European journal of pharmacology
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This study was conducted to characterize movement-induced pain in a rat model of knee joint osteoarthritis and validate this behavioral assessment by evaluating the effects of clinically used analgesic compounds. Unilateral intra-articular administration of a chondrocyte glycolytic inhibitor monoiodoacetate, was used to induce knee joint osteoarthritis in Sprague-Dawley rats. In this osteoarthritis model, histologically erosive disintegration of the articular surfaces of the ipsilateral joint are observed which closely mimic the clinical picture of osteoarthritis. ⋯ Finally, the effects of celecoxib were maintained following chronic dosing. The results indicate that this in vivo model utilizing a movement-induced pain behavior spawned by knee joint osteoarthritis may provide a valuable tool in examining the role of potential analgesic targets in osteoarthritic pain. As the model is clinically relevant, it will further enhance the mechanistic understanding of chronic arthritic joint pain and help in developing newer and better therapeutic strategies to manage osteoarthritis pain.
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Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. ⋯ To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.
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Beside their action on voltage-gated Na(+) channels, local anesthetics are known to exert a variety of effects via alternative mechanisms. The antinociceptive effect of lidocaine is well documented, yet the exact mechanism is not fully understood. Whether glycinergic mechanisms, which play a pivotal role in pain modulation, are involved in lidocaine-induced antinociception is hitherto unclear. ⋯ In the chronic constriction injury model, antinociception evoked by lidocaine was reduced by d-serine, strychnine and CGP 78608, while l-serine had no effect. These results indicate a modulatory effect of lidocaine on the NMDA-receptor. Additionally, since in our study lidocaine-induced antinociception was antagonized by both glycineB-site modulators and strychnine our results may favor the hypothesis of a general glycine-like action of lidocaine or some of its metabolites on inhibitory strychnine-sensitive receptors and on strychnine-insensitive glycine receptors.
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The L-arginine/nitric oxide/cyclic GMP pathway has been proposed as the mechanism of action for peripheral antinociception concerning several groups of drugs, including opioids and nonsteroidal analgesics. The aim of the present study was to investigate the involvement of the L-arginine/NO/cGMP pathway on antinociception induced by xylazine, an alpha(2)-adrenoceptor agonist extensively used in veterinary medicine and animal experimentation. The rat paw pressure test was used by inducing hyperalgesia via intraplantar injection of prostaglandin E(2) (2 microg). ⋯ Xylazine administration elicited a local antinociceptive effect, since only much higher doses produce a systemic effect in the contralateral paw. The peripheral antinociceptive effect induced by xylazine (100 microg/paw) was antagonized by L-NOarg and by ODQ; however, zaprinast potentiated the antinociceptive effect of xylazine at 25 microg/paw. The results provide evidence that xylazine probably induces peripheral antinociceptive effect by L-arginine/NO/cGMP pathway activation.
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Stromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. ⋯ Moreover, SDF-1alpha-mediated increase of kappaB-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK alpha/beta phosphorylation and binding of p65 and p50 to the NF-kappaB element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1alpha and IL-6, and provide additional support for the notion that SDF-1alpha plays a regulatory role in microglia activation.