European journal of pharmacology
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The present study was designed to investigate the role of glycine receptors in analgesia induced by injection of glycine in vivo. Glycine was injected intracerebroventricularly or intrathecally and strychnine, a glycine receptor antagonist, was injected intracerebroventricularly or intrathecally before glycine injection. The effects on the pain threshold index in hot-plate test and the writhing times in acetic acid-induced writhing test were observed. ⋯ Glycine increased the pain threshold index in hot-plate test and decreased the writhing times of the mice. Strychnine antagonized the effects induced by glycine above. These results demonstrated that intracerebroventricular or intrathecal injection of glycine can produce analgesia in thermal nociception and chemical nociception in vivo, which is mediated by glycine receptors.
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Compound 24, 1-benzyl-N-[3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl] pyrrolidine-2-carboxamide was recently identified as a nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) ligand. In this study, the in vitro and in vivo pharmacological profiles of Compound 24 were investigated. In vitro studies were performed measuring receptor and [(35)S]GTPgammaS binding and calcium mobilization in cells expressing the recombinant NOP receptor as well as using N/OFQ sensitive tissues. ⋯ Finally in vivo, in the mouse tail withdrawal assay, Compound 24 at 10 mg/kg antagonized the pronociceptive and antinociceptive effects of 1 nmol N/OFQ given supraspinally and spinally, respectively. Under the same experimental conditions Compound 24 did not affect the antinociceptive action of 3 nmol endomorphin-1 injected intrathecally. The present study demonstrated that Compound 24 is a pure, competitive, and highly potent non-peptide NOP receptor selective antagonist.
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Central neuroimmune activation contributes to the initiation and maintenance of neuropathic pain after nerve injury. The current study was aimed to examine the modulation of neuroimmune activation in the spinal cord by the alpha(2) adrenoceptor agonist, clonidine, in a rat model of neuropathic pain induced by partial sciatic nerve ligation (PSNL). Animals were randomly assigned into 6 groups: sham-operation with 20 microg clonidine or saline; and PSNL with clonidine (5, 10, and 20 microg) or saline. ⋯ Administration of clonidine resulted in a dose-dependent attenuation in PSNL-induced mechanical and thermal hyperalgesia. Furthermore, clonidine could markedly inhibit neuroimmune activation characterized by glial activation, production of cytokines, NF-kappaB activation as well as p38 activation. The antihyperalgesic effect of intrathecal clonidine in rats receiving PSNL might partly attribute to the inhibition of neuroimmune activation associated with the maintenance of neuropathic pain.
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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.