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)

Intracerebroventricular (i.c.v.) administration of immune sera raised against Gi2 alpha subunits to mice, significantly reduced the supraspinal antinociceptive effect of opioids when evaluated 24 h later in the tail-flick test. Antisera directed against Gi1 alpha subunits did not modify this opioid activity. In mice injected with sera anti-Gx/z alpha, the mu-preferential agonists, DAMGO and morphine, and the endogenous mu/delta opioid peptide beta-endorphin-(1-31) displayed a reduced antinociceptive activity, whereas, the potency of the delta-selective agonists DPDPE and [D-Ala2]Deltorphin II, was not altered. This reduction was present for 3 to 7 days and returned to the control values after 10 days. Anti-Gi2 alpha and anti-Gx/z alpha, but not anti-Gi1 alpha, reduced the specific binding of [3H]DAMGO to the opioid receptor in PAG. These results suggest the ability of the mu receptor to interact in vivo with different classes of G transducer proteins (Gx/z/Gi2) to produce an effect. This work also indicates a functional role of the pertussis toxin insensitive Gx/z protein, on the mu-mediated (but not delta-mediated) supraspinal antinociception in mice.
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PMID:Gx/z and Gi2 transducer proteins on mu/delta opioid-mediated supraspinal antinociception. 790 22

Opioid agonists inhibit DNA synthesis in C6 rat glioma cells that express opioid receptors, induced by desipramine (DMI). This inhibition was not observed in cells that were not treated with DMI, and thus did not express opioid-binding sites. Endothelin, a known mitogen, increased thymidine incorporation dose dependently (up to 1.7-fold) in DMI-treated C6 cells. This increase was reversed by an anti-idiotypic antibody to opioid receptors, Ab2AOR, which has opioid agonist properties. The opioid antagonist naltrexone blocked the inhibition caused by Ab2AOR. Endothelin also stimulated phosphoinositide (PI) turnover and this effect was inhibited by morphine (50%) or by Ab2AOR (72%) in DMI-treated but not in DMI-untreated C6 cells. These actions of morphine and Ab2AOR were reversed by naltrexone. The inhibition of PI turnover and of thymidine incorporation by Ab2AOR or morphine was insensitive to pertussis toxin (PTX). Since PI turnover is known to induce Ca2+ mobilization, it was of interest to examine the effects of the applied opioids on intracellular Ca2+ concentrations. Endothelin increased the concentration of cytosolic free Ca2+ in the cells while Ab2AOR, morphine, and beta-endorphin reversed the endothelin-induced Ca2+ mobilization in DMI-treated but not in DMI-untreated C6 cells. The effect of these agonists was also blocked by naltrexone. The results indicate that glial cells can be a target of an opioid receptor-mediated antimitogenic action and that an abatement in PI turnover and Ca2+ mobilization may be associated with this mechanism.
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PMID:Opioids inhibit endothelin-mediated DNA synthesis, phosphoinositide turnover, and Ca2+ mobilization in rat C6 glioma cells. 793 48

Physiological responses to opiates and opioid peptides are transduced via receptors coupled to G proteins. The effectors for these G proteins are often ion channels or second messenger systems that modulate channel activity. In cultured bovine adrenal medullary chromaffin cells (BAMCCs), the activity of a calcium-dependent, voltage-sensitive, potassium (BK) channel is robustly potentiated by a mu-type opioid receptor, an effect consistent with the inhibitory role of opioids versus neural excitability. Patch-clamp electrophysiology was used to investigate coupling between the mu receptor and BK channel, leading to rather surprising results. Potentiation of BK channel activity by the mu-selective agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 nM) was unaffected by all attempts to disrupt or alter G protein function, including incubation of cells with pertussis toxin (PTX) and inclusion of guanosine 5'-O-(2-thio)diphosphate (GDP beta S) or guanosine 5'-O-(3-thio)triphosphate (GTP gamma S) in intracellular recording solutions. However, dopamine D2 receptor potentiation of BK current in these same cells was affected by PTX, GDP beta S, and GTP gamma S in predictable fashion. Thus, PTX and GDP beta S inhibited dopamine potentiation of BK current, and GTP gamma S prolonged reversal of dopamine action. These results suggest that the BAMCC BK channel is not coupled to the mu receptor via a GTP-dependent mechanism, whereas in the same cells the dopamine D2 receptor modulates BK channel activity in a conventional GTP-dependent manner. In addition, replacement of both ATP and GTP with nonhydrolyzable analogs also failed to affect either potentiation or recovery of BK channel activity in response to [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin. These results indicate that in BAMCCs the mu-opioid receptor modulates BK channel activity independently of either G proteins or phosphorylation-dependent processes.
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PMID:Nucleotide-independent modulation of Ca(2+)-dependent K+ channel current by a mu-type opioid receptor. 796 64

The question of whether short- and long-term opioid agonist activities could be affected by receptor density is being addressed with Chinese hamster ovary (CHO) cell lines stably expressing delta-opioid receptors. CHO cells expressing different levels of delta-opioid binding sites were isolated and characterized. The opioid binding sites in these cell lines have stereoselective high affinity for 3H-diprenorphine (0.18 to 0.91 nM), with agonist binding sensitive to both Na+ and GTP gamma S, and are of the delta-2-opioid receptor subtype. This is conclude from observations that the delta-2-opioid receptor-selective agonist naltriben (NTB) has higher affinity than the delta-1-opioid receptor-selective agonist 7-benzylidenenaltrexone (BNTX). It also could be demonstrated that delta-opioid agonists inhibited forskolin-stimulated intracellular 3H-cAMP production and that agonist inhibition could be blocked by pretreating cells with pertussis toxin. Again, NTB is more potent than BNTX or naloxone in reversing DPDPE inhibition of intracellular 3H-cAMP production. When the ability of [D-Ala2,D-Leu5]enkephalin (DADLE) to regulate adenylyl cyclase activity was examined in three separate CHO cell lines: CHODORX1-15, CHODORX1-8 and CHODORX1-4, which express 1.42 +/- 0.08, 0.74 +/- 0.07 and 0.27 +/- 0.04 pmol/mg-protein of receptor, respectively, maximal inhibitory levels in clones X1-15 and X1-8 were similar, whereas maximal inhibitory level for clone X1-4 was 66% of the other two clones. However, when maximal inhibitory levels of other opioid receptor-selective agonists were examined, different levels of inhibition were observed among these three CHO clones.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of delta-opioid receptor activities stably expressed in CHO cell lines: function of receptor density? 799 85

The effect of Panax ginseng root extract on Ca2+ current of adult rat trigeminal ganglion neurons was investigated using whole-cell patch-clamp methods. The application of P. ginseng root extract (100 micrograms/ml) produced rapid, reversible reduction of the Ca2+ current by 22 +/- 4%. Treatment with pertussis toxin (250 ng/ml) for 16 h reduced the inhibition to 4 +/- 1%. The continual presence of 1 microM DAGO, a selective mu-opioid agonist that inhibits Ca2+ channels, occluded further inhibition of Ca2+ current by P. ginseng root extract. Yohimbine, phaclofen, atropine, and naloxone--antagonists of alpha 2-adrenergic, GABAB, muscarinic, and opiate receptors, respectively--did not block the inhibitory effect on Ca2+ current of P. ginseng root extract. Thus, P. ginseng root extract acts on sensory neurons through a similar pathway as mu-type opioids: both inhibit Ca2+ channels through pertussis toxin-sensitive GTP-binding proteins. However, the receptor for P. ginseng root extract is not an alpha 2-adrenergic, GABAB, muscarinic, or opioid receptor.
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PMID:Ginseng root extract inhibits calcium channels in rat sensory neurons through a similar path, but different receptor, as mu-type opioids. 804 43

The cellular mechanisms underlying opioid action remain to be fully determined, although there is now growing indirect evidence that some opioid receptors may be coupled to phospholipase C. Using SH-SY5Y human neuroblastoma cells (expressing both mu- and delta-opioid receptors), we demonstrated that fentanyl, a mu-preferring opioid, caused a dose-dependent (EC50 = 16 nM) monophasic increase in inositol (1,4,5)trisphosphate mass formation that peaked at 15 s and returned to basal within 1-2 min. This response was of similar magnitude (25.4 +/- 0.8 pmol/mg of protein for 0.1 microM fentanyl) to that found in the plateau phase (5 min) following stimulation with 1 mM carbachol (18.3 +/- 1.4 pmol/mg of protein), and was naloxone-, but not naltrindole- (a delta antagonist), reversible. Further studies using [D-Ala2, MePhe4, Gly(ol)5]enkephalin and [D-Pen2,5]enkephalin confirmed that the response was specific for the mu receptor. Incubation with Ni2+ (2.5 mM) or in Ca(2+)-free buffer abolished the response, as did pretreatment (100 ng/ml for 24 h) with pertussis toxin (control plus 0.1 microM fentanyl, 26.9 +/- 1.5 pmol/mg of protein; pertussis-treated plus 0.1 microM fentanyl, 5.1 +/- 1.3 pmol/mg of protein). In summary, we have demonstrated a mu-opioid receptor-mediated activation of phospholipase C, via a pertussis toxin-sensitive G protein, that is Ca(2+)-dependent. This stimulatory effect of opioids on phospholipase C, and the potential inositol (1,4,5)trisphosphate-mediated rises in intracellular Ca2+, could play a part in the cellular mechanisms of opioid action.
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PMID:mu-Opioid receptor stimulation of inositol (1,4,5)trisphosphate formation via a pertussis toxin-sensitive G protein. 811 87

Opiates are known to influence intestinal motility via modulation of cholinergic transmission. The aims of this study are to characterize the opioid receptor subtype that modulates cholinergic transmission and to investigate the intracellular mechanism responsible for inhibition of acetylcholine (ACh) release by opiates using longitudinal muscle-myenteric plexus preparations of the guinea pig ileum. The kappa-receptor agonist U50488H and the mu-receptors agonist [D-Ala2,N-Me-Phe4, Gly5-ol]enkephalin, inhibited the release of ACh evoked by electrical stimulation (0.2 and 2 Hz) in a dose-dependent fashion, whereas the delta-receptor agonist DPDPE, had no effect. ACh release evoked by depolarization with veratridine, which was more analogous to high frequency stimulation, was inhibited only by U50488H. Pertussis toxin abolished the inhibitory effect of U50488H on veratridine-induced ACh release suggesting that the principal mechanism by which opiates inhibit cholinergic transmission is via activation of an inhibitory regulatory G protein. Veratridine-stimulated release of ACh was antagonized by omega-Conotoxin GVIA (a preferential N channel blocker) but was not affected by nifedipine (an L channel blocker) or nickel (a T channel blocker). U50488H did not produce further inhibition of veratridine-evoked ACh release in the presence of omega-Conotoxin GVIA. These results suggest that both kappa- and mu-agonists can modulate cholinergic transmission, although the kappa-agonist appears to be more potent. The kappa receptors modulate ACh release by inhibition of N-type voltage-sensitive Ca++ channels via a pertussis toxin-sensitive G protein in guinea pig ileum.
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PMID:Inhibition of cholinergic transmission by opiates in ileal myenteric plexus is mediated by kappa receptor. Involvement of regulatory inhibitory G protein and calcium N-channels. 811 12

A mu opioid receptor and a G protein-activated K+ channel were coexpressed in Xenopus oocytes. Stimulation of the mu opioid receptor induced an inwardly rectifying current that was blocked by opioid receptor antagonist naloxone, indicating that the mu opioid receptor is functionally coupled to the K+ channel. The coupling is mediated by G proteins, since pertussis toxin treatment reduced the K+ current and injection of GTP gamma S (guanosine 5'-O-(thiotriphosphate)) enhanced it. Repeated stimulation of the mu receptor leads to desensitization, as the K+ current from the second stimulation was reduced to 70% of that from the first one. Both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) regulate this process, but in opposite direction. Activation of PKC by treatment of the oocyte with phorbol ester potentiated the desensitization of the mu receptor-induced current. However, incubation of the cell with a membrane-permeable cAMP analog, 8-chlorophenylthio-cAMP, completely abolished the desensitization. The cAMP effect appears to be mediated by PKA, since injection of a PKA catalytic subunit showed the same effect as cAMP incubation. These results suggest that PKA and PKC differentially regulate the mu opioid receptor coupling to the G protein-activated K+ channel.
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PMID:Differential regulation by cAMP-dependent protein kinase and protein kinase C of the mu opioid receptor coupling to a G protein-activated K+ channel. 813 98

Opioids elicit an increase in the intracellular free Ca2+ concentration ([Ca2+]i) in neuroblastoma x glioma hybrid NG108-15 cells, which, depending upon growth conditions, results from either Ca2+ influx in differentiated cells or Ca2+ release from internal stores in undifferentiated cells (Jin et al., 1992). In this report we describe fura-2-based digital imaging studies that demonstrate that opioid-evoked Ca2+ release in these cells results from the activation of phospholipase C (PLC) and subsequent mobilization of the inositol 1,4,5-trisphosphate (IP3)-sensitive store. D-Ala2-D-Leu5-enkephalin (DA-DLE) evoked concentration-dependent increases in [Ca2+]i (EC50 approximately equal to 4 nM). The response was blocked by naloxone (1 microM). In single cells, sequential application of selective opioid agonists (10 nM) evoked responses of the rank order DADLE = D-Pen2, D-Pen5-enkephalin (DPDPE) > trans-(+/-) 3,4-dichloro-N-methyl-N-(2-[1- pyrrolidinyl]cyclohexyl) benzeneacetamide (U50488) > D-ala2, N-Me-Phe4, Gly5-ol-enkephalin (DAMGO), consistent with activation of a delta-opioid receptor. Forty percent (n = 198) of the cells responded to 100 nM DADLE with a net [Ca2+]i increase of 483 +/- 40 nM. Bradykinin (100 nM) elicited a response in 91% of the cells with a mean net amplitude of 707 +/- 36 nM. The DADLE-evoked responses were not blocked by removal of extracellular Ca2+; instead, they were abolished by treatment with 10 nM thapsigargin, an agent that depletes and prevents refilling of IP3-sensitive Ca2+ stores. A 1 microM concentration of U73122, an aminosteroid inhibitor of PLC, completely blocked the DADLE-evoked [Ca2+]i increase, while an inactive analog, U73433, was without effect. To explore the possible role of G-proteins in mediating opioid-induced [Ca2+]i increases in NG108-15 cells, we pretreated cells with pertussis or cholera toxin; pertussis toxin blocked the opioid-induced response while cholera toxin was without effect, consistent with a Gi- or Go-mediated effect. Activation of the opioid inhibitory pathway previously described for these cells appears to stimulate the phosphoinositide (PI) cascade as well. Including the PI cascade among the multiple second messenger systems modulated by opioids may be key to understanding the biochemical events that underlie acute and chronic opioid action.
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PMID:Opioids mobilize calcium from inositol 1,4,5-trisphosphate-sensitive stores in NG108-15 cells. 815 47

In rat olfactory bulb, muscarinic and opioid receptor agonists stimulate basal adenylyl cyclase activity in a GTP-dependent and pertussis toxin-sensitive manner. However, in the present study, we show that in the same brain area activation of these receptors causes inhibition of adenylyl cyclase activity stimulated by Ca2+ and calmodulin (CaM) and by forskolin (FSK), two direct activators of the catalytic unit of the enzyme. The opioid and muscarinic inhibitions consist of a decrease of the maximal stimulation elicited by either CaM or FSK, without a change in the potency of these agents. [Leu5]-Enkephalin and selective delta- and mu-, but not kappa-, opioid receptor agonists inhibit the FSK stimulation of adenylyl cyclase activity with the same potencies displayed in stimulating basal enzyme activity. Similarly, the muscarinic inhibition of FSK-stimulated adenylyl cyclase activity shows agonist and antagonist sensitivities similar to those characterizing the muscarinic stimulation of basal enzyme activity. Fluoride stimulation of adenylyl cyclase is not affected by either carbachol or [Leu5]enkephalin. In vivo treatment of olfactory bulb with pertussis toxin prevents both opioid and muscarinic inhibition of Ca2+/CaM- and FSK-stimulated enzyme activities. These results indicate that in rat olfactory bulb delta- and mu-opioid receptors and muscarinic receptors, likely of the M4 subtype, can exert a dual effect on cyclic AMP formation by interacting with pertussis toxin-sensitive GTP-binding protein(s) and possibly by affecting different molecular forms of adenylyl cyclase.
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PMID:Activation of opioid and muscarinic receptors stimulates basal adenylyl cyclase but inhibits Ca2+/calmodulin- and forskolin-stimulated enzyme activities in rat olfactory bulb. 820 25


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