Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn
The mechanisms underlying neuropathic pain are poorly understood. However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and...
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| Veröffentlicht in: | Glia 2010-11, Vol.58 (15), p.1838-1846 |
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| creator | Maeda, Mitsuyo Tsuda, Makoto Tozaki-Saitoh, Hidetoshi Inoue, Kazuhide Kiyama, Hiroshi |
| description | The mechanisms underlying neuropathic pain are poorly understood. However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural components in the dorsal horn using electron microscopy. Microglia were more abundantly localized in layers II–III of the dorsal horn than in other areas, and some of them adhered to and engulfed both injured and uninjured myelinated axons. This microglial engulfment was rarely observed in the normal dorsal horn, and the number of microglia attached to myelinated axons was markedly increased on postoperative day 7 on the operated side. However, after blocking the P2Y12 ATP receptor in microglia by intrathecal administration of its antagonist, AR‐C69931MX, the increase in the number of microglia attached to myelinated axons, as well as the development of tactile allodynia, were markedly suppressed, although the number of activated microglia did not change remarkably. These results indicate that engulfment of myelinated axons by activated microglia via P2Y12 signaling in the dorsal horn may be a critical event in the pathogenesis of neuropathic pain. © 2010 Wiley‐Liss, Inc. |
| doi_str_mv | 10.1002/glia.21053 |
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However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural components in the dorsal horn using electron microscopy. Microglia were more abundantly localized in layers II–III of the dorsal horn than in other areas, and some of them adhered to and engulfed both injured and uninjured myelinated axons. This microglial engulfment was rarely observed in the normal dorsal horn, and the number of microglia attached to myelinated axons was markedly increased on postoperative day 7 on the operated side. However, after blocking the P2Y12 ATP receptor in microglia by intrathecal administration of its antagonist, AR‐C69931MX, the increase in the number of microglia attached to myelinated axons, as well as the development of tactile allodynia, were markedly suppressed, although the number of activated microglia did not change remarkably. 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However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural components in the dorsal horn using electron microscopy. Microglia were more abundantly localized in layers II–III of the dorsal horn than in other areas, and some of them adhered to and engulfed both injured and uninjured myelinated axons. This microglial engulfment was rarely observed in the normal dorsal horn, and the number of microglia attached to myelinated axons was markedly increased on postoperative day 7 on the operated side. However, after blocking the P2Y12 ATP receptor in microglia by intrathecal administration of its antagonist, AR‐C69931MX, the increase in the number of microglia attached to myelinated axons, as well as the development of tactile allodynia, were markedly suppressed, although the number of activated microglia did not change remarkably. These results indicate that engulfment of myelinated axons by activated microglia via P2Y12 signaling in the dorsal horn may be a critical event in the pathogenesis of neuropathic pain. © 2010 Wiley‐Liss, Inc.</description><subject>Adenosine Monophosphate - analogs & derivatives</subject><subject>Adenosine Monophosphate - pharmacology</subject><subject>Animals</subject><subject>Axons</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Disease Models, Animal</subject><subject>Dorsal horn</subject><subject>Electron microscopy</subject><subject>Functional Laterality</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - physiology</subject><subject>Hyperalgesia - drug therapy</subject><subject>Hyperalgesia - metabolism</subject><subject>Male</subject><subject>Microfilament Proteins</subject><subject>Microglia</subject><subject>Microglia - pathology</subject><subject>Microglia - ultrastructure</subject><subject>Microscopy, Immunoelectron - methods</subject><subject>Nerve Fibers, Myelinated - pathology</subject><subject>Nerve Fibers, Myelinated - ultrastructure</subject><subject>nerve injury</subject><subject>Nerves</subject><subject>Neuralgia - pathology</subject><subject>neuropathic pain</subject><subject>Neuropathy</subject><subject>P2Y12</subject><subject>Pain perception</subject><subject>peripheral nerve</subject><subject>Posterior Horn Cells - pathology</subject><subject>Posterior Horn Cells - ultrastructure</subject><subject>Purine P2 receptors</subject><subject>Purinergic P2Y Receptor Antagonists - pharmacology</subject><subject>rat</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Purinergic P2Y12 - genetics</subject><subject>Receptors, Purinergic P2Y12 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Spinal Cord - pathology</subject><subject>Spinal Nerves - pathology</subject><subject>Tactile stimuli</subject><issn>0894-1491</issn><issn>1098-1136</issn><issn>1098-1136</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0cFO3DAQBmCralW20EsfoPKtCCngcWI7PsKqbJFW0EMR6snyJpPFNHEWO6Hs29dhgSM9WJblb35pZgj5AuwYGOMn69bZYw5M5O_IDJguM4BcviczVuoig0LDHvkU4x1jkB7qI9njTEohJJuR-0sMD0idvxvDNrPV4B7sgDXtXBX6KZiiX49tQ7stts4__dnH3sdUQi39yX8Dp9GtvU2_66zGDfoa_UA76z2GSQ23SOs-RNvS2z74A_KhsW3Ez8_3Prk-__5r_iNbXi0u5qfLrCp0macWLFcSc1EjMCjrRpQNWsWmNmElgDeisgwblboqOErBqqKo1arkCa1A5fvk2y53E_r7EeNgOhcrbFvrsR-jUUJBOrpI8vBNmVjJc62U_j9loLRUQstEj3Y0DTLGgI3ZBNfZsE3ITHsz03jN094S_vqcO646rF_py6ISgB3461rcvhFlFsuL05fQbFfj4oCPrzU2_DFS5UqYm8uFKc7mWpypubnJ_wEG3LCM</recordid><startdate>20101115</startdate><enddate>20101115</enddate><creator>Maeda, Mitsuyo</creator><creator>Tsuda, Makoto</creator><creator>Tozaki-Saitoh, Hidetoshi</creator><creator>Inoue, Kazuhide</creator><creator>Kiyama, Hiroshi</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</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>7TK</scope><scope>7X8</scope></search><sort><creationdate>20101115</creationdate><title>Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn</title><author>Maeda, Mitsuyo ; Tsuda, Makoto ; Tozaki-Saitoh, Hidetoshi ; Inoue, Kazuhide ; Kiyama, Hiroshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4983-11a276e35de1018df58fea7010531b512f5ca0ef700142e650c44d7b82a70b173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenosine Monophosphate - analogs & derivatives</topic><topic>Adenosine Monophosphate - pharmacology</topic><topic>Animals</topic><topic>Axons</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Disease Models, Animal</topic><topic>Dorsal horn</topic><topic>Electron microscopy</topic><topic>Functional Laterality</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Expression Regulation - physiology</topic><topic>Hyperalgesia - drug therapy</topic><topic>Hyperalgesia - metabolism</topic><topic>Male</topic><topic>Microfilament Proteins</topic><topic>Microglia</topic><topic>Microglia - pathology</topic><topic>Microglia - ultrastructure</topic><topic>Microscopy, Immunoelectron - methods</topic><topic>Nerve Fibers, Myelinated - pathology</topic><topic>Nerve Fibers, Myelinated - ultrastructure</topic><topic>nerve injury</topic><topic>Nerves</topic><topic>Neuralgia - pathology</topic><topic>neuropathic pain</topic><topic>Neuropathy</topic><topic>P2Y12</topic><topic>Pain perception</topic><topic>peripheral nerve</topic><topic>Posterior Horn Cells - pathology</topic><topic>Posterior Horn Cells - ultrastructure</topic><topic>Purine P2 receptors</topic><topic>Purinergic P2Y Receptor Antagonists - pharmacology</topic><topic>rat</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Purinergic P2Y12 - genetics</topic><topic>Receptors, Purinergic P2Y12 - metabolism</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Spinal Cord - pathology</topic><topic>Spinal Nerves - pathology</topic><topic>Tactile stimuli</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maeda, Mitsuyo</creatorcontrib><creatorcontrib>Tsuda, Makoto</creatorcontrib><creatorcontrib>Tozaki-Saitoh, Hidetoshi</creatorcontrib><creatorcontrib>Inoue, Kazuhide</creatorcontrib><creatorcontrib>Kiyama, Hiroshi</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Glia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maeda, Mitsuyo</au><au>Tsuda, Makoto</au><au>Tozaki-Saitoh, Hidetoshi</au><au>Inoue, Kazuhide</au><au>Kiyama, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn</atitle><jtitle>Glia</jtitle><addtitle>Glia</addtitle><date>2010-11-15</date><risdate>2010</risdate><volume>58</volume><issue>15</issue><spage>1838</spage><epage>1846</epage><pages>1838-1846</pages><issn>0894-1491</issn><issn>1098-1136</issn><eissn>1098-1136</eissn><abstract>The mechanisms underlying neuropathic pain are poorly understood. However, several studies have implied a role for reactive microglia located in the dorsal horn in neuropathic pain. To clarify the roles of activated microglia in neuropathic pain, we investigated the interactions among microglia and other neural components in the dorsal horn using electron microscopy. Microglia were more abundantly localized in layers II–III of the dorsal horn than in other areas, and some of them adhered to and engulfed both injured and uninjured myelinated axons. This microglial engulfment was rarely observed in the normal dorsal horn, and the number of microglia attached to myelinated axons was markedly increased on postoperative day 7 on the operated side. However, after blocking the P2Y12 ATP receptor in microglia by intrathecal administration of its antagonist, AR‐C69931MX, the increase in the number of microglia attached to myelinated axons, as well as the development of tactile allodynia, were markedly suppressed, although the number of activated microglia did not change remarkably. These results indicate that engulfment of myelinated axons by activated microglia via P2Y12 signaling in the dorsal horn may be a critical event in the pathogenesis of neuropathic pain. © 2010 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>20665560</pmid><doi>10.1002/glia.21053</doi><tpages>9</tpages></addata></record> |
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| subjects | Adenosine Monophosphate - analogs & derivatives Adenosine Monophosphate - pharmacology Animals Axons Calcium-Binding Proteins - metabolism Cell Proliferation - drug effects Disease Models, Animal Dorsal horn Electron microscopy Functional Laterality Gene Expression Regulation - drug effects Gene Expression Regulation - physiology Hyperalgesia - drug therapy Hyperalgesia - metabolism Male Microfilament Proteins Microglia Microglia - pathology Microglia - ultrastructure Microscopy, Immunoelectron - methods Nerve Fibers, Myelinated - pathology Nerve Fibers, Myelinated - ultrastructure nerve injury Nerves Neuralgia - pathology neuropathic pain Neuropathy P2Y12 Pain perception peripheral nerve Posterior Horn Cells - pathology Posterior Horn Cells - ultrastructure Purine P2 receptors Purinergic P2Y Receptor Antagonists - pharmacology rat Rats Rats, Wistar Receptors, Purinergic P2Y12 - genetics Receptors, Purinergic P2Y12 - metabolism Signal Transduction - drug effects Signal Transduction - physiology Spinal Cord - pathology Spinal Nerves - pathology Tactile stimuli |
| title | Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn |
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