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  1. Article ; Online: PAR2 activation in the dura causes acute behavioral responses and priming to glyceryl trinitrate in a mouse migraine model.

    Mason, Bianca N / Hassler, Shayne N / DeFea, Kathryn / Boitano, Scott / Vagner, Josef / Price, Theodore J / Dussor, Greg

    The journal of headache and pain

    2023  Volume 24, Issue 1, Page(s) 42

    Abstract: Background: Migraine is a severely debilitating disorder that affects millions of people worldwide. Studies have indicated that activation of protease-activated receptor-2 (PAR2) in the dura mater causes headache responses in preclinical models. It is ... ...

    Abstract Background: Migraine is a severely debilitating disorder that affects millions of people worldwide. Studies have indicated that activation of protease-activated receptor-2 (PAR2) in the dura mater causes headache responses in preclinical models. It is also well known that vasodilators such as nitric oxide (NO) donors can trigger migraine attacks in migraine patients but not controls. In the current study we examined whether activation of PAR2 in the dura causes priming to the NO donor glyceryl trinitrate (GTN).
    Methods: A preclinical behavioral model of migraine was used where stimuli (PAR2 agonists: 2at-LIGRL-NH
    Results: We found that application of the selective PAR2 agonist 2at-LIGRL-NH
    Conclusions: These results indicate that PAR2 activation in the meninges can cause acute headache behavioral responses and priming to an NO donor, and support further exploration of PAR2 as a novel therapeutic target for migraine.
    MeSH term(s) Mice ; Animals ; Nitroglycerin/pharmacology ; Leukocyte Elastase ; Receptor, PAR-2 ; Interleukin-6 ; Migraine Disorders/chemically induced ; Dura Mater ; Headache ; Disease Models, Animal
    Chemical Substances Nitroglycerin (G59M7S0WS3) ; Leukocyte Elastase (EC 3.4.21.37) ; Receptor, PAR-2 ; Interleukin-6
    Language English
    Publishing date 2023-04-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 2036768-5
    ISSN 1129-2377 ; 1129-2369
    ISSN (online) 1129-2377
    ISSN 1129-2369
    DOI 10.1186/s10194-023-01574-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5464: Show issues Location:
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  2. Article ; Online: Reactive oxygen species and lipid peroxidation inhibitors reduce mechanical sensitivity in a chronic neuropathic pain model of spinal cord injury in rats.

    Hassler, Shayne N / Johnson, Kathia M / Hulsebosch, Claire E

    Journal of neurochemistry

    2014  Volume 131, Issue 4, Page(s) 413–417

    Abstract: Chronic neuropathic pain is a common consequence of spinal cord injury (SCI), develops over time and negatively impacts quality of life, often leading to substance abuse and suicide. Recent evidence has demonstrated that reactive oxygen species (ROS) ... ...

    Abstract Chronic neuropathic pain is a common consequence of spinal cord injury (SCI), develops over time and negatively impacts quality of life, often leading to substance abuse and suicide. Recent evidence has demonstrated that reactive oxygen species (ROS) play a role in contributing to neuropathic pain in SCI animal models. This investigation examines four compounds that reduce ROS and the downstream lipid peroxidation products, apocynin, 4-oxo-tempo, U-83836E, and tirilazad, and tests if these compounds can reduce nocioceptive behaviors in chronic SCI animals. Apocynin and 4-oxo-tempo significantly reduced abnormal mechanical hypersensitivity measured in forelimbs and hindlimbs in a model of chronic SCI-induced neuropathic pain. Thus, compounds that inhibit ROS or lipid peroxidation products can be used to ameliorate chronic neuropathic pain. We propose that the application of compounds that inhibit reactive oxygen species (ROS) and related downstream molecules will also reduce the behavioral measures of chronic neuropathic pain. Injury or trauma to nervous tissue leads to increased concentrations of ROS in the surviving tissue. Further damage from ROS molecules to dorsal lamina neurons leads to membrane excitability, the physiological correlate of chronic pain. Chronic pain is difficult to treat with current analgesics and this research will provide a novel therapy for this disease.
    MeSH term(s) Acetophenones/therapeutic use ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Fatty Acids/therapeutic use ; Hyperalgesia/drug therapy ; Hyperalgesia/etiology ; Hyperalgesia/metabolism ; Injections, Spinal ; Male ; Neuralgia/complications ; Neuralgia/etiology ; Pain Measurement/drug effects ; Pain Threshold/drug effects ; Physical Stimulation/adverse effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/antagonists & inhibitors ; Spinal Cord Injuries/complications
    Chemical Substances Acetophenones ; Fatty Acids ; Reactive Oxygen Species ; lipid peroxidation inhibitor ; acetovanillone (B6J7B9UDTR)
    Language English
    Publishing date 2014-08-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/jnc.12830
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui II Zs.170: Show issues Location:
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  3. Article ; Online: Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice.

    Hassler, Shayne N / Ahmad, Fatima B / Burgos-Vega, Carolina C / Boitano, Scott / Vagner, Josef / Price, Theodore J / Dussor, Gregory

    Cephalalgia : an international journal of headache

    2018  Volume 39, Issue 1, Page(s) 111–122

    Abstract: Background: Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine ... ...

    Abstract Background: Pain is the most debilitating symptom of migraine. The cause of migraine pain likely requires activation of meningeal nociceptors. Mast cell degranulation, with subsequent meningeal nociceptor activation, has been implicated in migraine pathophysiology. Degranulating mast cells release serine proteases that can cleave and activate protease activated receptors. The purpose of these studies was to investigate whether protease activated receptor 2 is a potential generator of nociceptive input from the meninges by using selective pharmacological agents and knockout mice.
    Methods: Ratiometric Ca
    Results: 2at-LIGRL-NH
    Conclusions: Functional protease activated receptor 2 receptors are expressed on both dural afferents and fibroblasts and activation of dural protease activated receptor 2 produces migraine-like behavioral responses. Protease activated receptor 2 may link resident immune cells to meningeal nociceptor activation, driving migraine-like pain and implicating protease activated receptor 2 as a therapeutic target for migraine in humans.
    MeSH term(s) Animals ; Cell Degranulation/immunology ; Male ; Mast Cells/immunology ; Meninges/immunology ; Meninges/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mice, Knockout ; Migraine Disorders/immunology ; Migraine Disorders/metabolism ; Neurons/metabolism ; Pain/immunology ; Pain/metabolism ; Receptor, PAR-2/metabolism
    Chemical Substances F2rl1 protein, mouse ; Receptor, PAR-2
    Language English
    Publishing date 2018-05-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 604567-4
    ISSN 1468-2982 ; 0333-1024
    ISSN (online) 1468-2982
    ISSN 0333-1024
    DOI 10.1177/0333102418779548
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1645: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  4. Article ; Online: A Role for Protease Activated Receptor Type 3 (PAR3) in Nociception Demonstrated Through Development of a Novel Peptide Agonist.

    Mwirigi, Juliet / Kume, Moeno / Hassler, Shayne N / Ahmad, Ayesha / Ray, Pradipta R / Jiang, Changyu / Chamessian, Alexander / Mseeh, Nakleh / Ludwig, Breya P / Rivera, Benjamin D / Nieman, Marvin T / Van de Ven, Thomas / Ji, Ru-Rong / Dussor, Gregory / Boitano, Scott / Vagner, Josef / Price, Theodore J

    The journal of pain

    2021  Volume 22, Issue 6, Page(s) 692–706

    Abstract: The protease activated receptor (PAR) family is a group of G-protein coupled receptors (GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in homeostasis, immune ... ...

    Abstract The protease activated receptor (PAR) family is a group of G-protein coupled receptors (GPCRs) activated by proteolytic cleavage of the extracellular domain. PARs are expressed in a variety of cell types with crucial roles in homeostasis, immune responses, inflammation, and pain. PAR3 is the least researched of the four PARs, with little known about its expression and function. We sought to better understand its potential function in the peripheral sensory nervous system. Mouse single-cell RNA sequencing data demonstrates that PAR3 is widely expressed in dorsal root ganglion (DRG) neurons. Co-expression of PAR3 mRNA with other PARs was identified in various DRG neuron subpopulations, consistent with its proposed role as a coreceptor of other PARs. We developed a lipid tethered PAR3 agonist, C660, that selectively activates PAR3 by eliciting a Ca
    MeSH term(s) Adaptor Proteins, Signal Transducing/agonists ; Adaptor Proteins, Signal Transducing/physiology ; Animals ; Cell Cycle Proteins/agonists ; Cell Cycle Proteins/physiology ; Ganglia, Spinal/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mice, Knockout ; Nociception/drug effects ; Nociception/physiology
    Chemical Substances Adaptor Proteins, Signal Transducing ; Cell Cycle Proteins ; Pard3 protein, mouse
    Language English
    Publishing date 2021-01-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2018789-0
    ISSN 1528-8447 ; 1526-5900
    ISSN (online) 1528-8447
    ISSN 1526-5900
    DOI 10.1016/j.jpain.2020.12.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5237: Show issues Location:
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  5. Article ; Online: The cellular basis of protease-activated receptor 2-evoked mechanical and affective pain.

    Hassler, Shayne N / Kume, Moeno / Mwirigi, Juliet M / Ahmad, Ayesha / Shiers, Stephanie / Wangzhou, Andi / Ray, Pradipta R / Belugin, Serge N / Naik, Dhananjay K / Burton, Michael D / Vagner, Josef / Boitano, Scott / Akopian, Armen N / Dussor, Gregory / Price, Theodore J

    JCI insight

    2020  Volume 5, Issue 11

    Abstract: Protease-activated receptor 2 (PAR2) has long been implicated in inflammatory and visceral pain, but the cellular basis of PAR2-evoked pain has not been delineated. Although PAR2-evoked pain has been attributed to sensory neuron expression, RNA- ... ...

    Abstract Protease-activated receptor 2 (PAR2) has long been implicated in inflammatory and visceral pain, but the cellular basis of PAR2-evoked pain has not been delineated. Although PAR2-evoked pain has been attributed to sensory neuron expression, RNA-sequencing experiments show ambiguous F2rl1 mRNA detection. Moreover, many pharmacological tools for PAR2 are nonspecific, acting also on the Mas-related GPCR family (Mrg) that are highly enriched in sensory neurons. We sought to clarify the cellular basis of PAR2-evoked pain. We developed a PAR2-conditional knockout mouse and specifically deleted PAR2 in all sensory neurons using the PirtCre mouse line. Our behavioral findings show that PAR2 agonist-evoked mechanical hyperalgesia and facial grimacing, but not thermal hyperalgesia, are dependent on PAR2 expression in sensory neurons that project to the hind paw in male and female mice. F2rl1 mRNA is expressed in a discrete population (~4%) of mostly small-diameter sensory neurons that coexpress the Nppb and IL31ra genes. This cell population has been implicated in itch, but our work shows that PAR2 activation in these cells causes clear pain-related behaviors from the skin. Our findings show that a discrete population of DRG sensory neurons mediate PAR2-evoked pain.
    MeSH term(s) Animals ; Female ; Ganglia, Spinal/metabolism ; Ganglia, Spinal/pathology ; Hyperalgesia/genetics ; Hyperalgesia/metabolism ; Hyperalgesia/pathology ; Male ; Mice ; Mice, Knockout ; Pain/genetics ; Pain/metabolism ; Pain/pathology ; Receptor, PAR-2/genetics ; Receptor, PAR-2/metabolism ; Sensory Receptor Cells/metabolism ; Sensory Receptor Cells/pathology
    Chemical Substances F2rl1 protein, mouse ; Receptor, PAR-2
    Language English
    Publishing date 2020-06-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.137393
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Protease-activated receptor 2 activation is sufficient to induce the transition to a chronic pain state.

    Tillu, Dipti V / Hassler, Shayne N / Burgos-Vega, Carolina C / Quinn, Tammie L / Sorge, Robert E / Dussor, Gregory / Boitano, Scott / Vagner, Josef / Price, Theodore J

    Pain

    2015  Volume 156, Issue 5, Page(s) 859–867

    Abstract: Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is ... ...

    Abstract Protease-activated receptor type 2 (PAR2) is known to play an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout (PAR2(-/-)) mice. We have tested the hypothesis that specific activation of PAR2 is sufficient to induce a chronic pain state through extracellular signal-regulated kinase (ERK) signaling to protein synthesis machinery. We have further tested whether the maintenance of this chronic pain state involves a brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (trkB)/atypical protein kinase C (aPKC) signaling axis. We observed that intraplantar injection of the novel highly specific PAR2 agonist, 2-aminothiazol-4-yl-LIGRL-NH2 (2-at), evokes a long-lasting acute mechanical hypersensitivity (median effective dose ∼12 pmoles), facial grimacing, and causes robust hyperalgesic priming as revealed by a subsequent mechanical hypersensitivity and facial grimacing to prostaglandin E2 (PGE2) injection. The promechanical hypersensitivity effect of 2-at is completely absent in PAR2(-/-) mice as is hyperalgesic priming. Intraplantar injection of the upstream ERK inhibitor, U0126, and the eukaryotic initiation factor (eIF) 4F complex inhibitor, 4EGI-1, prevented the development of acute mechanical hypersensitivity and hyperalgesic priming after 2-at injection. Systemic injection of the trkB antagonist ANA-12 similarly inhibited PAR2-mediated mechanical hypersensitivity, grimacing, and hyperalgesic priming. Inhibition of aPKC (intrathecal delivery of ZIP) or trkB (systemic administration of ANA-12) after the resolution of 2-at-induced mechanical hypersensitivity reversed the maintenance of hyperalgesic priming. Hence, PAR2 activation is sufficient to induce neuronal plasticity leading to a chronic pain state, the maintenance of which is dependent on a BDNF/trkB/aPKC signaling axis.
    MeSH term(s) Animals ; Azepines/pharmacology ; Behavior, Animal/drug effects ; Benzamides/pharmacology ; Brain-Derived Neurotrophic Factor/antagonists & inhibitors ; Brain-Derived Neurotrophic Factor/metabolism ; Butadienes/pharmacology ; Chronic Pain/chemically induced ; Chronic Pain/drug therapy ; Chronic Pain/metabolism ; Chronic Pain/psychology ; Dinoprostone/pharmacology ; Disease Models, Animal ; Facial Expression ; Hydrazones/pharmacology ; Hyperalgesia/chemically induced ; Hyperalgesia/drug therapy ; Hyperalgesia/metabolism ; Hyperalgesia/psychology ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Mice, Knockout ; Nitriles/pharmacology ; Protein Kinase C/antagonists & inhibitors ; Receptor, PAR-2/agonists ; Receptor, PAR-2/antagonists & inhibitors ; Receptor, PAR-2/deficiency ; Receptor, PAR-2/metabolism ; Receptor, trkB/antagonists & inhibitors ; Signal Transduction/drug effects ; Thiazoles/pharmacology
    Chemical Substances 4EGI-1 compound ; ANA 12 compound ; Azepines ; Benzamides ; Brain-Derived Neurotrophic Factor ; Butadienes ; Hydrazones ; Nitriles ; Receptor, PAR-2 ; Thiazoles ; U 0126 ; Receptor, trkB (EC 2.7.10.1) ; PKC-3 protein (EC 2.7.11.13) ; Protein Kinase C (EC 2.7.11.13) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2015-02-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; 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.0000000000000125
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1158: Show issues Location:
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