Methylmercury induces hyperalgesia/allodynia through spinal cord dorsal horn neuronal activation and subsequent somatosensory cortical circuit formation in rats
Methylmercury (MeHg) is known to cause serious neurological deficits in humans. In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking wa...
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| Veröffentlicht in: | Archives of toxicology 2021-06, Vol.95 (6), p.2151-2162 |
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| creator | Fujimura, Masatake Usuki, Fusako Nakamura, Atsushi |
| description | Methylmercury (MeHg) is known to cause serious neurological deficits in humans. In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking water) for 3 weeks. Neurological damage was observed in the primary afferent neuronal system, including the dorsal root nerve and the dorsal column of the spinal cord. The MeHg-exposed rats showed hyperalgesia/allodynia, compared to controls, as evidenced by a significant decrease in the threshold of mechanical pain evaluated using an algometer with calibrated forceps. Immunohistochemistry revealed the accumulation of activated microglia in the dorsal root nerve, dorsal column, and dorsal horn of the spinal cord. Western blot analyses of the dorsal part of the spinal cord demonstrated an increase in inflammotoxic and inflammatory cytokines and a neuronal activation related protein, phospho-CRE bunding protein (CREB). The results suggest that dorsal horn neuronal activation was mediated by inflammatory factors excreted by accumulated microglia. Furthermore, analyses of the cerebral cortex demonstrated increased expression of phospho-CREB and thrombospondin-1, which is known to be an important factor for excitatory synapse formation, specifically in the somatosensory cortical area. In addition, the expression of pre- and post-synaptic markers was increased in this cortex area. These results suggested that the new cortical circuit was wired specifically in the somatosensory cortex. In conclusion, MeHg-mediated dorsal horn neuronal activation with inflammatory microglia might induce somatosensory cortical rewiring, leading to hyperalgesia/allodynia. |
| doi_str_mv | 10.1007/s00204-021-03047-7 |
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In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking water) for 3 weeks. Neurological damage was observed in the primary afferent neuronal system, including the dorsal root nerve and the dorsal column of the spinal cord. The MeHg-exposed rats showed hyperalgesia/allodynia, compared to controls, as evidenced by a significant decrease in the threshold of mechanical pain evaluated using an algometer with calibrated forceps. Immunohistochemistry revealed the accumulation of activated microglia in the dorsal root nerve, dorsal column, and dorsal horn of the spinal cord. Western blot analyses of the dorsal part of the spinal cord demonstrated an increase in inflammotoxic and inflammatory cytokines and a neuronal activation related protein, phospho-CRE bunding protein (CREB). The results suggest that dorsal horn neuronal activation was mediated by inflammatory factors excreted by accumulated microglia. Furthermore, analyses of the cerebral cortex demonstrated increased expression of phospho-CREB and thrombospondin-1, which is known to be an important factor for excitatory synapse formation, specifically in the somatosensory cortical area. In addition, the expression of pre- and post-synaptic markers was increased in this cortex area. These results suggested that the new cortical circuit was wired specifically in the somatosensory cortex. In conclusion, MeHg-mediated dorsal horn neuronal activation with inflammatory microglia might induce somatosensory cortical rewiring, leading to hyperalgesia/allodynia.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-021-03047-7</identifier><identifier>PMID: 33847776</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Biomedical and Life Sciences ; Biomedicine ; Cerebral cortex ; Circuits ; Cortex (somatosensory) ; Cyclic AMP response element-binding protein ; Cytokines ; Cytokines - metabolism ; Dimethylmercury ; Dorsal horn ; Dorsal roots ; Drinking water ; Environmental Health ; Exposure ; Hyperalgesia ; Hyperalgesia - chemically induced ; Hyperalgesia - physiopathology ; Immunohistochemistry ; Inflammation ; Inflammation - chemically induced ; Inflammation - pathology ; Life Sciences & Biomedicine ; Male ; Medical instruments ; Mercury (metal) ; Methylmercury ; Methylmercury Compounds - toxicity ; Microglia ; Microglia - drug effects ; Microglia - pathology ; Neuralgia ; Neurological diseases ; Occupational Medicine/Industrial Medicine ; Organ Toxicity and Mechanisms ; Pain ; Pain perception ; Pharmacology/Toxicology ; Proteins ; Rats ; Rats, Sprague-Dawley ; Rewiring ; Science & Technology ; Sensory neurons ; Somatosensory Cortex - drug effects ; Somatosensory Cortex - metabolism ; Spinal cord ; Spinal Cord - drug effects ; Spinal Cord - pathology ; Spinal Cord Dorsal Horn - drug effects ; Spinal Cord Dorsal Horn - pathology ; Synaptogenesis ; Thrombospondin ; Toxicology</subject><ispartof>Archives of toxicology, 2021-06, Vol.95 (6), p.2151-2162</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>7</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000639760500005</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c441t-af9fa2684f2f28709adafa423df8dcd8ec436fe5cef59c0f4e8cd6c8e131e0a33</citedby><cites>FETCH-LOGICAL-c441t-af9fa2684f2f28709adafa423df8dcd8ec436fe5cef59c0f4e8cd6c8e131e0a33</cites><orcidid>0000-0002-8206-7078</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00204-021-03047-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00204-021-03047-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>315,781,785,27929,27930,39263,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33847776$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fujimura, Masatake</creatorcontrib><creatorcontrib>Usuki, Fusako</creatorcontrib><creatorcontrib>Nakamura, Atsushi</creatorcontrib><title>Methylmercury induces hyperalgesia/allodynia through spinal cord dorsal horn neuronal activation and subsequent somatosensory cortical circuit formation in rats</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><addtitle>ARCH TOXICOL</addtitle><addtitle>Arch Toxicol</addtitle><description>Methylmercury (MeHg) is known to cause serious neurological deficits in humans. In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking water) for 3 weeks. Neurological damage was observed in the primary afferent neuronal system, including the dorsal root nerve and the dorsal column of the spinal cord. The MeHg-exposed rats showed hyperalgesia/allodynia, compared to controls, as evidenced by a significant decrease in the threshold of mechanical pain evaluated using an algometer with calibrated forceps. Immunohistochemistry revealed the accumulation of activated microglia in the dorsal root nerve, dorsal column, and dorsal horn of the spinal cord. Western blot analyses of the dorsal part of the spinal cord demonstrated an increase in inflammotoxic and inflammatory cytokines and a neuronal activation related protein, phospho-CRE bunding protein (CREB). The results suggest that dorsal horn neuronal activation was mediated by inflammatory factors excreted by accumulated microglia. Furthermore, analyses of the cerebral cortex demonstrated increased expression of phospho-CREB and thrombospondin-1, which is known to be an important factor for excitatory synapse formation, specifically in the somatosensory cortical area. In addition, the expression of pre- and post-synaptic markers was increased in this cortex area. These results suggested that the new cortical circuit was wired specifically in the somatosensory cortex. In conclusion, MeHg-mediated dorsal horn neuronal activation with inflammatory microglia might induce somatosensory cortical rewiring, leading to hyperalgesia/allodynia.</description><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cerebral cortex</subject><subject>Circuits</subject><subject>Cortex (somatosensory)</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Dimethylmercury</subject><subject>Dorsal horn</subject><subject>Dorsal roots</subject><subject>Drinking water</subject><subject>Environmental Health</subject><subject>Exposure</subject><subject>Hyperalgesia</subject><subject>Hyperalgesia - chemically induced</subject><subject>Hyperalgesia - physiopathology</subject><subject>Immunohistochemistry</subject><subject>Inflammation</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - pathology</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Medical instruments</subject><subject>Mercury (metal)</subject><subject>Methylmercury</subject><subject>Methylmercury Compounds - 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drug effects</topic><topic>Somatosensory Cortex - metabolism</topic><topic>Spinal cord</topic><topic>Spinal Cord - drug effects</topic><topic>Spinal Cord - pathology</topic><topic>Spinal Cord Dorsal Horn - drug effects</topic><topic>Spinal Cord Dorsal Horn - pathology</topic><topic>Synaptogenesis</topic><topic>Thrombospondin</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fujimura, Masatake</creatorcontrib><creatorcontrib>Usuki, Fusako</creatorcontrib><creatorcontrib>Nakamura, Atsushi</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</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>Health and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</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 Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Research Library (Corporate)</collection><collection>Environmental Science 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>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Archives of toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fujimura, Masatake</au><au>Usuki, Fusako</au><au>Nakamura, Atsushi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methylmercury induces hyperalgesia/allodynia through spinal cord dorsal horn neuronal activation and subsequent somatosensory cortical circuit formation in rats</atitle><jtitle>Archives of toxicology</jtitle><stitle>Arch Toxicol</stitle><stitle>ARCH TOXICOL</stitle><addtitle>Arch Toxicol</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>95</volume><issue>6</issue><spage>2151</spage><epage>2162</epage><pages>2151-2162</pages><issn>0340-5761</issn><eissn>1432-0738</eissn><abstract>Methylmercury (MeHg) is known to cause serious neurological deficits in humans. In this study, we investigated the occurrence of MeHg-mediated neuropathic pain and identified the underlying pathophysiological mechanism in a rat model of MeHg exposure. Rats were exposed to MeHg (20 ppm in drinking water) for 3 weeks. Neurological damage was observed in the primary afferent neuronal system, including the dorsal root nerve and the dorsal column of the spinal cord. The MeHg-exposed rats showed hyperalgesia/allodynia, compared to controls, as evidenced by a significant decrease in the threshold of mechanical pain evaluated using an algometer with calibrated forceps. Immunohistochemistry revealed the accumulation of activated microglia in the dorsal root nerve, dorsal column, and dorsal horn of the spinal cord. Western blot analyses of the dorsal part of the spinal cord demonstrated an increase in inflammotoxic and inflammatory cytokines and a neuronal activation related protein, phospho-CRE bunding protein (CREB). The results suggest that dorsal horn neuronal activation was mediated by inflammatory factors excreted by accumulated microglia. Furthermore, analyses of the cerebral cortex demonstrated increased expression of phospho-CREB and thrombospondin-1, which is known to be an important factor for excitatory synapse formation, specifically in the somatosensory cortical area. In addition, the expression of pre- and post-synaptic markers was increased in this cortex area. These results suggested that the new cortical circuit was wired specifically in the somatosensory cortex. In conclusion, MeHg-mediated dorsal horn neuronal activation with inflammatory microglia might induce somatosensory cortical rewiring, leading to hyperalgesia/allodynia.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>33847776</pmid><doi>10.1007/s00204-021-03047-7</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-8206-7078</orcidid></addata></record> |
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| subjects | Animals Biomedical and Life Sciences Biomedicine Cerebral cortex Circuits Cortex (somatosensory) Cyclic AMP response element-binding protein Cytokines Cytokines - metabolism Dimethylmercury Dorsal horn Dorsal roots Drinking water Environmental Health Exposure Hyperalgesia Hyperalgesia - chemically induced Hyperalgesia - physiopathology Immunohistochemistry Inflammation Inflammation - chemically induced Inflammation - pathology Life Sciences & Biomedicine Male Medical instruments Mercury (metal) Methylmercury Methylmercury Compounds - toxicity Microglia Microglia - drug effects Microglia - pathology Neuralgia Neurological diseases Occupational Medicine/Industrial Medicine Organ Toxicity and Mechanisms Pain Pain perception Pharmacology/Toxicology Proteins Rats Rats, Sprague-Dawley Rewiring Science & Technology Sensory neurons Somatosensory Cortex - drug effects Somatosensory Cortex - metabolism Spinal cord Spinal Cord - drug effects Spinal Cord - pathology Spinal Cord Dorsal Horn - drug effects Spinal Cord Dorsal Horn - pathology Synaptogenesis Thrombospondin Toxicology |
| title | Methylmercury induces hyperalgesia/allodynia through spinal cord dorsal horn neuronal activation and subsequent somatosensory cortical circuit formation in rats |
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