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)

There is increasing evidence that ginseng influences pain modulation. In spite of extensive behavior studies, the detailed mechanism of ginseng actions at the cellular level and the identity of the active substance have not been elucidated yet. Whole-cell patch-clamp recordings were used to examine the modulation of high-voltage-activated Ca2+ channel currents by ginseng total saponins and its various individual ginsenosides in rat dorsal root ganglion neurons. Application of ginseng total saponins suppressed Ca2+ channel currents in a dose-dependent manner. Occlusion experiments using selective blockers revealed that ginseng total saponins could modulate L-, N-, and P-type currents. The co-application of ginseng total saponins and the gamma-opioid receptor agonist, D-Ala(2), N-MePhe(4), Gly(5)-ol-enkephalin (DAMGO), produced non-additive effects in most cells tested and each effect was significantly relieved by a depolarizing prepulse. Overnight treatment of cells with pertussis toxin profoundly reduced the inhibition. Furthermore, we now report that ginsenoside Rg3, among the major fractions of ginseng saponins, is a newly identified active component for the inhibition. These results suggest that the modulation of Ca2+ channels by ginseng total saponins, in particular by ginsenoside Rg3, could be part of the pharmacological basis of ginseng-mediated antinociception.
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PMID:Ginseng and ginsenoside Rg3, a newly identified active ingredient of ginseng, modulate Ca2+ channel currents in rat sensory neurons. 1185 94

The inhibitory effects of opioids on voltage-dependent calcium channels (VDCCs) were investigated in cultured porcine adrenal chromaffin cells using whole-cell patch clamp technique. The effects of the opioid on [Ca(2+)](i) increase and catecholamine secretion induced by high K(+) were also examined in single cells by fura-2 microfluorimetry and amperometry. A depolarizing pulse to 0 mV (test pulse) from a holding potential of -80 mV evoked an inward barium current (I(Ba)), which was reversibly inhibited by methionine-enkephalin. This inhibitory effect of methionine-enkephalin was abolished by naloxone. Selective agonists of opioid receptor subtypes (DAMGO: mu, DPDPE: delta, U50488: kappa) dose-dependently inhibited I(Ba). In inhibitory potency, the order was DAMGO>U50488>DPDPE. These agonists applied sequentially produced a reversible I(Ba) inhibition in the same cells. The inhibitory effect of DAMGO on I(Ba) almost disappeared in the presence of omega-conotoxin GVIA but not omega-agatoxin IVA plus nifedipine. Application of a conditioning prepulse to +100 mV prior to the test pulse partly retrieved the I(Ba) inhibition by DAMGO, suggesting the involvement of voltage-sensitive components in opioid-induced VDCC inhibition. Intracellular application of GDPbetaS or GTPgammaS as well as pretreatment with pertussis toxin significantly reduced the extent of I(Ba) inhibition induced by DAMGO. DAMGO reversibly inhibited the [Ca(2+)](i) increase and catecholamine release induced by high K(+). RT-PCR revealed the expression of mu-, delta- and kappa-opioid receptor mRNAs in cultured adrenal chromaffin cells. These results suggest that porcine adrenal chromaffin cells possess mu-, delta- and kappa-opioid receptors and activation of opioid receptors mainly inhibits N-type VDCCs via pertussis toxin-sensitive G-proteins.
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PMID:Inhibitory effects of opioids on voltage-dependent Ca(2+) channels and catecholamine secretion in cultured porcine adrenal chromaffin cells. 1203 48

Prolonged exposure to opioid agonists can induce adaptive changes resulting in tolerance and dependence. Here, rats were rendered tolerant by subcutaneous injections of increasing doses of morphine from 10 to 60 mg/kg for 3, 5, or 10 consecutive days. Binding parameters of the mu-opioid receptor in subcellular fractions were measured with [(3)H]DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin). Although the density of surface mu-sites did not change after the 5-day morphine treatment, up-regulation of synaptic plasma membrane binding was detected after the 10-day drug administration. In contrast, the number of mu-binding sites in a light vesicle or microsomal fraction (MI) was elevated by 68 and 30% after 5 and 10 days of morphine exposure, respectively. The up-regulated MI mu-sites displayed enhanced coupling to G proteins compared with those detected in saline-treated controls. Pertussis toxin catalyzed ADP ribosylation, and Western blotting with specific antisera was used to quantitate chronic morphine-induced changes in levels of various G protein alpha-subunits. Morphine treatment of 5 days and longer induced significant increases in levels of Galpha(o), Galpha(i1), and Galpha(i2) in MI fractions that are part of an adaptation process. Up-regulation of intracellular mu-sites may be the result of post-translational changes and in part de novo synthesis. The results provide the first evidence that distinct regulation of intracellular mu-opioid receptor G protein coupling and G protein levels may accompany the development of morphine tolerance.
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PMID:Chronic morphine-induced changes in mu-opioid receptors and G proteins of different subcellular loci in rat brain. 1213 Jul 43

Chronic sympathetic denervation entails subsensitivity to alpha(2)-adrenoceptor agonists and supersensitivity to kappa- and mu-opioid receptor agonists modulating cholinergic neurons in the guinea pig colon. A possible role for signal transduction G proteins in contributing to development of these sensitivity changes was investigated. Pertussis toxin (PTX), a blocker of the G(i/o)-type family of G proteins significantly reduced the inhibitory effects of UK14,304 (alpha(2)-adrenoceptor agonist), U69593 (kappa-opioid receptor agonist) and DAMGO (mu-opioid receptor agonist) on acetylcholine (ACh) overflow in preparations obtained from normal animals, but not in those obtained from sympathetically denervated animals. In this experimental condition, immunoblot analysis revealed reduced levels of G(alphao), G(alphai2), G(alphai3) and G(beta) in myenteric plexus synaptosomes. On reverse, synaptosomal levels of G(alphai1) and G(alphaz), a PTX-insensitive G-protein, increased after chronic ablation of the sympathetic pathways. These data suggest that changes in the function and expression of inhibitory G proteins coupled to alpha(2)-adrenoceptors, kappa- and mu-opioid receptors occur in the myenteric plexus of the guinea pig colon after chronic sympathetic denervation. The possibility that regulation of G proteins represents one of the biochemical mechanisms at the basis of the changes in sensitivity of enteric cholinergic neurons to alpha(2)-adrenoceptor, kappa- and mu-opioid receptor agonists is discussed.
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PMID:Sympathetic denervation-induced changes in G protein expression in enteric neurons of the guinea pig colon. 1217 91

In this report, we demonstrated that peripheral application of very low dose (amol ranges) of morphine induced flexor response through a substance P (SP) release at the nociceptor endings in mice. The intraplantar (i.pl.) application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000amol. The mu-opioid receptor (MOP-R) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also produced dose-dependent flexor response in same dose ranges. Morphine-induced flexor responses were markedly inhibited by naloxone and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) both MOP-R antagonists and by intrathecal injection of antisense oligodeoxynucleotide (AS-ODN) for MOP-R which is expected to reduce the receptor expression in sensory nerve endings. Prior incubation with capsaicin, a depletor of SP from polymodal C fibers and [(+)-(2S,3S)-(2-methoxybenzylamino)-2-phenylpiperidine] (CP-99994), a tachykinin 1 receptor antagonist, also blocked the morphine-induced flexor responses. Moreover, pertussis toxin (PTX) which inactivates G(alpha)(i/o); [(1-[6-([(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione)] (U-73122), an inhibitor of phospholipase C (PLC); ethyleneglycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), a Ca(2+) chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP(3)) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca(2+) concentration and diphenhydramine, a histamine (His) H1 receptor antagonist, were unable to block the morphine-induced flexor responses. These results suggest that extremely low doses of morphine can stimulate sensory nerve endings through activation of peripheral MOP-R and its downstream mechanisms include activation of PLC through a SP release from polymodal C fibers.
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PMID:Stimulation of peripheral nociceptor endings by low dose morphine and its signaling mechanism. 1221 27

The mu-opioid agonist DAMGO exerts a dual activity on cAMP production in SK-N-SH neuroblastoma cells. While the classic inhibitory effect was prevented by pretreating the cells with pertussis toxin (PTX), the stimulatory activity was PTX-resistant. The stimulatory effect was abolished by the selective phospholipase C (PLC) blocker U-73122, by the selective protein kinase C (PKC) blocker chelerythrine and by the calcium-channels blockers Ni++, Co++ and Cd++. Hence, it is suggested that the opioid receptor activates PLC (probably through Gq GTP-binding proteins), to mobilize PKC, that positively modulates calcium channels in the plasma membrane; the entry of Ca++ into the cells stimulates calcium-activated adenylyl cyclases to produce cAMP.
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PMID:The mu opioid agonist DAMGO stimulates cAMP production in SK-N-SH cells through a PLC-PKC-Ca++ pathway. 1259 Nov 62

Opioid peptides and alkaloids exert their effects via G protein-coupled receptors (GPCRs). It has been shown that, in addition to trophic factors, some GPCRs are able to activate the phosphatidylinositol 3-kinase/Akt (PI 3-K/Akt) signal transduction pathway, thus leading to cell survival. The aim of this study was to test whether activation of mu-opioid receptors has protective effects on serum withdrawal-induced cell death and to study the possible implication of PI 3-K in this process. In SH-SY5Y neuroblastoma cells fully differentiated by exposure to retinoic acid for five days, the enkephalin derivative selective mu-agonist DAMGO (0.1-2 microM) and the alkaloid morphine (0.1-10 microM) promoted cell survival after serum deprivation (MTT and trypan blue exclusion assays), without inducing cell proliferation. These effects were fully reversed by naloxone, by the selective mu-antagonist beta-funaltrexamine (beta-FNA) and also by the specific PI 3-K inhibitor LY294002. The two agonists stimulated Akt phosphorylation and the effect was also abolished by beta-FNA and by LY294002. In mouse primary cortical neurons, DAMGO reduced the percentage of apoptosis after 6, 12, 24 and 48 h of serum withdrawal; as determined by Hoechst staining. This effect was blocked by beta-FNA, by pre-treatment with pertussis toxin and by LY294002. DAMGO also stimulated Akt phosphorylation via PI 3-K in this primary neuronal culture. Together, these results indicate that stimulation of the mu-opioid receptor promotes neuronal survival in a G(i/o)-linked, PI 3-K-dependent signaling cascade and suggest that Akt may be a key downstream kinase involved in this anti-apoptotic effect.
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PMID:Mu-opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. 1264 85

Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress G-protein-coupled inward rectifier (GIRK) channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and the nucleus tuberomammillaris (TM) were used, as well as HEK293A cells transfected with GIRK1 and 2, either human orexin receptor type 1 (OX1R) or type 2 (OX2R), mu opioid receptor and GFP cDNAs. In GTPgammaS-loaded cells, orexin A (OXA, 3 microM) inhibited GIRK currents that had previously been activated by somatostatin (in LC cells), nociceptin (TM cells), or the mu opioid agonist DAMGO (HEK cells). In guanosine triphosphate (GTP)-loaded HEK cells, in which GIRK currents were not preactivated, OXA induced a biphasic response through both types of orexin receptors: an initial current increase and a subsequent decrease to below resting levels. Current-voltage (I-V) relationships revealed that both the OXA-induced and suppressed currents are inwardly rectifying with reversal potentials around EK. The OXA-induced initial current was partially pertussis toxin (PTX) sensitive and partially PTX insensitive, whereas the OXA-suppressed current was PTX insensitive. These data suggest that orexin receptors couple with more than one type of G-protein, including PTX-sensitive (such as Gi/o) and PTX-insensitive (such as Gq/11) G-proteins. The modulation of GIRK channels by orexins may be one of the cellular mechanisms for the regulation of brain nuclei (e.g., LC and TM) that are crucial for arousal, sleep, and appetite.
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PMID:Effects of orexin (hypocretin) on GIRK channels. 1270 4

Internalization and recycling of G protein-coupled receptors (GPCRs), such as the mu-opioid receptor, largely depend on agonist stimulation. Agonist-promoted internalization of some GPCRs has been shown to mediate receptor desensitization, resensitization, and down-regulation. In this study, we investigated whether different mu opioid agonists displayed different effects in receptor internalization and recycling, the potential mechanisms involved in ohmefentanyl-induced internalization process. In transfected Sf9 insect cells expressing 6His-tagged wild type mu opioid receptor, exposure to 100 nM ohmefentanyl caused a maximum internalization of the receptor at 30 min and receptors seemed to reappear at the cell membrane after 60 min as determined by radioligand binding assay. Ohmefentanyl-induced human mu opioid receptor internalization was concentration-dependent, with about 40% of the receptors internalized following a 30-min exposure to 1 microM ohmefentanyl. 10 microM morphine and 1 microM DAMGO could also induce about 40% internalization. The antagonist naloxone and pretreatment with pertussis toxin both blocked ohmefentanyl-induced internalization without affecting internalization themselves. Incubation with sucrose 0.45 M significantly inhibited ohmefentanyl-induced internalization of the mu receptor. The removal of agonists ohmefentanyl and morphine resulted in the receptors gradually returning to the cell surface over a 60 min period, while the removal of agonist DAMGO only partly resulted in the receptor recycling. The results of this study suggest that ohmefentanyl-induced internalization of human mu opioid receptor in Sf9 insect cells occurs via Gi/o protein-dependent process that likely involves clathrin-coated pits. In addition, the recycling process displays the differential modes of action of different agonists.
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PMID:Internalization and recycling of human mu opioid receptors expressed in Sf9 insect cells. 1272 92

Chronic exposure of cells to mu-opioid agonists leads to tolerance which can be measured by a reduced ability to activate signaling pathways in the cell. Cell signaling through inhibitory G proteins is negatively regulated by RGS (regulator of G protein signaling) proteins. Here we examine the hypothesis that the GTPase accelerating activity of RGS proteins, by altering the lifetime of Galpha and Gbetagamma, plays a role in the development of cellular tolerance to mu-opioids. C6 glioma cells were stably transfected with mu-opioid receptor and pertussis toxin (PTX)-insensitive Galpha(o) that was either sensitive or insensitive to endogenous RGS proteins. Cells were treated with PTX to uncouple endogenous Galpha proteins followed by exposure to the mu-opioid agonists [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) or morphine. Receptor desensitization as measured by agonist-stimulated [(35)S]GTPgammaS binding and receptor down-regulation as measured by [(3)H]diprenorphine binding were increased in cells expressing RGS-insensitive Galpha(o). Exposure to high concentrations of morphine or the peptidic mu-opioid agonist DAMGO led to a tolerance to inhibit adenylyl cyclase activity in both cell types with a rapid (30 min) and a slower component. Using a submaximal concentration of DAMGO to induce a reduced level of tolerance, a shift in the concentration-effect curve for DAMGO to inhibit adenylyl cyclase activity was seen in the cells expressing RGS-insensitive Galpha(o), but not in the cells expressing RGS-sensitive Galpha(o), which can be partly explained by an increased supersensitization of the adenylyl cyclase response. The results show that RGS proteins endogenously expressed in C6 cells reduce agonist-induced mu-opioid receptor desensitization, down-regulation, and sensitivity to tolerance to inhibit adenylyl cyclase activity.
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PMID:Endogenous regulator of g protein signaling proteins reduce {mu}-opioid receptor desensitization and down-regulation and adenylyl cyclase tolerance in C6 cells. 1538 33


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