Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
The activation of transient receptor potential vanilloid receptor subtype 1 by capsaicin without extracellular Ca2+ is involved in the mechanism of distinct substance P release in cultured rat dorsal root ganglion neurons.
Using a highly sensitive substance P (SP) radioimmunoassay, we attempted to elucidate the molecular mechanism of SP release from cultured adult rat dorsal root ganglion (DRG) neurons triggered by capsaicin. As a result, we found that capsaicin can induce SP release in the absence of extracellular Ca2+ by activating transient receptor potential vanilloid receptor subtype 1 (TRPV1). Therefore, we compared the pharmacological profile of SP release involved in several intracellular effectors (phosphoinositide 3-kinase (PI3K), Ca2+ release from intracellular stores, and mitogen-activated protein (MAP) kinases) in the presence/absence of extracellular Ca2+ by stimulating DRG neurons with various concentrations (10 to 1,000 nM) of capsaicin. ⋯ In contrast, in the absence of extracellular Ca2+, only a high concentration (1 microM) of capsaicin induced a significant increase in the SP release, which was then completely abolished by either a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or capsazepine, and significantly inhibited by either thapsigargin (a Ca2+-ATPase inhibitor) or BAPTA-AM (a rapid Ca2+ chelator). In summary, the activation of TRPV1 by capsaicin modulates the SP release from DRG neurons via two different mechanisms, one requiring extracellular Ca2+, the activation of PI3K and the IP3-dependent intracellular Ca2+ release, and the other which is independent of extracellular Ca2+ but involves the activation of MEK. These data suggest that a distinct SP release mechanism exists on DRG through the activation of TRPV1 without extracellular Ca2+ by capsaicin to facilitate neuropeptide release.
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Naunyn Schmiedebergs Arch. Pharmacol. · Apr 2008
Novel modulatory effects of SDZ 62-434 on inflammatory events in activated macrophage-like and monocytic cells.
In this study, we investigated the novel pharmacological activity of SDZ 62-434 on various inflammatory events mediated by monocytes/macrophages (peritoneal macrophages and U937/RAW 264.7 cells) and its putative mechanism of action. SDZ 62-434 strongly inhibited various inflammatory responses induced by lipopolysaccharide (LPS) or function-activating antibody to CD29 (beta1-integrins) including (1) the production of human and mouse tumor necrosis factor (TNF)-alpha, (2) the generation of prostaglandin E(2) (PGE(2)), (3) the release of nitric oxide (NO) and reactive oxygen species (ROS), (4) the increased level of phagocytic uptake, (5) the up-regulation of surface costimulatory molecules CD80, CD86, and CD40, (6) functional activation of beta1-integrin (CD29) assessed by U937 cell-cell adhesion, and (7) the transcriptional up-regulation of inducible NO synthase (iNOS), TNF-alpha, cyclooxygenase (COX)-2, interleukin (IL)-1beta, and IL-6. The anti-inflammatory effects of SDZ 62-434 seem to be mediated by interrupting the early-activated intracellular signaling cascades composed of phosphoinositide 3-kinase (PI3K)/Akt and NF-kappaB but not Janus kinase-2 (JAK-2), extracellular signal-regulated kinase (ERK), p38, or C-Jun N-terminal kinase (JNK), according to pharmacological, biochemical and functional analyses. Therefore, these results suggest that SDZ 62-434 may have anti-inflammatory features derived from PI3K/Akt/NF-kappaB inhibitory activity.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jan 2008
Differential modulation of K(+)-evoked (3)H-neurotransmitter release from human neocortex by gabapentin and pregabalin.
Anticonvulsant, analgesic, and anxiolytic effects have been observed both in preclinical and clinical studies with gabapentin (GBP) and pregabalin (PGB). These drugs appear to act by binding to the alpha(2)delta subunit of voltage-sensitive Ca(2+) channels (VSCC), resulting in the inhibition of neurotransmitter release. In this study, we examined the effects of GBP and PGB (mostly 100 microM, corresponding to relatively high preclinical/clinical plasma levels) on the release of neurotransmitters in human neocortical slices. ⋯ These results suggest that GBP and PGB are not general inhibitors of VSCC and neurotransmitter release. Such alpha(2)delta ligands appear to be selective modulators of the release of certain, but not all, neurotransmitters. This differential modulation of neurotransmission presumably contributes to their clinical profile.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jul 2007
Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells.
Dexmedetomidine, an alpha(2)-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the alpha(2)-adrenoceptor. ⋯ Dexmedetomidine reduced the ACh-induced Cl(-) currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca(2+)](i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M(3) receptors, in addition to its agonistic effects on alpha(2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.