The Experts below are selected from a list of 16548 Experts worldwide ranked by ideXlab platform
Brian L Schmidt - One of the best experts on this subject based on the ideXlab platform.
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serine proteases and protease activated receptor 2 dependent allodynia a novel cancer Pain Pathway
Pain, 2010Co-Authors: Brian L SchmidtAbstract:AbstractMediators involved in the generation of Pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we
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serine proteases and protease activated receptor 2 dependent allodynia a novel cancer Pain Pathway
Pain, 2010Co-Authors: David K Lam, Brian L SchmidtAbstract:Mediators involved in the generation of Pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer Pain. This previously unrecognized cancer Pain Pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer Pain.
Rami Burstein - One of the best experts on this subject based on the ideXlab platform.
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activation of the migraine Pain Pathway by cortical spreading depression do we need more evidence
Cephalalgia, 2012Co-Authors: Dan Levy, Rami Burstein, Michael A. Moskowitz, Rodrigo NosedaAbstract:This is a commentary on article Fioravanti B, Kasasbeh A, Edelmayer R, Skinner DP Jr, Hartings JA, Burklund RD, De Felice M, French ED, Dussor GO, Dodick DW, Porreca F, Vanderah TW. Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia. 2011Jul;31(10):1090-100.
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mast cell degranulation activates a Pain Pathway underlying migraine headache
Pain, 2007Co-Authors: Dan Levy, Vanessa Kainz, Moshe Jakubowski, Rami Burstein, Andrew M StrassmanAbstract:Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal Pain Pathway believed to underlie intracranial headaches such as that of migraine.
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an association between migraine and cutaneous allodynia
Annals of Neurology, 2000Co-Authors: Rami Burstein, David Yarnitsky, Itay Gooraryeh, Bernard J Ransil, Zahid H BajwaAbstract:Recent animal studies on the mechanism of migraine show that intracranial Pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular Pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central Pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal Pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is Pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred Pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well-defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central Pain Pathway that subserves intracranial sensation.
Dan Levy - One of the best experts on this subject based on the ideXlab platform.
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activation of the migraine Pain Pathway by cortical spreading depression do we need more evidence
Cephalalgia, 2012Co-Authors: Dan Levy, Rami Burstein, Michael A. Moskowitz, Rodrigo NosedaAbstract:This is a commentary on article Fioravanti B, Kasasbeh A, Edelmayer R, Skinner DP Jr, Hartings JA, Burklund RD, De Felice M, French ED, Dussor GO, Dodick DW, Porreca F, Vanderah TW. Evaluation of cutaneous allodynia following induction of cortical spreading depression in freely moving rats. Cephalalgia. 2011Jul;31(10):1090-100.
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endogenous mechanisms underlying the activation and sensitization of meningeal nociceptors the role of immuno vascular interactions and cortical spreading depression
Current Pain and Headache Reports, 2012Co-Authors: Dan LevyAbstract:Migraine is considered one of the most prevalent neurological disorders but its underlying pathophysiology is poorly understood. Over the past two decades, it became widely accepted that activation of primary afferent nociceptive neurons that innervate the intracranial meninges serves as a key process that mediates the throbbing head Pain of migraine. Knowledge about the endogenous factors that play a role in promoting this neural process during a migraine attack slowly begins to increase, and a better understanding remains one of the holy grails in migraine research. One endogenous process, which has been invoked as a major player in the genesis of migraine Pain, is cortical spreading depression (CSD). Until recently, however, this notion was only supported by indirect evidence. Recently, electrophysiological data provided the first direct evidence that CSD is indeed a powerful endogenous process that can lead to persistent activation of meningeal nociceptors and the migraine Pain Pathway. CSD has been suggested to promote persistent sensitization and ensuing activation of meningeal nociceptors through a mechanism involving local neurogenic inflammation including the activation of mast cells and macrophages and subsequent release of inflammatory mediators. Local action of such nociceptive mediators can increase the responsiveness of meningeal nociceptors. Recent studies provided key experimental data implicating complex meningeal immuno-vascular interactions, in particular, the interplay between proinflammatory cytokines, the meningeal vasculature and immune cells, in enhancing the responses of meningeal nociceptors.
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mast cell degranulation activates a Pain Pathway underlying migraine headache
Pain, 2007Co-Authors: Dan Levy, Vanessa Kainz, Moshe Jakubowski, Rami Burstein, Andrew M StrassmanAbstract:Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal Pain Pathway believed to underlie intracranial headaches such as that of migraine.
David Julius - One of the best experts on this subject based on the ideXlab platform.
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Spider toxins activate the capsaicin receptor to produce inflammatory Pain
Nature, 2006Co-Authors: Jan Siemens, Sharleen Zhou, Rebecca Piskorowski, Tetsuro Nikai, Ellen Lumpkin, Allan Basbaum, David King, David JuliusAbstract:Bites and stings from venomous creatures can produce Pain and inflammation as part of their defensive strategy to ward off predators or competitors. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce Pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the Pain Pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit Pain and inflammation.
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pungent products from garlic activate the sensory ion channel trpa1
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Diana M Bautista, David Julius, Edward D Hogestatt, Pouya Movahed, Andrew Hinman, Helena E Axelsson, Olov Sterner, Sveneric Jordt, Peter M ZygmuntAbstract:Garlic belongs to the Allium family of plants that produce organosulfur compounds, such as allicin and diallyl disulfide (DADS), which account for their pungency and spicy aroma. Many health benefits have been ascribed to Allium extracts, including hypotensive and vasorelaxant activities. However, the molecular mechanisms underlying these effects remain unknown. Intriguingly, allicin and DADS share structural similarities with allyl isothiocyanate, the pungent ingredient in wasabi and other mustard plants that induces Pain and inflammation by activating TRPA1, an excitatory ion channel on primary sensory neurons of the Pain Pathway. Here we show that allicin and DADS excite an allyl isothiocyanate-sensitive subpopulation of sensory neurons and induce vasodilation by activating capsaicin-sensitive perivascular sensory nerve endings. Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems. These and other results suggest that garlic excites sensory neurons primarily through activation of TRPA1. Thus different plant genera, including Allium and Brassica, have developed evolutionary convergent strategies that target TRPA1 channels on sensory nerve endings to achieve chemical deterrence.
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a modular pip2 binding site as a determinant of capsaicin receptor sensitivity
Science, 2003Co-Authors: Elizabeth D Prescott, David JuliusAbstract:The capsaicin receptor (TRPV1), a heat-activated ion channel of the Pain Pathway, is sensitized by phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis after phospholipase C activation. We identify a site within the C-terminal domain of TRPV1 that is required for PIP2-mediated inhibition of channel gating. Mutations that weaken PIP2-TRPV1 interaction reduce thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region is replaced with a lipid-binding domain from PIP2-activated potassium channels remain inhibited by PIP2. The PIP2-interaction domain therefore serves as a critical determinant of thermal threshold and dynamic sensitivity range, tuning TRPV1, and thus the sensory neuron, to appropriately detect heat under normal or pathophysiological conditions.
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The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway
Annual review of neuroscience, 2001Co-Authors: Michael J. Caterina, David JuliusAbstract:▪ Abstract The detection of Painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of Pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of Pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in Pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation ...
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The capsaicin receptor: A heat-activated ion channel in the Pain Pathway
Nature, 1997Co-Authors: Michael J. Caterina, Mark A. Schumacher, Tobias A Rosen, Masahiro Tominaga, Jon D. Levine, David JuliusAbstract:Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning Pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of Painful thermal stimuli in vivo.
Gerald W Zamponi - One of the best experts on this subject based on the ideXlab platform.
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Disrupting USP5/Cav3.2 interactions protects female mice from mechanical hypersensitivity during peripheral inflammation
'Springer Science and Business Media LLC', 2018Co-Authors: Vinicius M Gadotti, Gerald W ZamponiAbstract:Abstract Cav3.2 T-type calcium channels are important for the signaling of nociceptive information in the primary afferent Pain Pathway. During neuropathy and peripheral inflammation, Cav3.2 channels are upregulated due to an increased association with the deubiquitinase USP5. Disrupting these interactions in male mice by the use of cell permeant peptides reverses mechanical and thermal hypersensitivity. Here we explore the effects of interfering with USP5 binding to the channel in female mice with synchronized estrous cycle. We show that intrathecal delivery of a cell-penetrating TAT peptide corresponding to the UBPc domain of USP5 fully reverses mechanical hypersensitivity in mice intraplantarly injected with Complete Freund’s Adjuvant. Hence, the USP5 mediated dysregulation of Cav3.2 channel activity does not exhibit sex differences, and potential therapeutics targeting this interaction should be effective in both male and female subjects
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trpv1 nociceptor activity initiates usp5 t type channel mediated plasticity
Cell Reports, 2016Co-Authors: Patrick L Stemkowski, Vinicius M Gadotti, Said Mdahoma, Agustin Garciacaballero, Ivana A Souza, Lina Chen, Shuo Huang, Stefanie Alice Gertrud Black, Zizhen Zhang, Gerald W ZamponiAbstract:Summary Peripheral nerve injury and tissue inflammation result in upregulation of the deubiquitinase USP5, thus causing a dysregulation of T-type calcium channel activity and increased Pain sensitivity. Here, we have explored the role of afferent fiber activity in this process. Conditioning stimulation of optogenetically targeted cutaneous TRPV1 expressing nociceptors, but not that of non-nociceptive fibers, resulted in enhanced expression of USP5 in mouse dorsal root ganglia and spinal dorsal horn, along with decreased withdrawal thresholds for thermal and mechanical stimuli that abated after 24 hr. This sensitization was drastically reduced by an interfering peptide that prevented USP5-Cav3.2 association. Sensitization was relieved by pharmacological block of TRPV1 afferents, but not of myelinated neurons. In spinal cord slice recordings, we could optogenetically trigger an activity-dependent potentiation of presynaptic neurotransmission in the spinal dorsal horn that relied on Cav3.2 channel activity. This neuronal-activity-induced USP5 upregulation may underlie a protective, transient sensitization of the Pain Pathway.
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synthesis and characterization of a disubstituted piperazine derivative with t type channel blocking action and analgesic properties
Molecular Pain, 2016Co-Authors: Zubaidha Pudukulatham, Fangxiong Zhang, Vinicius M Gadotti, Said Mdahoma, Prabhuling Swami, Yasinalli Tamboli, Gerald W ZamponiAbstract:BackgroundT-type calcium channels are important contributors to signaling in the primary afferent Pain Pathway and are thus important targets for the development of analgesics. It has been previous...
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calcium permeable ion channels in Pain signaling
Physical Review, 2014Co-Authors: Emmanuel Bourinet, Christophe Altier, Michael E Hildebrand, Tuan Trang, Michael W Salter, Gerald W ZamponiAbstract:The detection and processing of Painful stimuli in afferent sensory neurons is critically dependent on a wide range of different types of voltage- and ligand-gated ion channels, including sodium, calcium, and TRP channels, to name a few. The functions of these channels include the detection of mechanical and chemical insults, the generation of action potentials and regulation of neuronal firing patterns, the initiation of neurotransmitter release at dorsal horn synapses, and the ensuing activation of spinal cord neurons that project to Pain centers in the brain. Long-term changes in ion channel expression and function are thought to contribute to chronic Pain states. Many of the channels involved in the afferent Pain Pathway are permeable to calcium ions, suggesting a role in cell signaling beyond the mere generation of electrical activity. In this article, we provide a broad overview of different calcium-permeable ion channels in the afferent Pain Pathway and their role in Pain pathophysiology.