ethanol caused a large (3.6-fold), dose-dependent increase in the abundance of alpha 2BAR mRNA (rat cDNA probe RNG, 4.1-kb transcript). Ethanol-induced increases in alpha 2BAR and alpha 2CAR (rat probe RG10, 2.5-kb transcript) mRNAs were first detected after 6 h of exposure to 100 mM ethanol, became maximal after 24 h, and persisted for up to 5 days. In contrast, ethanol caused only a small (1.3-fold) increase in the abundance of hm4 mAChR mRNA and did not change levels of G alpha i2 and G alpha s mRNAs. Our data indicate that clinically attainable concentrations of ethanol regulate alpha 2AR gene expression within the time frame of a single session of drinking.
 ...
PMID:Ethanol differentially increases alpha 2-adrenergic and muscarinic acetylcholine receptor gene expression in NG108-15 cells. 822 69

The effect of intracerebroventricular (i.c.v.) pretreatment with pertussis toxin (PTX) on the development of physical dependence on morphine was investigated in mice. Twenty four hours after PTX (0.5 microgram, i.c.v.) or vehicle pretreatment, the mice were chronically treated with morphine (8-45 mg/kg, s.c.) for 5 days. Several withdrawal signs were observed following naloxone challenge in morphine-dependent mice which had been pretreated with vehicle. In addition, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and noradrenaline (NA) turnover (MHPG/NA) levels in the cerebral cortex were increased following naloxone challenge in morphine-dependent mice. These findings indicate that activation of the central noradrenergic system may mediate the expression of some withdrawal signs. In contrast, pretreatment with PTX attenuated the naloxone-precipitated withdrawal signs in morphine-dependent mice. The incidence of withdrawal signs such as jumping, "wet dog" shakes, and rearing was significantly reduced by PTX pretreatment. PTX pretreatment also prevented the naloxone-precipitated increases in MHPG concentration and NA ratio (MHPG/NA) in the cerebral cortex, suggesting that central PTX-sensitive GTP-binding proteins (G-proteins) may be involved in the elevation of NA transmission in the cortex which projects from the locus coeruleus (LC) during morphine withdrawal. The blocking effects of PTX on the behavioral and biochemical changes after withdrawal suggest that central PTX-sensitive G-proteins (Gi/Go) may play an important role in the development of physical dependence on morphine.
 ...
PMID:Effect of pretreatment with pertussis toxin on the development of physical dependence on morphine. 837 45

Baclofen-induced hyperpolarization of hippocampal CA1 and CA3 pyramidal neurons was examined to assess the impact of ethanol on postsynaptic GABAB receptors. These receptors activate outward K+ currents via a pertussis toxin-sensitive G protein cascade to reduce membrane potential during the slow inhibitory postsynaptic potential. This inhibitory action may play a role in ethanol intoxication and withdrawal excitability. In both types of pyramidal neurons, baclofen applied consecutively in increasing concentrations caused concentration dependent hyperpolarization. There were no significant differences in resting membrane potential, input resistance, maximum baclofen-induced hyperpolarization or EC50 between CA1 and CA3 neurons, although slope values were significantly smaller in the former neurons. These parameters were not significantly changed in the presence of ethanol 10-100 mM. Chronic ethanol treatment (12 days) sufficient to induce physical dependence also did not shift sensitivity or maximum response to baclofen in CA1 neurons. These results suggest that GABAB receptors in this model are essentially insensitive to ethanol and do not confirm our earlier preliminary observation of a possible down-regulation of postsynaptic GABAB receptor function by chronic ethanol treatment.
 ...
PMID:Sensitivity of postsynaptic GABAB receptors on hippocampal CA1 and CA3 pyramidal neurons to ethanol. 891 62

Opioid tolerance and physical dependence in mammals can be rapidly induced by chronic exposure to opioid agonists. Recently, opioid receptors have been shown to interact with the pertussis toxin (PTX)-insensitive Gz (a member of the Gi subfamily), which inhibits adenylyl cyclase and stimulates mitogen-activated protein kinases (MAPKs). Here, we established stable human embryonic kidney 293 cell lines expressing delta-opioid receptors with or without Gz to examine the role of Gz in opioid receptor-regulated signaling systems. Each cell line was acutely or chronically treated with [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta-selective agonist, in the absence or presence of PTX. Subsequently, the activities of adenylyl cyclase, cyclic AMP (cAMP)-dependent response element-binding proteins (CREBs), and MAPKs were measured by determining cAMP accumulation and phosphorylation of CREBs and the extracellular signal-regulated protein kinases (ERKs) 1 and 2. In cells coexpressing Gz, DPDPE inhibited forskolin-stimulated cAMP accumulation in a PTX-insensitive manner, but Gz could not replace Gi to mediate adenylyl cyclase supersensitization upon chronic opioid treatment. DPDPE-induced adenylyl cyclase supersensitization was not associated with an increase in the phosphorylation of CREBs. Both Gi and Gz mediated DPDPE-induced activation of ERK1/2, but these responses were abolished by chronic opioid treatment. Collectively, our results show that although Gz mediated opioid-induced inhibition of adenylyl cyclase and activation of ERK1/2, Gz alone was insufficient to mediate opioid-induced adenylyl cyclase supersensitization.
 ...
PMID:Regulation of adenylyl cyclase, ERK1/2, and CREB by Gz following acute and chronic activation of the delta-opioid receptor. 1073 27