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  1. Article ; Online: Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain.

    Caspi, Yaki / Mazar, Michael / Kushnir, Yishai / Mazor, Yoav / Katz, Ben / Lev, Shaya / Binshtok, Alexander M

    Pain

    2022  Volume 164, Issue 6, Page(s) 1388–1401

    Abstract: Abstract: Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal ... ...

    Abstract Abstract: Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. We show that in naive conditions, AIS in SDH inhibitory neurons is located closer to the soma than in excitatory neurons. Shortly after inducing inflammation, when the inflammatory hyperalgesia is at its peak, AIS in inhibitory neurons is shifted distally away from the soma. The shift in AIS location is accompanied by the decrease in excitability of SDH inhibitory neurons. These AIS location and excitability changes are selective for inhibitory neurons and reversible. We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.
    MeSH term(s) Animals ; Rats ; Axon Initial Segment/physiology ; Hyperalgesia ; Neurons/physiology ; Pain ; Inflammation ; Spinal Cord ; Neuronal Plasticity/physiology
    Language English
    Publishing date 2022-11-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 193153-2
    ISSN 1872-6623 ; 0304-3959
    ISSN (online) 1872-6623
    ISSN 0304-3959
    DOI 10.1097/j.pain.0000000000002829
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1158: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  2. Article ; Online: Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain.

    Leibovich, Hodaya / Buzaglo, Nahum / Tsuriel, Shlomo / Peretz, Liat / Caspi, Yaki / Katz, Ben / Lev, Shaya / Lichtstein, David / Binshtok, Alexander M

    Cells

    2020  Volume 9, Issue 4

    Abstract: An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the ... ...

    Abstract An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique-PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats' paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.
    MeSH term(s) Animals ; Behavior, Animal/physiology ; Ganglia, Spinal/injuries ; Ganglia, Spinal/physiopathology ; Hyperalgesia/complications ; Hyperalgesia/physiopathology ; Male ; Neuralgia/etiology ; Neuralgia/physiopathology ; Neurogenesis/physiology ; Neurons/pathology ; Neurons/physiology ; Rats, Sprague-Dawley ; Skin/innervation ; Skin/pathology
    Language English
    Publishing date 2020-04-18
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9041007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors.

    Barkai, Omer / Goldstein, Robert H / Caspi, Yaki / Katz, Ben / Lev, Shaya / Binshtok, Alexander M

    Frontiers in molecular neuroscience

    2017  Volume 10, Page(s) 181

    Abstract: Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological ... ...

    Abstract Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of K
    Language English
    Publishing date 2017-06-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2017.00181
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Differential cytotoxicity and intracellular calcium-signalling following activation of the calcium-permeable ion channels TRPV1 and TRPA1.

    Stueber, Thomas / Eberhardt, Mirjam J / Caspi, Yaki / Lev, Shaya / Binshtok, Alexander / Leffler, Andreas

    Cell calcium

    2017  Volume 68, Page(s) 34–44

    Abstract: Several members of the transient receptor channel (TRP) family can mediate a calcium-dependent cytotoxicity. In sensory neurons, vanilloids like capsaicin induce neurotoxicity by activating TRPV1. The closely related ion channel TRPA1 is also activated ... ...

    Abstract Several members of the transient receptor channel (TRP) family can mediate a calcium-dependent cytotoxicity. In sensory neurons, vanilloids like capsaicin induce neurotoxicity by activating TRPV1. The closely related ion channel TRPA1 is also activated by irritants, but it is unclear if and how TRPA1 mediates cell death. In the present study we explored cytotoxicity and intracellular calcium signalling resulting from activation of TRPV1 and TRPA1, either heterologously expressed in HEK 293 cells or in native mouse dorsal root ganglion (DRG) neurons. While activation of TRPV1 by the vanilloids capsaicin, resiniferatoxin and anandamide results in calcium-dependent cell death, activation by protons and the oxidant chloramine-T failed to reduce cell viability. The TRPA1-agonists acrolein, carvacrol and capsazepine all induced cytotoxicity, but this effect is independent of TRPA1. Activation of both TRPA1 and TRPV1 triggers a strong influx of external calcium, but also a strong calcium-release from intracellular stores most likely including the endoplasmic reticulum (ER). Activation of TRPV1, but not TRPA1 also results in a strong increase of mitochondrial calcium both in HEK 293 cells and mouse DRG neurons. Our data demonstrate that activation of TRPV1, but not TRPA1 mediates a calcium-dependent cell death. While both receptors mediate a release of calcium from intracellular stores, only activation of TRPV1 seems to mediate a robust and probably lethal increase in mitochondrial calcium.
    MeSH term(s) Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cell Death/drug effects ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/metabolism ; HEK293 Cells ; Humans ; Ion Channel Gating/drug effects ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/metabolism ; Recombinant Proteins/pharmacology ; TRPA1 Cation Channel/metabolism ; TRPV Cation Channels/metabolism
    Chemical Substances Recombinant Proteins ; TRPA1 Cation Channel ; TRPA1 protein, human ; TRPV Cation Channels ; TRPV1 protein, human ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2017
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 757687-0
    ISSN 1532-1991 ; 0143-4160
    ISSN (online) 1532-1991
    ISSN 0143-4160
    DOI 10.1016/j.ceca.2017.10.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1596: Show issues Location:
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  5. Article ; Online: The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-α-mediated increase in nociceptors excitability.

    Gudes, Sagi / Barkai, Omer / Caspi, Yaki / Katz, Ben / Lev, Shaya / Binshtok, Alexander M

    Journal of neurophysiology

    2014  Volume 113, Issue 2, Page(s) 601–619

    Abstract: Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to ... ...

    Abstract Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.
    MeSH term(s) Acetamides ; Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Cells, Cultured ; Computer Simulation ; Disease Models, Animal ; Electron Transport Complex IV/antagonists & inhibitors ; Electron Transport Complex IV/metabolism ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/physiopathology ; Lacosamide ; Male ; Models, Neurological ; Nociceptors/drug effects ; Nociceptors/physiology ; Pain/physiopathology ; Patch-Clamp Techniques ; Rats, Sprague-Dawley ; Sodium Channel Blockers/pharmacology ; Sodium Channels/metabolism ; Tetrodotoxin/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
    Chemical Substances Acetamides ; Sodium Channel Blockers ; Sodium Channels ; Tumor Necrosis Factor-alpha ; Tetrodotoxin (4368-28-9) ; Lacosamide (563KS2PQY5) ; Electron Transport Complex IV (EC 1.9.3.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
    Language English
    Publishing date 2014-10-29
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80161-6
    ISSN 1522-1598 ; 0022-3077
    ISSN (online) 1522-1598
    ISSN 0022-3077
    DOI 10.1152/jn.00652.2014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.224: Show issues Location:
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  6. Article: Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception.

    Nita, Iulia I / Caspi, Yaki / Gudes, Sagi / Fishman, Dimitri / Lev, Shaya / Hersfinkel, Michal / Sekler, Israel / Binshtok, Alexander M

    Biochimica et biophysica acta

    2016  Volume 1863, Issue 12, Page(s) 2868–2880

    Abstract: The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by ... ...

    Abstract The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca
    MeSH term(s) Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Calcium/metabolism ; Calcium Channels/genetics ; Calcium Channels/metabolism ; Capsaicin/pharmacology ; Egtazic Acid/analogs & derivatives ; Egtazic Acid/pharmacology ; Ganglia, Spinal/cytology ; Ganglia, Spinal/drug effects ; Ganglia, Spinal/metabolism ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Membrane Potential, Mitochondrial/physiology ; Molecular Imaging ; Nociceptors/cytology ; Nociceptors/drug effects ; Nociceptors/metabolism ; Primary Cell Culture ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Rats ; Rats, Sprague-Dawley ; Single-Cell Analysis ; Sodium/metabolism ; Sodium-Calcium Exchanger/antagonists & inhibitors ; Sodium-Calcium Exchanger/genetics ; Sodium-Calcium Exchanger/metabolism ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/genetics ; TRPV Cation Channels/metabolism
    Chemical Substances Calcium Channels ; RNA, Small Interfering ; SLC8B1 protein, human ; Sodium-Calcium Exchanger ; TRPV Cation Channels ; TRPV1 protein, human ; mitochondrial calcium uniporter ; Egtazic Acid (526U7A2651) ; Sodium (9NEZ333N27) ; 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (K22DDW77C0) ; Capsaicin (S07O44R1ZM) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2016-09-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2016.09.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.247: Show issues Location:
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  7. Article ; Online: TRPM2 Mediates Neutrophil Killing of Disseminated Tumor Cells.

    Gershkovitz, Maya / Caspi, Yaki / Fainsod-Levi, Tanya / Katz, Ben / Michaeli, Janna / Khawaled, Saleh / Lev, Shaya / Polyansky, Lola / Shaul, Merav E / Sionov, Ronit V / Cohen-Daniel, Leonor / Aqeilan, Rami I / Shaul, Yoav D / Mori, Yasuo / Karni, Rotem / Fridlender, Zvi G / Binshtok, Alexander M / Granot, Zvi

    Cancer research

    2018  Volume 78, Issue 10, Page(s) 2680–2690

    Abstract: Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally ... ...

    Abstract Neutrophils play a critical role in cancer, with both protumor and antitumor neutrophil subpopulations reported. The antitumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Because cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils use to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H
    MeSH term(s) Animals ; Breast Neoplasms/pathology ; CRISPR-Cas Systems/genetics ; Calcium/metabolism ; Calcium Channels/metabolism ; Cell Line, Tumor ; Cell Proliferation/genetics ; Female ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Inbred BALB C ; Neoplastic Cells, Circulating/immunology ; Neoplastic Cells, Circulating/pathology ; Neutrophils/immunology ; Neutrophils/metabolism ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism
    Chemical Substances Calcium Channels ; TRPM Cation Channels ; TRPM2 protein, mouse ; Hydrogen Peroxide (BBX060AN9V) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2018-02-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-17-3614
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.135/5: Show issues Location:
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