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)

We have previously shown that the antinociceptive effects produced by the delta opioid-selective agonist deltorphin II are preserved in mu-opioid receptor (MOR)-deficient mice. We have now investigated rewarding effects and physical dependence produced by deltorphin II in these animals. Wild-type and MOR-deficient mice were implanted with a cannula into the third ventricle and deltorphin II was administered centrally. The rewarding effects induced by deltorphin II were then investigated using the place preference paradigm. Wild-type mice showed place preference for the compartment previously associated with deltorphin II and this effect was not observed in MOR-deficient mice. In a second experiment, mice received a chronic perfusion of deltorphin II over 6 days, via an Alzet minipump connected to the intraventricular cannula, and withdrawal was precipitated by naloxone administration. Wild-type animals showed a moderate but significant incidence of several somatic signs of withdrawal. This withdrawal response was suppressed in MOR-deficient mice. Analysis of the immunoreactivity levels of PKC-alpha, PKC-beta (I and II) and PKC-gamma isozymes in the cerebral cortex of mice infused chronically with deltorphin II showed a significant up-regulation of all these isozymes in the soluble fraction in wild-type but not in MOR-deficient mice. In conclusion, mu-opioid receptors, which are not involved in deltorphin II antinociception, appear to mediate the effects of chronic deltorphin II on rewarding responses, physical dependence and adaptive changes to PKC.
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PMID:Lack of dependence and rewarding effects of deltorphin II in mu-opioid receptor-deficient mice. 1113 13

Our studies indicate that, in the presence of particular isoforms of adenylyl cyclase (i.e., type 7 AC), moderately intoxicating concentrations of ethanol will significantly potentiate transmitter-mediated activation of the cAMP signaling cascade. Activation of this signaling cascade may have important implications for the mechanisms by which ethanol produces intoxication, and/or for the mechanisms of neuroadaptation leading to tolerance to, and physical dependence on, ethanol. We initiated a series of studies to investigate the phosphorylation of AC7 by PKC, the role of this phosphorylation in modulating the sensitivity of AC7 to activation by Gsalpha, and the PKC isotype(s) involved in the phosphorylation of AC7. The T7 epitope-tagged AC7 expressed in Sf9 and HEK293 cells was found to be phosphorylated in vitro by the catalytic subunit of PKC. Treatment of AC7-transfected HEK293 cells with phorbol dibutyrate (PDBu) or ethanol increased the phosphorylation of AC7 and its responsiveness to Gsalpha. In human erythroleukemia (HEL) cells, which endogeneously express AC7, ethanol and PDBu increased AC activity stimulated by PGE(1). The potentiation by both PDBu and ethanol was found to be sensitive to the PKC delta-selective inhibitor, rottlerin. The potentiation of AC activity by ethanol in HEL cells was also selectively attenuated by the RACK inhibitory peptide specific for PKC delta, and by expression of the dominant negative, catalytically inactive, form of PKC delta. These data demonstrate that AC7 can be phosphorylated by PKC, leading to an increase in functional activity, and ethanol can potentiate AC7 activity through a PKC delta-mediated phosphorylation of AC7.
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PMID:Phosphorylation cascades control the actions of ethanol on cell cAMP signalling. 1117 75

The use of alcohol and nicotine are highly correlated, suggesting an underlying biochemical interaction. Chronic nicotine exposure results in a deactivation and subsequent upregulation of the expression of nicotinic acetylcholine receptors (nAChRs). Upregulation is thought to represent certain aspects of physical dependence on nicotine. If alcohol also alters nAChR expression or modulates the nicotine-induced upregulation, it could partially explain the high rate of co-abuse of these two drugs. We examined the effects of ethanol on the expression and nicotine-induced upregulation of nAChRs in two cell lines expressing different receptor subtypes. As measured by ligand binding, ethanol initially decreased nAChR expression in M10 cells but increased expression with a more chronic exposure. In the presence of nicotine, the effect of ethanol was similar; initially acting to blunt the upregulation of receptor expression caused by nicotine but enhancing the upregulation with 96 h of exposure. The upregulation of nAChRs was long lasting, remaining above control levels for as long as 7 days following removal of nicotine and ethanol. In PC12 cells, ethanol increased expression at all time points examined. A protein phosphatase inhibitor reduced nicotine-induced upregulation and a PKC inhibitor blocked the ethanol-induced decrease in nAChR expression. These data suggest that ethanol and nicotine interact at the level of the PKC pathway to regulate expression of nAChRs.
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PMID:Ethanol modulates nicotine-induced upregulation of nAChRs. 1276 96

Several groups maintain that morphine tolerance and dependence correlate with increased activity of protein kinases ERK1/2 and P38 MAPK and PKC as well as elevated levels of the neuropeptides dynorphin (DYN), substance P (sP), and calcitonin gene-related peptide (CGRP) in spinal cord dorsal horn (SCDH). They demonstrate that tolerance and dependence can be prevented, and sometimes reversed, by constitutive genetic deletion or pharmacological inhibition of these factors. Recently, we showed that mice with a constitutive deletion of the GluR5 subunit of kainate receptors (GluR5 KO) are not different from wild type (WT) littermates with respect to baseline nociceptive thresholds as well as acute morphine antinociception, morphine physical dependence and conditioned place preference. However, unlike WT, GluR5 KO mice do not develop antinociceptive tolerance following systemic morphine administration. In this report, we examined levels of these mediators in SCDH of WT and GluR5 KO mice following subcutaneous implantation of placebo or morphine pellets. Surprisingly, spinal DYN and CGRP, along with phosphorylated ERK2 (pERK2), P38 (pP38) and PKCgamma (pPKCgamma) are elevated by deletion of GluR5. Additionally, chronic systemic morphine administration increased spinal pERK2, pP38 and pPKCgamma levels in both tolerant WT and non-tolerant GluR5 KO mice. In contrast, while morphine increased spinal DYN and CGRP in WT mice, DYN remained unchanged and CGRP was reduced in GluR5 KO mice. These observations suggest that spinal ERK2, P38 and PKCgamma are likely involved in multiple adaptive responses following systemic morphine administration, whereas DYN and CGRP may contribute selectively to the development of antinociceptive tolerance.
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PMID:Spinal mediators that may contribute selectively to antinociceptive tolerance but not other effects of morphine as revealed by deletion of GluR5. 2035 26