Human sensory neurons: Membrane properties and sensitization by inflammatory mediators
Naïve hDRG neurons cultured from young adults without chronic pain are highly chemosensitive to algogens and pruritogens, and can be sensitized by inflammatory mediators. Small- to medium-size hDRG neurons exhibit AP waveforms similar to what has been described for rodent nociceptors. Cultured hDRG...
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| Veröffentlicht in: | Pain (Amsterdam) 2014-09, Vol.155 (9), p.1861-1870 |
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| creator | Davidson, Steve Copits, Bryan A. Zhang, Jingming Page, Guy Ghetti, Andrea Gereau, Robert W. |
| description | Naïve hDRG neurons cultured from young adults without chronic pain are highly chemosensitive to algogens and pruritogens, and can be sensitized by inflammatory mediators. Small- to medium-size hDRG neurons exhibit AP waveforms similar to what has been described for rodent nociceptors. Cultured hDRG neurons represent a more direct way of studying analgesic translational efficacy and confirming target validation before initiating expensive and time-consuming clinical trials.
Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons ( |
| doi_str_mv | 10.1016/j.pain.2014.06.017 |
| format | Article |
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Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. A high proportion of hDRG neurons were responsive to the algogens allyl isothiocyanate (AITC) and ATP, as well as the pruritogens histamine and chloroquine. We show that a subset of hDRG neurons responded to the inflammatory compounds bradykinin and prostaglandin E2 with action potential discharge and show evidence of sensitization including lower rheobase. Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.</description><identifier>ISSN: 0304-3959</identifier><identifier>EISSN: 1872-6623</identifier><identifier>DOI: 10.1016/j.pain.2014.06.017</identifier><identifier>PMID: 24973718</identifier><identifier>CODEN: PAINDB</identifier><language>eng</language><publisher>Philadelphia, PA: Elsevier B.V</publisher><subject>Action Potentials - drug effects ; Action Potentials - physiology ; Adenosine Triphosphate - pharmacology ; Adolescent ; Biological and medical sciences ; Bradykinin ; Bradykinin - pharmacology ; Capsaicin - pharmacology ; Cell Membrane - drug effects ; Cell Membrane - physiology ; Chloroquine - pharmacology ; Dinoprostone - pharmacology ; Dorsal root ganglia ; Female ; Fundamental and applied biological sciences. Psychology ; Ganglia, Spinal - drug effects ; Ganglia, Spinal - physiology ; Histamine - pharmacology ; Human ; Humans ; Itch ; Male ; Nociception ; Pain ; Patch-Clamp Techniques ; Sensitization ; Sensory Receptor Cells - drug effects ; Sensory Receptor Cells - physiology ; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors ; Vertebrates: nervous system and sense organs ; Young Adult</subject><ispartof>Pain (Amsterdam), 2014-09, Vol.155 (9), p.1861-1870</ispartof><rights>2014 International Association for the Study of Pain</rights><rights>International Association for the Study of Pain</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.</rights><rights>2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6002-2583fb1ddc17c7d650894daedd21f36a4a6b9a02f32fbbece41358e111b2cbfe3</citedby><cites>FETCH-LOGICAL-c6002-2583fb1ddc17c7d650894daedd21f36a4a6b9a02f32fbbece41358e111b2cbfe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28776175$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24973718$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Davidson, Steve</creatorcontrib><creatorcontrib>Copits, Bryan A.</creatorcontrib><creatorcontrib>Zhang, Jingming</creatorcontrib><creatorcontrib>Page, Guy</creatorcontrib><creatorcontrib>Ghetti, Andrea</creatorcontrib><creatorcontrib>Gereau, Robert W.</creatorcontrib><title>Human sensory neurons: Membrane properties and sensitization by inflammatory mediators</title><title>Pain (Amsterdam)</title><addtitle>Pain</addtitle><description>Naïve hDRG neurons cultured from young adults without chronic pain are highly chemosensitive to algogens and pruritogens, and can be sensitized by inflammatory mediators. Small- to medium-size hDRG neurons exhibit AP waveforms similar to what has been described for rodent nociceptors. Cultured hDRG neurons represent a more direct way of studying analgesic translational efficacy and confirming target validation before initiating expensive and time-consuming clinical trials.
Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. A high proportion of hDRG neurons were responsive to the algogens allyl isothiocyanate (AITC) and ATP, as well as the pruritogens histamine and chloroquine. We show that a subset of hDRG neurons responded to the inflammatory compounds bradykinin and prostaglandin E2 with action potential discharge and show evidence of sensitization including lower rheobase. Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.</description><subject>Action Potentials - drug effects</subject><subject>Action Potentials - physiology</subject><subject>Adenosine Triphosphate - pharmacology</subject><subject>Adolescent</subject><subject>Biological and medical sciences</subject><subject>Bradykinin</subject><subject>Bradykinin - pharmacology</subject><subject>Capsaicin - pharmacology</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - physiology</subject><subject>Chloroquine - pharmacology</subject><subject>Dinoprostone - pharmacology</subject><subject>Dorsal root ganglia</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - physiology</subject><subject>Histamine - pharmacology</subject><subject>Human</subject><subject>Humans</subject><subject>Itch</subject><subject>Male</subject><subject>Nociception</subject><subject>Pain</subject><subject>Patch-Clamp Techniques</subject><subject>Sensitization</subject><subject>Sensory Receptor Cells - drug effects</subject><subject>Sensory Receptor Cells - physiology</subject><subject>Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors</subject><subject>Vertebrates: nervous system and sense organs</subject><subject>Young Adult</subject><issn>0304-3959</issn><issn>1872-6623</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAURi0EotPCC7BA2SCxSfBf7AShSqiiFKmIDbC1HPuG8ZDYwU5aDU-P0xkKbFjZls9377UPQs8Irggm4tWumrTzFcWEV1hUmMgHaEMaSUshKHuINphhXrK2bk_QaUo7jDGltH2MTihvJZOk2aCvV8uofZHApxD3hYclBp9eFx9h7KL2UEwxTBBnB6nQ3t6BbnY_9eyCL7p94Xw_6HHU8xofwbp1l56gR70eEjw9rmfoy-W7zxdX5fWn9x8u3l6XRuRhSlo3rO-ItYZII62ocdNyq8FaSnomNNeiazWmPaN914EBTljdACGko6brgZ2h80PdaelycwN-jnpQU3SjjnsVtFP_3ni3Vd_CjeKkbjCVucDLY4EYfiyQZjW6ZGAY8tvDkhSpBcGMY95mlB5QE0NKEfr7NgSrVYjaqVWIWoUoLFQWkkPP_x7wPvLbQAZeHAGdjB76_OnGpT9cI6Ugss4cP3C3YZghpu_DcgtRbUEP81ZltViwVpRrb9zmU3lnO8feHGKQLdy4nEjGgTdZVAQzKxvc_8b_BbZLvHk</recordid><startdate>20140901</startdate><enddate>20140901</enddate><creator>Davidson, Steve</creator><creator>Copits, Bryan A.</creator><creator>Zhang, Jingming</creator><creator>Page, Guy</creator><creator>Ghetti, Andrea</creator><creator>Gereau, Robert W.</creator><general>Elsevier B.V</general><general>International Association for the Study of Pain</general><general>Elsevier</general><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140901</creationdate><title>Human sensory neurons: Membrane properties and sensitization by inflammatory mediators</title><author>Davidson, Steve ; Copits, Bryan A. ; Zhang, Jingming ; Page, Guy ; Ghetti, Andrea ; Gereau, Robert W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6002-2583fb1ddc17c7d650894daedd21f36a4a6b9a02f32fbbece41358e111b2cbfe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Action Potentials - drug effects</topic><topic>Action Potentials - physiology</topic><topic>Adenosine Triphosphate - pharmacology</topic><topic>Adolescent</topic><topic>Biological and medical sciences</topic><topic>Bradykinin</topic><topic>Bradykinin - pharmacology</topic><topic>Capsaicin - pharmacology</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - physiology</topic><topic>Chloroquine - pharmacology</topic><topic>Dinoprostone - pharmacology</topic><topic>Dorsal root ganglia</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Ganglia, Spinal - drug effects</topic><topic>Ganglia, Spinal - physiology</topic><topic>Histamine - pharmacology</topic><topic>Human</topic><topic>Humans</topic><topic>Itch</topic><topic>Male</topic><topic>Nociception</topic><topic>Pain</topic><topic>Patch-Clamp Techniques</topic><topic>Sensitization</topic><topic>Sensory Receptor Cells - drug effects</topic><topic>Sensory Receptor Cells - physiology</topic><topic>Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors</topic><topic>Vertebrates: nervous system and sense organs</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Davidson, Steve</creatorcontrib><creatorcontrib>Copits, Bryan A.</creatorcontrib><creatorcontrib>Zhang, Jingming</creatorcontrib><creatorcontrib>Page, Guy</creatorcontrib><creatorcontrib>Ghetti, Andrea</creatorcontrib><creatorcontrib>Gereau, Robert W.</creatorcontrib><collection>Pascal-Francis</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Pain (Amsterdam)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Davidson, Steve</au><au>Copits, Bryan A.</au><au>Zhang, Jingming</au><au>Page, Guy</au><au>Ghetti, Andrea</au><au>Gereau, Robert W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human sensory neurons: Membrane properties and sensitization by inflammatory mediators</atitle><jtitle>Pain (Amsterdam)</jtitle><addtitle>Pain</addtitle><date>2014-09-01</date><risdate>2014</risdate><volume>155</volume><issue>9</issue><spage>1861</spage><epage>1870</epage><pages>1861-1870</pages><issn>0304-3959</issn><eissn>1872-6623</eissn><coden>PAINDB</coden><abstract>Naïve hDRG neurons cultured from young adults without chronic pain are highly chemosensitive to algogens and pruritogens, and can be sensitized by inflammatory mediators. Small- to medium-size hDRG neurons exhibit AP waveforms similar to what has been described for rodent nociceptors. Cultured hDRG neurons represent a more direct way of studying analgesic translational efficacy and confirming target validation before initiating expensive and time-consuming clinical trials.
Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. A high proportion of hDRG neurons were responsive to the algogens allyl isothiocyanate (AITC) and ATP, as well as the pruritogens histamine and chloroquine. We show that a subset of hDRG neurons responded to the inflammatory compounds bradykinin and prostaglandin E2 with action potential discharge and show evidence of sensitization including lower rheobase. Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.</abstract><cop>Philadelphia, PA</cop><pub>Elsevier B.V</pub><pmid>24973718</pmid><doi>10.1016/j.pain.2014.06.017</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Action Potentials - drug effects Action Potentials - physiology Adenosine Triphosphate - pharmacology Adolescent Biological and medical sciences Bradykinin Bradykinin - pharmacology Capsaicin - pharmacology Cell Membrane - drug effects Cell Membrane - physiology Chloroquine - pharmacology Dinoprostone - pharmacology Dorsal root ganglia Female Fundamental and applied biological sciences. Psychology Ganglia, Spinal - drug effects Ganglia, Spinal - physiology Histamine - pharmacology Human Humans Itch Male Nociception Pain Patch-Clamp Techniques Sensitization Sensory Receptor Cells - drug effects Sensory Receptor Cells - physiology Somesthesis and somesthetic pathways (proprioception, exteroception, nociception) interoception electrolocation. Sensory receptors Vertebrates: nervous system and sense organs Young Adult |
| title | Human sensory neurons: Membrane properties and sensitization by inflammatory mediators |
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