The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo
Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory...
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| description | Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg(-1); -2 h, 1 mg kg(-1) i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg(-1) fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10(-5)M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg(-1) i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules ( |
| doi_str_mv | 10.1371/journal.pone.0074943 |
| format | Article |
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This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg(-1); -2 h, 1 mg kg(-1) i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg(-1) fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10(-5)M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg(-1) i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg(-1) UFP-101 (i.v., jugular vein). Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0074943</identifier><identifier>PMID: 24086402</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Arterioles ; Cardiac arrhythmia ; Cardiovascular System - drug effects ; Cardiovascular System - pathology ; Cardiovascular System - physiopathology ; CHO Cells ; Cricetinae ; Cricetulus ; Critical care ; Endothelium ; Endotoxemia ; Fluorescein-5-isothiocyanate - metabolism ; Fluorescence ; Infection ; Inflammation ; Inflammation - metabolism ; Inflammation - pathology ; Jugular vein ; Leukocyte rolling ; Leukocyte Rolling - drug effects ; Leukocytes ; Lipopolysaccharides ; Macromolecules ; Male ; Microcirculation - drug effects ; Microscopy ; Microvasculature ; Microvessels - drug effects ; Microvessels - pathology ; Mitogens ; Narcotic Antagonists ; Narcotics ; Nociceptin ; Nociceptin Receptor ; Nociceptin receptors ; Opioid Peptides - metabolism ; Opioid Peptides - pharmacology ; Opioids ; Pain management ; Peptides ; Pharmaceutical sciences ; Rats ; Rats, Wistar ; Receptor mechanisms ; Receptors ; Receptors, Opioid - metabolism ; Recombinant Proteins - metabolism ; Rodents ; Sepsis</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e74943</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Brookes et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Brookes et al 2013 Brookes et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c717t-8fdc7298d7c883311642ad90d15f554aa8197c64df463ad2b4471cd16eca0eb33</citedby><cites>FETCH-LOGICAL-c717t-8fdc7298d7c883311642ad90d15f554aa8197c64df463ad2b4471cd16eca0eb33</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/PMC3781147/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781147/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24086402$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brookes, Zoë L S</creatorcontrib><creatorcontrib>Stedman, Emily N</creatorcontrib><creatorcontrib>Brown, Nicola J</creatorcontrib><creatorcontrib>Hebbes, Christopher P</creatorcontrib><creatorcontrib>Guerrini, Remo</creatorcontrib><creatorcontrib>Calo, Girolamo</creatorcontrib><creatorcontrib>Reilly, Charles S</creatorcontrib><creatorcontrib>Lambert, David G</creatorcontrib><title>The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg(-1); -2 h, 1 mg kg(-1) i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg(-1) fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10(-5)M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg(-1) i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg(-1) UFP-101 (i.v., jugular vein). Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.</description><subject>Analysis</subject><subject>Animals</subject><subject>Arterioles</subject><subject>Cardiac arrhythmia</subject><subject>Cardiovascular System - drug effects</subject><subject>Cardiovascular System - pathology</subject><subject>Cardiovascular System - physiopathology</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Critical care</subject><subject>Endothelium</subject><subject>Endotoxemia</subject><subject>Fluorescein-5-isothiocyanate - metabolism</subject><subject>Fluorescence</subject><subject>Infection</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - pathology</subject><subject>Jugular vein</subject><subject>Leukocyte rolling</subject><subject>Leukocyte Rolling - drug effects</subject><subject>Leukocytes</subject><subject>Lipopolysaccharides</subject><subject>Macromolecules</subject><subject>Male</subject><subject>Microcirculation - drug effects</subject><subject>Microscopy</subject><subject>Microvasculature</subject><subject>Microvessels - drug effects</subject><subject>Microvessels - pathology</subject><subject>Mitogens</subject><subject>Narcotic Antagonists</subject><subject>Narcotics</subject><subject>Nociceptin</subject><subject>Nociceptin Receptor</subject><subject>Nociceptin receptors</subject><subject>Opioid Peptides - metabolism</subject><subject>Opioid Peptides - pharmacology</subject><subject>Opioids</subject><subject>Pain management</subject><subject>Peptides</subject><subject>Pharmaceutical sciences</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptor mechanisms</subject><subject>Receptors</subject><subject>Receptors, Opioid - metabolism</subject><subject>Recombinant Proteins - metabolism</subject><subject>Rodents</subject><subject>Sepsis</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01v1DAQhiMEoqXwDxBEQkJw2K0dO3ZyQaoqFlaqVD5artas42xcOXawk4X-exw2rTaoB-RDrPEz72S-kuQlRktMOD69cYO3YJads2qJEKclJY-SY1ySbMEyRB4f3I-SZyHcIJSTgrGnyVFGUcEoyo6TX1eNSq2TWqqu1_bU-a4Bq226-pp6NRqdT8H2sHVWhz69Xn1ZYITjWzVIFdJWS-92EORgwKfa1gbaFnrtbNq71OjOdc7cBpCyAa8rFZF0p3fuefKkBhPUi-l7klyvPl6df15cXH5an59dLCTHvF8UdSV5VhYVl0VBCMaMZlCVqMJ5necUoMAll4xWNWUEqmxDKceywkxJQGpDyEnyeq_bGRfEVLMgMCU5JYRiFon1nqgc3IjO6xb8rXCgxV-D81sBvtfSKEEUh5wxyuoSUUmhRJJlQDe4hKzIaRa1PkzRhk2rKqls78HMROcvVjdi63aC8AJjyqPAu0nAu5-DCr1odZDKGLDKDeN_U0IRytiY2Zt_0Iezm6gtxARif1yMK0dRcUZjUJJxNlLLB6h4KhUbHAes1tE-c3g_c4hMr373WxhCEOvv3_6fvfwxZ98esI0C0zfBmWEcqDAH6R6M4xeCV_V9kTES437cVUOM-yGm_Yhurw4bdO90txDkD54ECx0</recordid><startdate>20130923</startdate><enddate>20130923</enddate><creator>Brookes, Zoë L S</creator><creator>Stedman, Emily N</creator><creator>Brown, Nicola J</creator><creator>Hebbes, Christopher P</creator><creator>Guerrini, Remo</creator><creator>Calo, Girolamo</creator><creator>Reilly, Charles S</creator><creator>Lambert, David G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130923</creationdate><title>The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo</title><author>Brookes, Zoë L S ; Stedman, Emily N ; Brown, Nicola J ; Hebbes, Christopher P ; Guerrini, Remo ; Calo, Girolamo ; Reilly, Charles S ; Lambert, David G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c717t-8fdc7298d7c883311642ad90d15f554aa8197c64df463ad2b4471cd16eca0eb33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Arterioles</topic><topic>Cardiac arrhythmia</topic><topic>Cardiovascular System - drug effects</topic><topic>Cardiovascular System - pathology</topic><topic>Cardiovascular System - physiopathology</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Critical care</topic><topic>Endothelium</topic><topic>Endotoxemia</topic><topic>Fluorescein-5-isothiocyanate - metabolism</topic><topic>Fluorescence</topic><topic>Infection</topic><topic>Inflammation</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - pathology</topic><topic>Jugular vein</topic><topic>Leukocyte rolling</topic><topic>Leukocyte Rolling - drug effects</topic><topic>Leukocytes</topic><topic>Lipopolysaccharides</topic><topic>Macromolecules</topic><topic>Male</topic><topic>Microcirculation - drug effects</topic><topic>Microscopy</topic><topic>Microvasculature</topic><topic>Microvessels - drug effects</topic><topic>Microvessels - pathology</topic><topic>Mitogens</topic><topic>Narcotic Antagonists</topic><topic>Narcotics</topic><topic>Nociceptin</topic><topic>Nociceptin Receptor</topic><topic>Nociceptin receptors</topic><topic>Opioid Peptides - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brookes, Zoë L S</au><au>Stedman, Emily N</au><au>Brown, Nicola J</au><au>Hebbes, Christopher P</au><au>Guerrini, Remo</au><au>Calo, Girolamo</au><au>Reilly, Charles S</au><au>Lambert, David G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-09-23</date><risdate>2013</risdate><volume>8</volume><issue>9</issue><spage>e74943</spage><pages>e74943-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia). Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg(-1); -2 h, 1 mg kg(-1) i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography. 200 nM kg(-1) fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10(-5)M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg(-1) i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg(-1) UFP-101 (i.v., jugular vein). Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24086402</pmid><doi>10.1371/journal.pone.0074943</doi><tpages>e74943</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2013-09, Vol.8 (9), p.e74943 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1435433416 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Analysis Animals Arterioles Cardiac arrhythmia Cardiovascular System - drug effects Cardiovascular System - pathology Cardiovascular System - physiopathology CHO Cells Cricetinae Cricetulus Critical care Endothelium Endotoxemia Fluorescein-5-isothiocyanate - metabolism Fluorescence Infection Inflammation Inflammation - metabolism Inflammation - pathology Jugular vein Leukocyte rolling Leukocyte Rolling - drug effects Leukocytes Lipopolysaccharides Macromolecules Male Microcirculation - drug effects Microscopy Microvasculature Microvessels - drug effects Microvessels - pathology Mitogens Narcotic Antagonists Narcotics Nociceptin Nociceptin Receptor Nociceptin receptors Opioid Peptides - metabolism Opioid Peptides - pharmacology Opioids Pain management Peptides Pharmaceutical sciences Rats Rats, Wistar Receptor mechanisms Receptors Receptors, Opioid - metabolism Recombinant Proteins - metabolism Rodents Sepsis |
| title | The nociceptin/orphanin FQ receptor antagonist UFP-101 reduces microvascular inflammation to lipopolysaccharide in vivo |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T15%3A23%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20nociceptin/orphanin%20FQ%20receptor%20antagonist%20UFP-101%20reduces%20microvascular%20inflammation%20to%20lipopolysaccharide%20in%20vivo&rft.jtitle=PloS%20one&rft.au=Brookes,%20Zo%C3%AB%20L%20S&rft.date=2013-09-23&rft.volume=8&rft.issue=9&rft.spage=e74943&rft.pages=e74943-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0074943&rft_dat=%3Cgale_plos_%3EA478132766%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1435433416&rft_id=info:pmid/24086402&rft_galeid=A478132766&rft_doaj_id=oai_doaj_org_article_3e7a56646f904c4a90c62a4b19a28542&rfr_iscdi=true |