Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain
Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG syn...
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| Veröffentlicht in: | Pain (Amsterdam) 2015-11, Vol.156 (11), p.2295-2309 |
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| creator | Cheng, Chau-Fu Cheng, Jen-Kun Chen, Chih-Yang Rau, Ruey-Horng Chang, Yu-Cheng Tsaur, Meei-Ling |
| description | Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP(+)) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3(+) nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3(+) but not CGRP(+) nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain. |
| doi_str_mv | 10.1097/j.pain.0000000000000280 |
| format | Article |
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Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP(+)) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3(+) nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3(+) but not CGRP(+) nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain.</description><identifier>ISSN: 0304-3959</identifier><identifier>EISSN: 1872-6623</identifier><identifier>DOI: 10.1097/j.pain.0000000000000280</identifier><identifier>PMID: 26121254</identifier><language>eng</language><publisher>United States: International Association for the Study of Pain</publisher><subject>Animals ; Disease Models, Animal ; Disks Large Homolog 4 Protein ; Functional Laterality - physiology ; Ganglia, Spinal - drug effects ; Ganglia, Spinal - metabolism ; Gene Expression Regulation - physiology ; Hyperalgesia - etiology ; Hyperalgesia - metabolism ; Intracellular Signaling Peptides and Proteins - metabolism ; Luminescent Proteins - genetics ; Luminescent Proteins - metabolism ; Male ; Membrane Proteins - metabolism ; Nerve Growth Factor - metabolism ; Nerve Tissue Proteins - metabolism ; Neuralgia - complications ; Neuralgia - metabolism ; Neuralgia - pathology ; Neurites - pathology ; Rats ; Rats, Sprague-Dawley ; RNA, Small Interfering - metabolism ; Shal Potassium Channels - genetics ; Shal Potassium Channels - metabolism ; Spinal Puncture ; Transfection ; Tyrosine 3-Monooxygenase - metabolism</subject><ispartof>Pain (Amsterdam), 2015-11, Vol.156 (11), p.2295-2309</ispartof><rights>International Association for the Study of Pain</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4243-e5af95070fd1edef0fbc39c37cc51553ad07f779a53beb1db28ce950458d717e3</citedby><cites>FETCH-LOGICAL-c4243-e5af95070fd1edef0fbc39c37cc51553ad07f779a53beb1db28ce950458d717e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,778,782,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26121254$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cheng, Chau-Fu</creatorcontrib><creatorcontrib>Cheng, Jen-Kun</creatorcontrib><creatorcontrib>Chen, Chih-Yang</creatorcontrib><creatorcontrib>Rau, Ruey-Horng</creatorcontrib><creatorcontrib>Chang, Yu-Cheng</creatorcontrib><creatorcontrib>Tsaur, Meei-Ling</creatorcontrib><title>Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain</title><title>Pain (Amsterdam)</title><addtitle>Pain</addtitle><description>Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP(+)) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3(+) nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3(+) but not CGRP(+) nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain.</description><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Disks Large Homolog 4 Protein</subject><subject>Functional Laterality - physiology</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - metabolism</subject><subject>Gene Expression Regulation - physiology</subject><subject>Hyperalgesia - etiology</subject><subject>Hyperalgesia - metabolism</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Luminescent Proteins - genetics</subject><subject>Luminescent Proteins - metabolism</subject><subject>Male</subject><subject>Membrane Proteins - metabolism</subject><subject>Nerve Growth Factor - metabolism</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neuralgia - complications</subject><subject>Neuralgia - metabolism</subject><subject>Neuralgia - pathology</subject><subject>Neurites - pathology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Shal Potassium Channels - genetics</subject><subject>Shal Potassium Channels - metabolism</subject><subject>Spinal Puncture</subject><subject>Transfection</subject><subject>Tyrosine 3-Monooxygenase - metabolism</subject><issn>0304-3959</issn><issn>1872-6623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkM1uEzEUhS0EoqHtK4CXbBz8Mx5nlqiiUKmCTVlbHs-dxKljB9tDlA3iHXhDnqQeUhDqXfjK8nfOvT4IvWF0yWin3m2Xe-PCkv5ffEWfoQVbKU7alovnaEEFbYjoZHeGXuW8nRnOu5fojLeMMy6bBfrxGdJ3wOsUD2WDR2NLTL9__nJhmCwMOB-D2Wcg3t0DziVNtkwJMnYB2xhKMt4UqCfOEHJMR7w2Ye2dOb26fiqAS8R2k2JwFu9cSjERtzNrwPMPLtCL0fgMl4_9HH29_nB39Yncfvl4c_X-ltiGN4KANGMnqaLjwGCAkY69FZ0VylrJpBRmoGpUqjNS9NCzoecrC1XQyNWgmAJxjt6efPcpfpsgF71z2YL3JkCcsmaqBiMEZ7Ki6oTaFHNOMOp9qguno2ZUz-HrrZ5X10_Dr8rXj0OmfgfDP93ftCvQnIBD9DW2fO-nAyS9AePL5o9fK7qWcMokY_VGZmMhHgCkEpVt</recordid><startdate>20151101</startdate><enddate>20151101</enddate><creator>Cheng, Chau-Fu</creator><creator>Cheng, Jen-Kun</creator><creator>Chen, Chih-Yang</creator><creator>Rau, Ruey-Horng</creator><creator>Chang, Yu-Cheng</creator><creator>Tsaur, Meei-Ling</creator><general>International Association for the Study of Pain</general><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>7X8</scope></search><sort><creationdate>20151101</creationdate><title>Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain</title><author>Cheng, Chau-Fu ; Cheng, Jen-Kun ; Chen, Chih-Yang ; Rau, Ruey-Horng ; Chang, Yu-Cheng ; Tsaur, Meei-Ling</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4243-e5af95070fd1edef0fbc39c37cc51553ad07f779a53beb1db28ce950458d717e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Disks Large Homolog 4 Protein</topic><topic>Functional Laterality - physiology</topic><topic>Ganglia, Spinal - drug effects</topic><topic>Ganglia, Spinal - metabolism</topic><topic>Gene Expression Regulation - physiology</topic><topic>Hyperalgesia - etiology</topic><topic>Hyperalgesia - metabolism</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Luminescent Proteins - genetics</topic><topic>Luminescent Proteins - metabolism</topic><topic>Male</topic><topic>Membrane Proteins - metabolism</topic><topic>Nerve Growth Factor - metabolism</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neuralgia - complications</topic><topic>Neuralgia - metabolism</topic><topic>Neuralgia - pathology</topic><topic>Neurites - pathology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Shal Potassium Channels - genetics</topic><topic>Shal Potassium Channels - metabolism</topic><topic>Spinal Puncture</topic><topic>Transfection</topic><topic>Tyrosine 3-Monooxygenase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cheng, Chau-Fu</creatorcontrib><creatorcontrib>Cheng, Jen-Kun</creatorcontrib><creatorcontrib>Chen, Chih-Yang</creatorcontrib><creatorcontrib>Rau, Ruey-Horng</creatorcontrib><creatorcontrib>Chang, Yu-Cheng</creatorcontrib><creatorcontrib>Tsaur, Meei-Ling</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Pain (Amsterdam)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cheng, Chau-Fu</au><au>Cheng, Jen-Kun</au><au>Chen, Chih-Yang</au><au>Rau, Ruey-Horng</au><au>Chang, Yu-Cheng</au><au>Tsaur, Meei-Ling</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain</atitle><jtitle>Pain (Amsterdam)</jtitle><addtitle>Pain</addtitle><date>2015-11-01</date><risdate>2015</risdate><volume>156</volume><issue>11</issue><spage>2295</spage><epage>2309</epage><pages>2295-2309</pages><issn>0304-3959</issn><eissn>1872-6623</eissn><abstract>Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP(+)) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3(+) nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3(+) but not CGRP(+) nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain.</abstract><cop>United States</cop><pub>International Association for the Study of Pain</pub><pmid>26121254</pmid><doi>10.1097/j.pain.0000000000000280</doi><tpages>15</tpages></addata></record> |
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| subjects | Animals Disease Models, Animal Disks Large Homolog 4 Protein Functional Laterality - physiology Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism Gene Expression Regulation - physiology Hyperalgesia - etiology Hyperalgesia - metabolism Intracellular Signaling Peptides and Proteins - metabolism Luminescent Proteins - genetics Luminescent Proteins - metabolism Male Membrane Proteins - metabolism Nerve Growth Factor - metabolism Nerve Tissue Proteins - metabolism Neuralgia - complications Neuralgia - metabolism Neuralgia - pathology Neurites - pathology Rats Rats, Sprague-Dawley RNA, Small Interfering - metabolism Shal Potassium Channels - genetics Shal Potassium Channels - metabolism Spinal Puncture Transfection Tyrosine 3-Monooxygenase - metabolism |
| title | Nerve growth factor–induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain |
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