Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A possible role for G proteins in contributing to the chronic actions of opiates was investigated in the rat locus coeruleus (LC). The LC is a relatively homogeneous brain region that appears to play an important role in mediating acute and chronic opiate action in animals, as well as in humans. It was found that chronic, but not acute, treatment of rats with morphine, under conditions known to induce states of opiate tolerance and dependence, produced an increase in the level of pertussis toxin-mediated ADP-ribosylation of G proteins in the LC. The morphine-induced increase in ADP-ribosylation occurred in both Gi and Go, and was observed over a 30-fold range of NAD concentrations used. Concomitant treatment of rats with the opiate receptor antagonist naltrexone blocked the ability of morphine to produce this effect. In contrast, chronic morphine had no effect on pertussis toxin-mediated ADP-ribosylation of Gi and Go in the other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. Chronic morphine also had no effect on cholera toxin-mediated ADP-ribosylation of Gs in the LC and these other brain regions. Preliminary immunoblot analysis revealed that increased ADP-ribosylation levels of the alpha subunit of Go in the LC were associated with equivalent increases in the immunoreactivity of this protein in this brain region. It is possible that the observed regulation of G-proteins by morphine in the LC represents part of the changes that underlie opiate addiction in these neurons.
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PMID:Regulation of G proteins by chronic morphine in the rat locus coeruleus. 249 49

We have studied the molecular and cellular mechanisms underlying the acute and chronic effects of opiate on neurons of the rat locus coeruleus (LC). Acutely, opiates inhibit LC neurons by activating K+ channels and inhibiting a novel sodium-dependent inward current. Both of these actions are mediated via pertussis toxin-sensitive G-proteins, and regulation of the sodium current occurs through inhibition of the cyclic AMP pathway. In contrast to the acute effects of opiates, chronic treatment of rats with opiates increases levels of specific G-protein subunits, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the possibility that this upregulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these noradrenergic LC neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms by which opiates regulate the expression of these intracellular messenger proteins in the LC. These studies will lead to an improved understanding of the molecular and cellular basis of opiate addiction.
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PMID:Molecular and cellular mechanisms of opiate action: studies in the rat locus coeruleus. 785 10

The pertussis toxin (PTX)-sensitive G proteins Gi and G(o) may be implicated in drug reinforcement and addiction, since certain reward-related dopamine and opiate receptor subtypes are coupled to these G proteins, and since chronic exposure to cocaine or morphine alters levels of these G proteins in the nucleus accumbens (NAc). As a direct test of this hypothesis, Gi and G(o) proteins in the NAc were selectively inactivated by intra-accumbens injections of PTX in rats self-administering either cocaine or heroin. In control animals, bilateral injections of inactive PTX (0.1 microgram/1 microliter/side) in the NAc failed to alter baseline rates of cocaine and heroin self-administration. In contrast, the same dose of active PTX produced significant, long-lasting increases (up to 1 month) in the self-administration of both drugs, and shifted the dose-response curves to the right. These results suggest that PTX reduces or shortens the reinforcing efficacy of cocaine and heroin, leading to compensatory increases in drug self-administration. Similar NAc injections of PTX reduced the level of Gi alpha and G(o) alpha subunits as measured by both ADP-ribosylation and Western blot, without affecting levels of Gs alpha or G beta subunits. The effect of the toxin was mainly limited to the NAc, and no evidence of abnormal cell death or gliosis was observed. The onset of changes in self-administration rate coincided with the onset of changes in ADP-ribosylation, suggesting that, initially, the increased drug self-administration results directly from a reduction in functional Gi and G(o) proteins. After 28 d, self-administration baselines began to recover while levels of G protein ADP-ribosylation and immunoreactivity remained low, suggesting that adaptive mechanisms are involved at later time points. These results provide direct support for a common role of Gi and G(o) proteins in the NAc in the reinforcing and addictive properties of psychostimulant and opiate drugs.
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PMID:Inactivation of Gi and G(o) proteins in nucleus accumbens reduces both cocaine and heroin reinforcement. 793 76

Buprenorphine is an opiate drug with a mixed agonist-antagonist profile and has therapeutic efficacy in attenuating drug craving and addiction. Because the adenylyl cyclase system has been implicated in the biochemical basis of opiate withdrawal phenomena, we have compared the acute and chronic effects of buprenorphine with the full opiate agonist etorphine on cyclic AMP (cAMP) synthesis in the human neuroblastoma cell SK-N-SH. Both drugs acutely inhibited prostaglandin (PG)E1-stimulated cAMP accumulation; the inhibition caused by either drug was prevented by pretreatment with the opiate antagonist naltrexone or with pertussis toxin. Chronic treatment of the cells with etorphine induced an increase in PGE1-stimulated cAMP synthesis which was observed after withdrawal of the inhibitory drug. Chronic treatment with buprenorphine appeared to have the opposite effect, resulting in an attenuated PGE1 stimulation; additionally, buprenorphine prevented the etorphine-induced enhancement in cAMP synthesis, whether administered before or after prolonged incubation of the cells with etorphine. The attenuating effect of buprenorphine occurred within 5 min and was prevented by a prior application of naltrexone, but could not be reversed by a subsequent treatment with antagonist. These findings suggest that buprenorphine was binding (pseudo)irreversibly to the opiate receptor, resulting in a persistent inhibition of cAMP synthesis which masks the etorphine-induced enhancement of adenylyl cyclase activity. This hypothesis was confirmed by experiments demonstrating that treatment of the cells with buprenorphine significantly reduced available opiate receptor binding sites despite extensive washing of the cells to remove unbound buprenorphine. These pharmacodynamic actions of buprenorphine may be relevant to its therapeutic efficacy in treating drug abuse and addiction.
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PMID:Buprenorphine prevents and reverses the expression of chronic etorphine-induced sensitization of adenylyl cyclase in SK-N-SH human neuroblastoma cells. 838 Aug 66

It has been known for some time that chronic treatment of neuronal cells and tissues with opioids, contrary to their acute effect, leads to an increase in cAMP accumulation. This phenomenon, defined as adenylyl cyclase superactivation, has been implicated in opiate addiction, yet the mechanism by which it is induced remains unclear. Here, we show that this phenomenon can be reproduced and studied in COS-7 cells cotransfected with adenylyl cyclase type V and mu-opioid receptor cDNAs. These cells display acute opioid inhibition of adenylyl cyclase activity, whereas prolonged exposure to the mu-agonist morphine or [-Ala2, N-methyl-Phe4, Gly-ol5]enkephalin leads to a time-dependent superactivation of adenylyl cyclase. This superactivated state is reversible, because it is gradually lost following agonist withdrawal. Adenylyl cyclase superactivation can be prevented by pertussis toxin pretreatment, indicating the involvement of Gi/o proteins, or by cotransfection with the carboxyl terminus of beta-adrenergic receptor kinase or with alpha-transducin (scavengers of Gbetagamma dimers), indicating a role for the G protein betagamma dimers in adenylyl cyclase superactivation. However, contrary to several other Gbetagamma-dependent signal transduction mechanisms (e.g. the extracellular signal-regulated kinase 2/MAP kinase pathway), adenylyl cyclase superactivation is not affected by the Ras dominant negative mutant N17-Ras.
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PMID:Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma. 870 9

Opiate-induced immunosuppression has been implicated in the pathogenesis of infections caused by a variety of microorganisms, including human immunodeficiency virus (HIV). Although effects of opiates on lymphocyte function have been studied more extensively, morphine also has been shown to inhibit several functional activities of mononuclear phagocytes (e.g. chemotaxis, respiratory burst activity and phagocytosis). Opiate addiction has been identified as a risk factor for clinical tuberculosis prior to the HIV epidemic, and macrophages are a key cell in the pathogenesis of Mycobacterium tuberculosis. Thus, the hypothesis was tested in the present study that morphine would suppress phagocytosis of M. tuberculosis by human microglial cells, the resident macrophages of the brain. Contrary to this hypothesis, treatment of human fetal microglial cell cultures with morphine (10(-8) M) was found to stimulate phagocytosis of nonopsonized M. tuberculosis H37Rv. The stimulatory effect of morphine was blocked by naloxone and the mu opiate receptor selective antagonist beta-funaltrexamine. Also, morphine-induced increase in phagocytic activity was markedly inhibited by pertussis toxin and was unaffected by cholera toxin, suggesting the mechanism of morphine's stimulatory effect on microglial cell phagocytosis involves a Gi protein-coupled mu opiate receptor. The results of this in vitro study support the concept that exogenous and endogenous opioids play an immunomodulatory role within the central nervous system through their interaction with G protein-coupled receptors on microglial cells.
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PMID:Morphine stimulates phagocytosis of Mycobacterium tuberculosis by human microglial cells: involvement of a G protein-coupled opiate receptor. 874 73

Mu opioid receptors mediate the analgesia induced by morphine. Prolonged use of morphine causes tolerance development and dependence. To investigate the molecular basis of tolerance and dependence, the cloned mouse mu opioid receptor with an amino-terminal epitope tag was stably expressed in human embryonic kidney (HEK) 293 cells, and the effects of prolonged opioid agonist treatment on receptor regulation were examined. In HEK 293 cells the expressed mu receptor showed high affinity, specific, saturable binding of radioligands and a pertussis toxin-sensitive inhibition of adenylyl cyclase. Pretreatment (1 h, 3 h, or overnight) of cells with 1 microM morphine or [D-Ala2MePhe4,Gly(ol)5]enkephalin (DAMGO) resulted in no apparent receptor desensitization, as assessed by opioid inhibition of forskolin-stimulated cAMP levels. In contrast, the morphine and DAMGO pretreatments (3 h) resulted in a 3-4-fold compensatory increase in forskolin-stimulated cAMP accumulation. The opioid agonists methadone and buprenorphine are used in the treatment of addiction because of a markedly lower abuse potential. Pretreatment of mu receptor-expressing HEK 293 cells with methadone or buprenorphine abolished the ability of opioids to inhibit adenylyl cyclase. No compensatory increase in forskolin-stimulated cAMP accumulation was found with methadone or buprenorphine; these opioids blocked the compensatory effects observed with morphine and DAMGO. Taken together, these results indicate that methadone and buprenorphine interact differently with the mouse mu receptor than either morphine or DAMGO. The ability of methadone and buprenorphine to desensitize the mu receptor and block the compensatory rise in forskolin-stimulated cAMP accumulation may be an underlying mechanism by which these agents are effective in the treatment of morphine addiction.
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PMID:Differential opioid agonist regulation of the mouse mu opioid receptor. 899 64

Opiates have been used extensively in the treatment of pain but with the severe side effect of addiction, which is believed to be related to opiates' direct (primary) or indirect (secondary) neurotoxicity. In this study, the effects of opioids on cell growth and apoptosis have been examined in human neuroblastoma cell line SK-N-SH. Etorphine, a wide-spectrum and potent agonist of opioid receptors, was found to significantly inhibit cell growth and to induce apoptosis. The inhibitory and apoptotic activities of etorphine followed a dose- and time-dependent manner. The more specific agonists of opioid receptors such as morphine, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAGO), [D-Pen2, D-Pen5]-enkephalin (DPDPE), dynorphin A and nociceptin/orphanin FQ did not show similar toxic activities under the same conditions. In addition, the effects of etorphine could not be blocked by the opioid receptor antagonist naloxone, suggesting that the effects of etorphine might not be mediated by a classical opioid receptor. However, pretreatment of SK-N-SH cells with pertussis toxin (PTX) blocked the inhibition of cell growth and apoptosis induced by etorphine, indicating the involvement of PTX-sensitive G proteins in the processes. It was also shown that etorphine-induced apoptosis was prevented by actinomycin D (AD) and interleukin-1beta converting enzyme inhibitor I. Interestingly, etorphine was similarly potent to inhibit growth of pheochromocytoma (PC12) cells but less effective in SH-SY5Y neuroblastoma cells and C6 glioma cells. We propose that inhibition of cell growth and induction of apoptosis may be one mechanism of opioid neurotoxicity.
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PMID:Etorphine inhibits cell growth and induces apoptosis in SK-N-SH cells: involvement of pertussis toxin-sensitive G proteins. 935 60

Repeated cocaine exposure upregulates kappa opioids and their receptors in the mesocorticolimbic system; the ensuing kappa-mediated dysphoria appears to contribute to addiction and withdrawal. As a potential rehabilitation strategy to reverse cocaine-induced kappa sensitization, the present study used tritiated dopamine release assays to examine the induction of kappa-opioid tolerance in cultured mesencephalic neurons. Administration of the kappa agonist U69,593 inhibited tetrodotoxin-sensitive, spontaneous (EC(50) = 1.5 nM), and potassium-stimulated (EC(50) = 10 nM) release. These effects were blocked by pertussis toxin and by the kappa antagonist nor-binaltorphimine. The 2 d agonist exposure (1 microM) caused a shift in the U69,593 dose-response curve that was greater in the potassium-stimulated paradigm (140-fold) than in the spontaneous release assay (sixfold). These results were attributable to the attenuation of kappa-receptor signaling mechanisms and to dependence. In the stimulated release assay, attenuation of kappa signaling caused by 4 hr of U69,593 exposure recovered with a half-life of 1.1 hr, whereas attenuation after 144 hr of exposure recovered slowly (t(1/2) = 20 hr). In the spontaneous release assay, attenuation of kappa-opioid signaling occurred slowly (t(1/2) = 22 hr), and resensitization after a 144 hr exposure was rapid (t(1/2) < 1 hr). kappa-Opioid dependence was observed after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to kappa-opioid exposure occur in mesocorticolimbic neurons. These data support the idea that the administration of kappa opioids might facilitate drug rehabilitation.
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PMID:kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain neurons. 1040 16

Many types of cells exhibit increased adenylyl cyclase (AC) activity after chronic agonist treatment of G(i/o)-coupled receptors. This phenomenon, defined as AC superactivation or sensitization, has mostly been studied for the opioid receptors and is implicated in opiate addiction. Here we show that this phenomenon is also observed on chronic activation of the CB(1) cannabinoid receptor. Moreover, using COS-7 cells cotransfected with CB(1) receptor and individual AC isozymes, we could show selective superactivation of AC types I, III, V, VI, and VIII. The level of superactivation was dependent on the concentration of agonist and time of agonist exposure and was not dependent on the AC stimulator used. No superactivation of AC types II, IV, or VII was observed in COS-7 cells cotransfected with CB(1). The superactivation of AC type V was abolished by pretreatment with pertussis toxin and by cotransfection with the carboxy terminus of beta-adrenergic receptor kinase, which serves as a scavenger of G(betagamma) dimers, implying a role for the G(i/o) proteins and especially G(betagamma) dimers in the cannabinoid-induced superactivation of AC.
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PMID:Differential superactivation of adenylyl cyclase isozymes after chronic activation of the CB(1) cannabinoid receptor. 1072 21


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