The Experts below are selected from a list of 63 Experts worldwide ranked by ideXlab platform
S. H. Ferreira - One of the best experts on this subject based on the ideXlab platform.
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The Role of Interleukins and Nitric Oxide in the Mediation of Inflammatory Pain and its Control by Peripheral Analgesics
Drugs, 1993Co-Authors: S. H. FerreiraAbstract:Tissue injury or the presence of foreign material initiates a series of pathophysiological events that may manifest as inflammatory Pain. The physicochemical characteristics of the initiating factor trigger the release of a unique range of Pain mediators that control the threshold and activation of nociceptors. It has been suggested that many nociceptors associated with inflammatory Pain are dormant, and are activated by cyclo-oxygenase metabolites and sympathomimetic amines into a state of hyperalgesia. In this state, Pain Receptors may be activated by previously ineffective stimuli. The relative contribution of the mediators to the activation process varies with the experimental model or the pathophysiological process involved. The mechanisms that control the activity of the Pain Receptor are unfolding. Indeed, research has shown a central role for bradykinin (released from plasma) and cytokines (released from tissues and resident cells) in this process. The release of tumour necrosis factor-α (TNF-α) initiates the release of interleukin-1 and interleukin-8, which in turn liberate cyclo-oxygenase metabolites and sympathomimetic amines, respectively. In some models of inflammatory Pain, bradykinin causes hyperalgesia via release of TNF-α. Drugs blocking cyclo-oxygenase (aspirin-like drugs), or those antagonising the effects of sympathomimetic amines (β-blockers), prevent sensitisation of the Pain Receptors. However, during hyperalgesia only specific types of analgesics are capable of nociceptor downregulation. It is assumed that sensitisation of nociceptors is due to increased concentrations of cAMP/Ca^++ in the sensory neurons. The effect of increased cAMP concentrations may be counteracted by stimulation of the arginine/nitric oxide/cGMP pathway. Peripherally acting opiates and dipyrone are examples of analgesics that act via this mechanism. The analgesic effects of glucocorticoids and nimesulide appear to be attributable to inhibition of cytokine release.
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The role of interleukins and nitric oxide in the mediation of inflammatory Pain and its control by peripheral analgesics.
Drugs, 1993Co-Authors: S. H. FerreiraAbstract:Tissue injury or the presence of foreign material initiates a series of pathophysiological events that may manifest as inflammatory Pain. The physicochemical characteristics of the initiating factor trigger the release of a unique range of Pain mediators that control the threshold and activation of nociceptors. It has been suggested that many nociceptors associated with inflammatory Pain are dormant, and are activated by cyclo-oxygenase metabolites and sympathomimetic amines into a state of hyperalgesia. In this state, Pain Receptors may be activated by previously ineffective stimuli. The relative contribution of the mediators to the activation process varies with the experimental model or the pathophysiological process involved. The mechanisms that control the activity of the Pain Receptor are unfolding. Indeed, research has shown a central role for bradykinin (released from plasma) and cytokines (released from tissues and resident cells) in this process. The release of tumour necrosis factor-alpha (TNF-alpha) initiates the release of interleukin-1 and interleukin-8, which in turn liberate cyclo-oxygenase metabolites and sympathomimetic amines, respectively. In some models of inflammatory Pain, bradykinin causes hyperalgesia via release of TNF-alpha. Drugs blocking cyclo-oxygenase (aspirin-like drugs), or those antagonising the effects of sympathomimetic amines (beta-blockers), prevent sensitisation of the Pain Receptors. However, during hyperalgesia only specific types of analgesics are capable of nociceptor downregulation. It is assumed that sensitisation of nociceptors is due to increased concentrations of cAMP/Ca++ in the sensory neurons. The effect of increased cAMP concentrations may be counteracted by stimulation of the arginine/nitric oxide/cGMP pathway. Peripherally acting opiates and dipyrone are examples of analgesics that act via this mechanism. The analgesic effects of glucocorticoids and nimesulide appear to be attributable to inhibition of cytokine release.
Nobutaka Hirokawa - One of the best experts on this subject based on the ideXlab platform.
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the molecular motor kif1a transports the trka neurotrophin Receptor and is essential for sensory neuron survival and function
Neuron, 2016Co-Authors: Yosuke Tanaka, Shinsuke Niwa, Ming Dong, Atena Farkhondeh, Li Wang, Ruyun Zhou, Nobutaka HirokawaAbstract:Summary KIF1A is a major axonal transport motor protein, but its functional significance remains elusive. Here we show that KIF1A-haploinsufficient mice developed sensory neuropathy. We found progressive loss of TrkA(+) sensory neurons in Kif1a +/− dorsal root ganglia (DRGs). Moreover, axonal transport of TrkA was significantly disrupted in Kif1a +/− neurons. Live imaging and immunoprecipitation assays revealed that KIF1A bound to TrkA-containing vesicles through the adaptor GTP-Rab3, suggesting that TrkA is a cargo of the KIF1A motor. Physiological measurements revealed a weaker capsaicin response in Kif1a +/− DRG neurons. Moreover, these neurons were hyposensitive to nerve growth factor, which could explain the reduced neuronal survival and the functional deficiency of the Pain Receptor TRPV1. Because phosphatidylinositol 3-kinase (PI3K) signaling significantly rescued these phenotypes and also increased Kif1a mRNA, we propose that KIF1A is essential for the survival and function of sensory neurons because of the TrkA transport and its synergistic support of the NGF/TrkA/PI3K signaling pathway.
Elias Utreras - One of the best experts on this subject based on the ideXlab platform.
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tgf β1 sensitizes trpv1 through cdk5 signaling in odontoblast like cells
Molecular Pain, 2013Co-Authors: Elias Utreras, Michaela Prochazkova, Anita Terse, Jacklyn R Gross, Jason M Keller, Michael J Iadarola, Ashok B KulkarniAbstract:Background Odontoblasts are specialized cells that form dentin and they are believed to be sensors for tooth Pain. Transforming growth factor-β1 (TGF-β1), a pro-inflammatory cytokine expressed early in odontoblasts, plays an important role in the immune response during tooth inflammation and infection. TGF-β1 is also known to participate in Pain signaling by regulating cyclin-dependent kinase 5 (Cdk5) in nociceptive neurons of the trigeminal and dorsal root ganglia. However, the precise role of TGF-β1 in tooth Pain signaling is not well characterized. The aim of our present study was to determine whether or not in odontoblasts Cdk5 is functionally active, if it is regulated by TGF-β1, and if it affects the downstream Pain Receptor, transient Receptor potential vanilloid-1 (TRPV1).
Avi Priel - One of the best experts on this subject based on the ideXlab platform.
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The Pain Receptor TRPV1 displays agonist-dependent activation stoichiometry.
Scientific Reports, 2015Co-Authors: Adina Hazan, Henry Matzner, Rakesh Kumar, Avi PrielAbstract:The Receptor channel TRPV1 (Transient Receptor Potential Vanilloid 1) is expressed by primary afferent sensory neurons of the Pain pathway, where it functions as a sensor of noxious heat and various chemicals, including eicosanoids, capsaicin, protons and peptide toxins. Comprised of four identical subunits that organize into a non-selective cationic permeable channel, this Receptor has a variety of binding sites responsible for detecting their respective agonists. Although its physiological role as a chemosensor has been described in detail, the stoichiometry of TRPV1 activation by its different ligands remains unknown. Here, we combined the use of concatemeric constructs harboring mutated binding sites with patch-clamp recordings in order to determine the stoichiometry for TRPV1 activation through the vanilloid binding site and the outer-pore domain by capsaicin and protons, respectively. We show that, while a single capsaicin-bound subunit was sufficient to achieve a maximal open-channel lifetime, all four proton-binding sites were required. Thus, our results demonstrate a distinct stoichiometry of TRPV1 activation through two of its different agonist-binding domains.
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The Pain Receptor TRPV1 displays agonist-dependent activation
2015Co-Authors: R. Rakesh Kumar, Henry Matzner, Avi PrielAbstract:The Receptor channel TRPV1 (Transient Receptor Potential Vanilloid 1) is expressed by primary afferent sensory neurons of the Pain pathway, where it functions as a sensor of noxious heat and various chemicals, including eicosanoids, capsaicin, protons and peptide toxins. Comprised of four identical subunits that organize into a non-selective cationic permeable channel, this Receptor has a variety of binding sites responsible for detecting their respective agonists. Although its physiological role as a chemosensor has been described in detail, the stoichiometry of TRPV1 activation by its different ligands remains unknown. Here, we combined the use of concatemeric constructs harboring mutated binding sites with patch-clamp recordings in order to determine the stoichiometry for TRPV1 activation through the vanilloid binding site and the outer-pore domain by capsaicin and protons, respectively. We show that, while a single capsaicin-bound subunit was sufficient to achieve a maximal open-channel lifetime, all four proton-binding sites were required. Thus, our results demonstrate a distinct stoichiometry of TRPV1 activation through two of its different agonist-binding domains.
Ashok B Kulkarni - One of the best experts on this subject based on the ideXlab platform.
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tgf β1 sensitizes trpv1 through cdk5 signaling in odontoblast like cells
Molecular Pain, 2013Co-Authors: Elias Utreras, Michaela Prochazkova, Anita Terse, Jacklyn R Gross, Jason M Keller, Michael J Iadarola, Ashok B KulkarniAbstract:Background Odontoblasts are specialized cells that form dentin and they are believed to be sensors for tooth Pain. Transforming growth factor-β1 (TGF-β1), a pro-inflammatory cytokine expressed early in odontoblasts, plays an important role in the immune response during tooth inflammation and infection. TGF-β1 is also known to participate in Pain signaling by regulating cyclin-dependent kinase 5 (Cdk5) in nociceptive neurons of the trigeminal and dorsal root ganglia. However, the precise role of TGF-β1 in tooth Pain signaling is not well characterized. The aim of our present study was to determine whether or not in odontoblasts Cdk5 is functionally active, if it is regulated by TGF-β1, and if it affects the downstream Pain Receptor, transient Receptor potential vanilloid-1 (TRPV1).
