Naunyn-Schmiedeberg's archives of pharmacology
-
Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2008
ReviewCandidate gene polymorphisms predicting individual sensitivity to opioids.
Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. ⋯ Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.
-
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.
-
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.
-
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.