Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Jun 2009
Comparative StudyAnalgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain.
Cannabinoid receptor (CB) agonists are known to attenuate allodynia in a range of pain models, but their long-term effects and their mechanisms of action are controversial. The present study compares the antiallodynic effects of long-term treatment with a mixed CB1/CB2 (WIN55,212-2) and a selective CB2 (GW405833) cannabinoid receptor agonist and correlates these effects with their influences on spinal cord (SC) glial activation. The substances were applied daily in a rat neuropathic pain model. ⋯ A daily injection of either substance for 8 days was sufficient to induce a sustained antiallodynic effect, which persisted up to 6 days after the last injection. The re-appearance of mechanical allodynia after this period was associated with a breakout of a strong gliotic response in the lumbar SC. Our results emphasize the therapeutic efficacy of cannabinoid receptor agonists and their inhibitory effects on the formation of gliosis.
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Naunyn Schmiedebergs Arch. Pharmacol. · Apr 2009
Effects of gabapentin and pregabalin on K+-evoked 3H-GABA and 3H-glutamate release from human neocortical synaptosomes.
One site of action of the anticonvulsant, analgesic, and anxiolytic drugs gabapentin and pregabalin is the alpha(2)delta-subunit of voltage-sensitive Ca(2+) channels (VSCC). We therefore analyzed the effects of gabapentin and pregabalin on K(+)-evoked release of (3)H-gamma-aminobutyric acid (GABA) and (3)H-glutamate from superfused human neocortical synaptosomes. These neurotransmitters are released by Ca(2+)-dependent exocytosis and by Ca(2+)-independent uptake reversal. ⋯ Both drugs had no effect on exocytotic (3)H-glutamate release and also failed to modulate the release of (3)H-GABA and (3)H-glutamate caused by reversed uptake in the absence of external Ca(2+). Thus, an inhibition of glutamate release by gabapentin and pregabalin as main anticonvulsant principle is not supported by our experiments. An anticonvulsant mode of action of both drugs may be the reduction of a proconvulsant exocytotic GABA release.
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Naunyn Schmiedebergs Arch. Pharmacol. · Mar 2009
S-nitroso human serum albumin given after LPS challenge reduces acute lung injury and prolongs survival in a rat model of endotoxemia.
Endotoxemia leads to the induction of inducible nitric oxide synthase (NOS-2) and increased expression of numerous inflammatory mediators contributing to endotoxin-induced acute lung injury. We tested the hypothesis that supplementation of nitric oxide (NO) by the novel NO donor S-nitroso human serum albumin (S-NO-HSA) given after lipopolysaccharide (LPS) challenge may reduce NOS-2 expression, lung inflammation and acute lung injury. Rats were divided into four groups: sham-operated (no treatment), LPS, LPS+HSA (human serum albumin), and LPS+S-NO-HSA. ⋯ S-NO-HSA but not HSA prolonged survival of endotoxemic rats, reduced the hypotensive response to LPS, minimized LPS-induced lung edema and injury, normalized MPO activity as well as diminished lung expression of pro-inflammatory molecules such as ICAM-1, NOS-2, and COX-2. Continuous supplementation of NO by S-NO-HSA after LPS challenge prevents induction of NOS-2, provides significant protection of endotoxin-induced acute lung injury, and prevents early mortality in endotoxic shock in rats. Our results suggest a potential therapeutic role for S-NO-HSA in endotoxemia.
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Naunyn Schmiedebergs Arch. Pharmacol. · Dec 2008
Comparative StudyBinding of the novel radioligand [(3)H]UFP-101 to recombinant human and native rat nociceptin/orphanin FQ receptors.
Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP). Binding studies have relied on [leucyl-(3)H]N/OFQ, but as this is an agonist G-protein coupling will affect affinity. In this paper, we describe a new [(3)H]labeled NOP antagonist, [Nphe(1),4'-(3)H-Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2) ([(3)H]UFP-101). ⋯ Unlike the agonist [leucyl-(3)H]N/OFQ, the antagonist [(3)H]UFP-101 was unaffected by GTPgammaS. [(3)H]UFP-101 binds to human and rat NOP with high affinity and good agreement with standard [leucyl-(3)H]N/OFQ in competition experiments. In addition, the binding of [(3)H]UFP-101 is unaffected by GTPgammaS. This radioligand will be useful to further characterize NOP in a range of binding paradigms.
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Naunyn Schmiedebergs Arch. Pharmacol. · Nov 2008
Role of the soluble guanylyl cyclase alpha1/alpha2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus.
Carbon monoxide (CO) has been shown to cause enteric smooth muscle relaxation by activating soluble guanylyl cyclase (sGC). In gastric fundus, the sGCalpha1beta1 heterodimer is believed to be the most important isoform. The aim of our study was to investigate the role of the sGCalpha1/alpha2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus using wild-type (WT) and sGCalpha1 knock-out (KO) mice. ⋯ Both in WT and sGCalpha1 KO mice, CO-evoked relaxations were associated with a significant cGMP increase; however, basal and CO-elicited cGMP levels were markedly lower in sGCalpha1 KO mice. These data indicate that besides the predominant sGCalpha1beta1 isoform, also the less abundantly expressed sGCalpha2beta1 isoform plays an important role in the relaxant effect of CO in murine gastric fundus; however, the sGC stimulator YC-1 loses its potentiating effect towards CO in sGCalpha1 KO mice. Prolonged administration of CO-either by the addition of CORM-2 or by continuous infusion of CO-mediates gastric fundus relaxation in both a sGC-dependent and sGC-independent manner.