Abstract:
:Chronic morphine treatment has been shown to produce constitutive activation of mu-opioid receptors, and this transition might contribute to the development of tolerance and dependence. The apparent ability of chronic morphine to increase the spontaneous, agonist-independent activation of mu-opioid receptors may be unique, due to its distinct partial agonist properties of possessing a relatively high intrinsic activity coupled with a poor ability to produce desensitization and down-regulation. Therefore, the present study tested the hypothesis that prolonged exposure to morphine would produce greater constitutive activity of mu-opioid receptors than exposure to the full agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO). GH(3) cells expressing mu-opioid receptors were exposed to chronic morphine, DAMGO, or no opioid under conditions determined to produce maximal desensitization, down-regulation, and cAMP rebound. After chronic treatment, the mu-opioid antagonists naloxone and beta-chlornaltrexamine (beta-CNA) were evaluated in two assays predictive of inverse agonist activity. Both antagonists produced a concentration-dependent inhibition of [(35)S]GTP gamma S binding only in membranes prepared from cells chronically exposed to opioids. This effect was reversed by the neutral mu-opioid antagonist CTAP. Additionally, conditions known to uncouple G protein-coupled receptors from G proteins produced a leftward shift in the competition curve of beta-CNA for [(3)H]DAMGO binding only in membranes prepared from chronically treated cells. In contrast, these conditions produced no shift in the competition curve by the neutral antagonist CTAP in cells exposed to chronic DAMGO. Therefore, prolonged exposure of GH(3)MOR cells to opioids produced constitutive activation of mu-opioid receptors. Surprisingly, chronic treatment with the more efficacious agonist DAMGO produced greater increases in both measures of inverse agonist activity than did morphine. These observations may lend novel insight into the mechanisms of opioid tolerance and dependence.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Liu JG,Prather PLdoi
10.1124/mol.60.1.53keywords:
subject
Has Abstractpub_date
2001-07-01 00:00:00pages
53-62issue
1eissn
0026-895Xissn
1521-0111journal_volume
60pub_type
杂志文章abstract::The constitutive androstane receptor (CAR) regulates mouse and human CYP2B genes through binding to the direct repeat-4 (DR4) motifs present in the phenobarbital-responsive enhancer module (PBREM). The preference of PBREM elements for nuclear receptors and the extent of cross-talk between CAR and other nuclear recepto...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.2.366
更新日期:2002-08-01 00:00:00
abstract::Accumulated evidence suggests that dopamine and dopamine D1 agonists can activate phospholipase C in both brain and peripheral tissue. The receptor that mediates the hydrolysis of phosphoinositides has not been identified. The cloned dopamine D1A receptor that is generally thought to be linked to adenylyl cyclase, has...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.1.6
更新日期:1997-01-01 00:00:00
abstract::Mammalian A2-adenosine receptor binding subunits (A2AR) can be visualized by covalent labeling with the photoaffinity crosslinking ligand 125I-2-[4-[2-[2-[(4-aminophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl]phenyl]ethylamino-5'-N-ethylcarboxamidoad enosine or directly with the azide derivative described in th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract::PC-12 cells, derived from a rat pheochromocytoma, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 0.39 microM and the Vmax was 0.40 pmole/min/10(6) cells. The uptake was temperature-de...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::Pregnanolone [5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha)] and allopregnanolone [5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha)] are neuroactive steroids that are reduced metabolites of progesterone. Both 5 beta 3 alpha and 5 alpha 3 alpha are potent positive modulators of the gamma-aminobutyric acid respon...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-07-01 00:00:00
abstract::Several novel phenylaminotetralins (PATs) cause functional changes in brain that are associated with binding to saturable, high affinity sites that are not identical to any known central nervous system receptor. These PATs were tested for their ability to cause receptor-mediated functional effects on tyrosine hydroxyl...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-12-01 00:00:00
abstract::Computer simulations on a new model of the alpha1b-adrenergic receptor based on the crystal structure of rhodopsin have been combined with experimental mutagenesis to investigate the role of residues in the cytosolic half of helix 6 in receptor activation. Our results support the hypothesis that a salt bridge between ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1025
更新日期:2002-05-01 00:00:00
abstract::The insecticide imidacloprid and structurally related neonicotinoids act selectively on insect nicotinic acetylcholine receptors (nAChRs). To investigate the mechanism of neonicotinoid selectivity, we have examined the effects of mutations to basic amino acid residues in loop D of the nAChR acetylcholine (ACh) binding...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.026815
更新日期:2006-10-01 00:00:00
abstract::Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of del...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.1.51
更新日期:2003-07-01 00:00:00
abstract::Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term pote...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.082891
更新日期:2013-04-01 00:00:00
abstract::Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.030601
更新日期:2007-03-01 00:00:00
abstract::Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the alpha1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the alpha1 subunit. We generated concatemers of subunits so that the alpha...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.053629
更新日期:2009-04-01 00:00:00
abstract::The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the α7 subunit are unique because of their high Ca(2+) permeability and fast desensitization. nAChR agonists elicit a t...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.116.104240
更新日期:2016-09-01 00:00:00
abstract::The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.117234
更新日期:2019-12-01 00:00:00
abstract::Metabolism of [3H]-(+/-)-trans-1,2-dihydroxy-1,2-dihydrobenz[a] anthracene by liver microsomes isolated from control, phenobarbital-treated, and 3-methylcholanthrene-treated Long-Evans rats and from 3-methylcholanthrene-treated Sprague-Dawley rats was examined. Liver microsomes from both control and phenobarbital-trea...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-07-01 00:00:00
abstract::The GABA type A receptor (GABA(A)R) is the major inhibitory receptor in the mammalian central nervous system and the target of numerous pharmaceuticals. The alpha-subunit of these pentameric Cys-loop neurotransmitter-gated ion channels contributes to the binding of both GABA and allosteric modulators such as the benzo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.059832
更新日期:2010-07-01 00:00:00
abstract::When expressed via an inducible promoter in human embryonic kidney 293 cells, the rat Mas-related gene D (rMrgD) receptor responded to beta-alanine but not L-alanine by elevating intracellular [Ca(2+)], stimulating phosphorylation of the mitogenactivated protein kinases known as extracellular signal-regulated kinase (...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.018788
更新日期:2006-02-01 00:00:00
abstract::Chemokine receptors belong to the class A of G protein-coupled receptors (GPCRs) and are implicated in a wide variety of physiologic functions, mostly related to the homeostasis of the immune system. Chemokine receptors are also involved in multiple pathologic processes, including immune and autoimmune diseases, as we...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.119.117168
更新日期:2019-12-01 00:00:00
abstract::Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect and mammalian neurons, although recent studies have raised the possibility that these compounds ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.040741
更新日期:2008-03-01 00:00:00
abstract::The compound 4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (DQP-1105) is a representative member of a new class of N-methyl-d-aspartate (NMDA) receptor antagonists. DQP-1105 inhibited GluN2C- and GluN2D-containing receptors with IC(50) values ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.073239
更新日期:2011-11-01 00:00:00
abstract::We cloned and expressed a human metabotropic glutamate receptor 1 alpha (HmGluR1 alpha) in a novel cell line. The human mGluR1 alpha cDNA was found to be 86% identical to rat mGluR1 alpha, and the predicted protein sequence was found to be 93% identical to rat mGluR1 alpha. We expressed HmGluR1 alpha in AV12-664, an a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-10-01 00:00:00
abstract::Allosteric modulators of G-protein-coupled receptors can regulate conformational states involved in receptor activation ( Mol Pharmacol 58: 1412-1423, 2000 ). This hypothesis was investigated for the corticotropin-releasing factor type 1 (CRF(1)) receptor using a novel series of ligands with varying allosteric effect ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.042978
更新日期:2008-05-01 00:00:00
abstract::Neuromedin U (NmU) is a 25 amino acid peptide prominently expressed in the upper gastrointestinal (GI) tract and central nervous system. It is highly conserved throughout evolution and induces smooth muscle contraction in a variety of species. Our understanding of NmU biology has been limited because the identity of i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.4.870
更新日期:2000-10-01 00:00:00
abstract::The biliary excretion of several organic anions is mediated by the canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats such as Eisai hyperbilirubinemic rats (EHBR). In addition, using a kinetic study with isolated canalicular membrane vesicles, we recently sugges...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract::G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107854
更新日期:2017-09-01 00:00:00
abstract::The human caudate and putamen contain two high affinity binding sites for [3H]spiroperidol. Both of these affinity states exhibit dopaminergic selectivity. Ascorbic acid, at 0.1 mM, induces a slow loss of the low affinity component of [3H]spiroperidol binding in these tissues. The addition of guanyl nucleotides to the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-02-01 00:00:00
abstract::An opioid-like receptor has been cloned by several groups of researchers and recently shown to be activated by an endogenous heptadecapeptide termed orphanin FQ (or nociceptin). We isolated the corresponding mouse cDNA and coexpressed it in Xenopus laevis oocytes with the potassium channel subunits Kir3.1 (GIRK1) and ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::An alteration in the balance between a T-helper type 2 cell (Th2) response and a Th1 response may predispose to the development of bronchial asthma. Interleukin-18 (IL-18) has an ability to promote both Th1 and Th2 responses, depending on the surrounding cytokine environment. Reactive oxygen species (ROS) play a cruci...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.024737
更新日期:2006-10-01 00:00:00
abstract::Quinones undergo redox cycling and/or arylation reactions with key biomolecules involved with cellular Ca2+ regulation. The present study utilizes nanomolar quantities of the fluorogenic maleimide 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) to measure the reactivity of hyperreactive sulfhydryl moieti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-05-01 00:00:00