P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia
Objective Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic...
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| Veröffentlicht in: | Molecular pain 2018-01, Vol.14, p.1744806918795930-1744806918795930 |
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| container_title | Molecular pain |
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| creator | Liu, Chaoyang Zhang, Yixin Liu, Qing Jiang, Li Li, Maolin Wang, Sha Long, Ting He, Wei Kong, Xueying Qin, Guangcheng Chen, Lixue Zhang, Yuhong Zhou, Jiying |
| description | Objective
Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model.
Methods
P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis.
Results
Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons.
Conclusions
These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia–neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy. |
| doi_str_mv | 10.1177/1744806918795930 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6111400</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.1177_1744806918795930</sage_id><sourcerecordid>2094415339</sourcerecordid><originalsourceid>FETCH-LOGICAL-c528t-f95a00dd83630784e9647accf3ff3c596f5bc06b30de4ada5892058e3c3601f43</originalsourceid><addsrcrecordid>eNp1kUFv1DAQhS0EomXhzglZ4sIlMI4dJ74gbUsLSBVwWCRu1qxjBxcnTu2kUv89ibaUUonTjGa-eZ7xI-Qlg7eM1fU7VgvRgFSsqVWlODwix2upWGuP7-VH5FnOlwC8BsmekiMOTEgl4Jj4b-UPUSRr7DjFREdMkzd-xMlm6gd6tt3uOE22mwNOPg702iM9-fDlvNilXyc0-27A4IduZZH2sbWBRken5Dvb-6VHMYTY3gwen5MnDkO2L27jhnw_P9udfiouvn78fLq9KExVNlPhVIUAbdtwyaFuhFVS1GiM485xUynpqr0BuefQWoEtVo0qoWosN1wCc4JvyPuD7jjve9saO0wJgx6T7zHd6Ihe_9sZ_E_dxWstGWNi-aMNeXMrkOLVbPOke5-NDQEHG-esS1BCsIpztaCvH6CXcU7L2QslhCiV4mrdCA6USTHnZN3dMgz06qN-6OMy8ur-EXcDf4xbgOIAZOzs31f_K_gblhGkrg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2444299394</pqid></control><display><type>article</type><title>P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia</title><source>MEDLINE</source><source>Sage Journals GOLD Open Access 2024</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Liu, Chaoyang ; Zhang, Yixin ; Liu, Qing ; Jiang, Li ; Li, Maolin ; Wang, Sha ; Long, Ting ; He, Wei ; Kong, Xueying ; Qin, Guangcheng ; Chen, Lixue ; Zhang, Yuhong ; Zhou, Jiying</creator><creatorcontrib>Liu, Chaoyang ; Zhang, Yixin ; Liu, Qing ; Jiang, Li ; Li, Maolin ; Wang, Sha ; Long, Ting ; He, Wei ; Kong, Xueying ; Qin, Guangcheng ; Chen, Lixue ; Zhang, Yuhong ; Zhou, Jiying</creatorcontrib><description>Objective
Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model.
Methods
P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis.
Results
Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons.
Conclusions
These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia–neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.</description><identifier>ISSN: 1744-8069</identifier><identifier>EISSN: 1744-8069</identifier><identifier>DOI: 10.1177/1744806918795930</identifier><identifier>PMID: 30146940</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>Adenosine Triphosphate - analogs & derivatives ; Adenosine Triphosphate - toxicity ; Amino acids ; Analysis of Variance ; Animals ; Azepines - pharmacology ; Benzamides - pharmacology ; Brain-derived neurotrophic factor ; Brain-Derived Neurotrophic Factor - metabolism ; c-Fos protein ; Calcitonin ; Calcitonin gene-related peptide ; Disease Models, Animal ; Excitatory Amino Acid Transporter 3 - metabolism ; Excitatory amino acid transporters ; Headache ; Hyperalgesia ; Hyperalgesia - etiology ; Immunofluorescence ; Inflammation ; Kinases ; Localization ; Male ; Microglia ; Microglial cells ; Migraine ; Neuralgia ; Pain perception ; Peptides ; Physical Stimulation - adverse effects ; Proteins ; Rats ; Rats, Sprague-Dawley ; Receptors, Purinergic P2X4 - genetics ; Receptors, Purinergic P2X4 - metabolism ; RNA, Messenger - metabolism ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Trigeminal Neuralgia - chemically induced ; Trigeminal Neuralgia - complications ; TrkB receptors ; Tyrosine</subject><ispartof>Molecular pain, 2018-01, Vol.14, p.1744806918795930-1744806918795930</ispartof><rights>The Author(s) 2018</rights><rights>The Author(s) 2018. This work is licensed under the Creative Commons Attribution – Non-Commercial License http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2018 2018 SAGE Publications Inc., unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c528t-f95a00dd83630784e9647accf3ff3c596f5bc06b30de4ada5892058e3c3601f43</citedby><cites>FETCH-LOGICAL-c528t-f95a00dd83630784e9647accf3ff3c596f5bc06b30de4ada5892058e3c3601f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111400/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111400/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,21966,27853,27924,27925,44945,45333,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30146940$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Chaoyang</creatorcontrib><creatorcontrib>Zhang, Yixin</creatorcontrib><creatorcontrib>Liu, Qing</creatorcontrib><creatorcontrib>Jiang, Li</creatorcontrib><creatorcontrib>Li, Maolin</creatorcontrib><creatorcontrib>Wang, Sha</creatorcontrib><creatorcontrib>Long, Ting</creatorcontrib><creatorcontrib>He, Wei</creatorcontrib><creatorcontrib>Kong, Xueying</creatorcontrib><creatorcontrib>Qin, Guangcheng</creatorcontrib><creatorcontrib>Chen, Lixue</creatorcontrib><creatorcontrib>Zhang, Yuhong</creatorcontrib><creatorcontrib>Zhou, Jiying</creatorcontrib><title>P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia</title><title>Molecular pain</title><addtitle>Mol Pain</addtitle><description>Objective
Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model.
Methods
P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis.
Results
Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons.
Conclusions
These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia–neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.</description><subject>Adenosine Triphosphate - analogs & derivatives</subject><subject>Adenosine Triphosphate - toxicity</subject><subject>Amino acids</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Azepines - pharmacology</subject><subject>Benzamides - pharmacology</subject><subject>Brain-derived neurotrophic factor</subject><subject>Brain-Derived Neurotrophic Factor - metabolism</subject><subject>c-Fos protein</subject><subject>Calcitonin</subject><subject>Calcitonin gene-related peptide</subject><subject>Disease Models, Animal</subject><subject>Excitatory Amino Acid Transporter 3 - metabolism</subject><subject>Excitatory amino acid transporters</subject><subject>Headache</subject><subject>Hyperalgesia</subject><subject>Hyperalgesia - etiology</subject><subject>Immunofluorescence</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Localization</subject><subject>Male</subject><subject>Microglia</subject><subject>Microglial cells</subject><subject>Migraine</subject><subject>Neuralgia</subject><subject>Pain perception</subject><subject>Peptides</subject><subject>Physical Stimulation - adverse effects</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Purinergic P2X4 - genetics</subject><subject>Receptors, Purinergic P2X4 - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Trigeminal Neuralgia - chemically induced</subject><subject>Trigeminal Neuralgia - complications</subject><subject>TrkB receptors</subject><subject>Tyrosine</subject><issn>1744-8069</issn><issn>1744-8069</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>AFRWT</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp1kUFv1DAQhS0EomXhzglZ4sIlMI4dJ74gbUsLSBVwWCRu1qxjBxcnTu2kUv89ibaUUonTjGa-eZ7xI-Qlg7eM1fU7VgvRgFSsqVWlODwix2upWGuP7-VH5FnOlwC8BsmekiMOTEgl4Jj4b-UPUSRr7DjFREdMkzd-xMlm6gd6tt3uOE22mwNOPg702iM9-fDlvNilXyc0-27A4IduZZH2sbWBRken5Dvb-6VHMYTY3gwen5MnDkO2L27jhnw_P9udfiouvn78fLq9KExVNlPhVIUAbdtwyaFuhFVS1GiM485xUynpqr0BuefQWoEtVo0qoWosN1wCc4JvyPuD7jjve9saO0wJgx6T7zHd6Ihe_9sZ_E_dxWstGWNi-aMNeXMrkOLVbPOke5-NDQEHG-esS1BCsIpztaCvH6CXcU7L2QslhCiV4mrdCA6USTHnZN3dMgz06qN-6OMy8ur-EXcDf4xbgOIAZOzs31f_K_gblhGkrg</recordid><startdate>201801</startdate><enddate>201801</enddate><creator>Liu, Chaoyang</creator><creator>Zhang, Yixin</creator><creator>Liu, Qing</creator><creator>Jiang, Li</creator><creator>Li, Maolin</creator><creator>Wang, Sha</creator><creator>Long, Ting</creator><creator>He, Wei</creator><creator>Kong, Xueying</creator><creator>Qin, Guangcheng</creator><creator>Chen, Lixue</creator><creator>Zhang, Yuhong</creator><creator>Zhou, Jiying</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><scope>AFRWT</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201801</creationdate><title>P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia</title><author>Liu, Chaoyang ; Zhang, Yixin ; Liu, Qing ; Jiang, Li ; Li, Maolin ; Wang, Sha ; Long, Ting ; He, Wei ; Kong, Xueying ; Qin, Guangcheng ; Chen, Lixue ; Zhang, Yuhong ; Zhou, Jiying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c528t-f95a00dd83630784e9647accf3ff3c596f5bc06b30de4ada5892058e3c3601f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adenosine Triphosphate - analogs & derivatives</topic><topic>Adenosine Triphosphate - toxicity</topic><topic>Amino acids</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Azepines - pharmacology</topic><topic>Benzamides - pharmacology</topic><topic>Brain-derived neurotrophic factor</topic><topic>Brain-Derived Neurotrophic Factor - metabolism</topic><topic>c-Fos protein</topic><topic>Calcitonin</topic><topic>Calcitonin gene-related peptide</topic><topic>Disease Models, Animal</topic><topic>Excitatory Amino Acid Transporter 3 - metabolism</topic><topic>Excitatory amino acid transporters</topic><topic>Headache</topic><topic>Hyperalgesia</topic><topic>Hyperalgesia - etiology</topic><topic>Immunofluorescence</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Localization</topic><topic>Male</topic><topic>Microglia</topic><topic>Microglial cells</topic><topic>Migraine</topic><topic>Neuralgia</topic><topic>Pain perception</topic><topic>Peptides</topic><topic>Physical Stimulation - adverse effects</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Purinergic P2X4 - genetics</topic><topic>Receptors, Purinergic P2X4 - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Trigeminal Neuralgia - chemically induced</topic><topic>Trigeminal Neuralgia - complications</topic><topic>TrkB receptors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Chaoyang</creatorcontrib><creatorcontrib>Zhang, Yixin</creatorcontrib><creatorcontrib>Liu, Qing</creatorcontrib><creatorcontrib>Jiang, Li</creatorcontrib><creatorcontrib>Li, Maolin</creatorcontrib><creatorcontrib>Wang, Sha</creatorcontrib><creatorcontrib>Long, Ting</creatorcontrib><creatorcontrib>He, Wei</creatorcontrib><creatorcontrib>Kong, Xueying</creatorcontrib><creatorcontrib>Qin, Guangcheng</creatorcontrib><creatorcontrib>Chen, Lixue</creatorcontrib><creatorcontrib>Zhang, Yuhong</creatorcontrib><creatorcontrib>Zhou, Jiying</creatorcontrib><collection>Sage Journals GOLD Open Access 2024</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular pain</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Chaoyang</au><au>Zhang, Yixin</au><au>Liu, Qing</au><au>Jiang, Li</au><au>Li, Maolin</au><au>Wang, Sha</au><au>Long, Ting</au><au>He, Wei</au><au>Kong, Xueying</au><au>Qin, Guangcheng</au><au>Chen, Lixue</au><au>Zhang, Yuhong</au><au>Zhou, Jiying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia</atitle><jtitle>Molecular pain</jtitle><addtitle>Mol Pain</addtitle><date>2018-01</date><risdate>2018</risdate><volume>14</volume><spage>1744806918795930</spage><epage>1744806918795930</epage><pages>1744806918795930-1744806918795930</pages><issn>1744-8069</issn><eissn>1744-8069</eissn><abstract>Objective
Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model.
Methods
P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis.
Results
Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons.
Conclusions
These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia–neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>30146940</pmid><doi>10.1177/1744806918795930</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1744-8069 |
| ispartof | Molecular pain, 2018-01, Vol.14, p.1744806918795930-1744806918795930 |
| issn | 1744-8069 1744-8069 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6111400 |
| source | MEDLINE; Sage Journals GOLD Open Access 2024; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Triphosphate - analogs & derivatives Adenosine Triphosphate - toxicity Amino acids Analysis of Variance Animals Azepines - pharmacology Benzamides - pharmacology Brain-derived neurotrophic factor Brain-Derived Neurotrophic Factor - metabolism c-Fos protein Calcitonin Calcitonin gene-related peptide Disease Models, Animal Excitatory Amino Acid Transporter 3 - metabolism Excitatory amino acid transporters Headache Hyperalgesia Hyperalgesia - etiology Immunofluorescence Inflammation Kinases Localization Male Microglia Microglial cells Migraine Neuralgia Pain perception Peptides Physical Stimulation - adverse effects Proteins Rats Rats, Sprague-Dawley Receptors, Purinergic P2X4 - genetics Receptors, Purinergic P2X4 - metabolism RNA, Messenger - metabolism Signal Transduction - drug effects Signal Transduction - physiology Trigeminal Neuralgia - chemically induced Trigeminal Neuralgia - complications TrkB receptors Tyrosine |
| title | P2X4-receptor participates in EAAT3 regulation via BDNF-TrkB signaling in a model of trigeminal allodynia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T07%3A31%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=P2X4-receptor%20participates%20in%20EAAT3%20regulation%20via%20BDNF-TrkB%20signaling%20in%20a%20model%20of%20trigeminal%20allodynia&rft.jtitle=Molecular%20pain&rft.au=Liu,%20Chaoyang&rft.date=2018-01&rft.volume=14&rft.spage=1744806918795930&rft.epage=1744806918795930&rft.pages=1744806918795930-1744806918795930&rft.issn=1744-8069&rft.eissn=1744-8069&rft_id=info:doi/10.1177/1744806918795930&rft_dat=%3Cproquest_pubme%3E2094415339%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2444299394&rft_id=info:pmid/30146940&rft_sage_id=10.1177_1744806918795930&rfr_iscdi=true |