{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:52:47Z","timestamp":1792201967975,"version":"4.4.0"},"reference-count":34,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T00:00:00Z","timestamp":1534377600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["20200"],"award-info":[{"award-number":["20200"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G0901905"],"award-info":[{"award-number":["G0901905"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["200183"],"award-info":[{"award-number":["200183"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["101054"],"award-info":[{"award-number":["101054"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Functional deletion of the\n                    <ns4:italic>Scn9a<\/ns4:italic>\n                    (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the\n                    <ns4:italic>Penk<\/ns4:italic>\n                    gene.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    We used specific \u00b5-, \u03b4- and \u03ba-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used \u00b5- and \u03b4-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in\n                    <ns4:italic>Nav1.7<\/ns4:italic>\n                    knockouts pain free phenotype. Finally, we examined the levels of\n                    <ns4:italic>Penk<\/ns4:italic>\n                    mRNA in\n                    <ns4:italic>Nfat5<\/ns4:italic>\n                    -null mutant mice, as this transcription factor binds to consensus sequences upstream of the\n                    <ns4:italic>Penk<\/ns4:italic>\n                    gene.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    The pharmacological block or deletion of both \u00b5- and \u03b4-opioid receptors was required to abolish\n                    <ns4:italic>Nav1.7<\/ns4:italic>\n                    -null opioid-related analgesia. \u03ba-opioid receptor antagonists were without effect. Enkephalins encoded by the\n                    <ns4:italic>Penk<\/ns4:italic>\n                    gene are upregulated in\n                    <ns4:italic>Nav1.7<\/ns4:italic>\n                    nulls. Deleting\n                    <ns4:italic>Nfat5<\/ns4:italic>\n                    , a transcription factor with binding motifs upstream of\n                    <ns4:italic>Penk<\/ns4:italic>\n                    , induces the same level of enkephalin mRNA expression as found in\n                    <ns4:italic>Nav1<\/ns4:italic>\n                    <ns4:italic>.7<\/ns4:italic>\n                    nulls, but without consequent analgesia. These data confirm that a combination of events linked to\n                    <ns4:italic>Scn9a<\/ns4:italic>\n                    gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in\n                    <ns4:italic>Nav1.7<\/ns4:italic>\n                    -null mouse and human mutants.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14687.1","type":"journal-article","created":{"date-parts":[[2018,8,16]],"date-time":"2018-08-16T11:10:05Z","timestamp":1534417805000},"page":"101","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Analgesia linked to Nav1.7 loss of function requires \u00b5- and \u03b4-opioid receptors"],"prefix":"10.12688","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5416-6856","authenticated-orcid":false,"given":"Vanessa","family":"Pereira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Queensta","family":"Millet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Aramburu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Lopez-Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3523-8102","authenticated-orcid":false,"given":"Claire","family":"Gaveriaux-Ruff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9166-8158","authenticated-orcid":false,"given":"John N.","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2018,8,16]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"769-780","DOI":"10.1016\/j.jpain.2015.05.002","article-title":"Estimates of pain prevalence and severity in adults: United States, 2012.","volume":"16","author":"R Nahin","year":"2015","journal-title":"J Pain."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"123-142","DOI":"10.1146\/annurev-pharmtox-010617-052554","article-title":"Wood, The Genetics of Pain: Implications for Therapeutics.","volume":"58","author":"J Sexton","year":"2018","journal-title":"Annu Rev Pharmacol Toxicol."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"975-983","DOI":"10.1517\/14728222.2016.1162295","article-title":"Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief.","volume":"20","author":"E Emery","year":"2016","journal-title":"Expert Opin Ther Targets."},{"key":"ref-4","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1795","article-title":"Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons.","volume":"3","author":"M Minett","year":"2012","journal-title":"Nat Commun."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"301-312","DOI":"10.1016\/j.celrep.2013.12.033","article-title":"Pain without nociceptors? 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.15991.r33711, C. Geoffrey Woods, Department\u00a0of\u00a0Medical Genetics, Cambridge Institute For Medical Research, Cambridge, UK, 03 Sep 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-101\/v1#referee-response-33711","order":0,"name":"referee-response-33711","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15991.r33712, Terrance P. Snutch, Michael Smith Laboratories, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada, 11 Sep 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-101\/v1#referee-response-33712","order":1,"name":"referee-response-33712","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was funded by the Wellcome Trust (grants 101054 and 200183), the Meidcal Research Council (grant G0901905) and Arthritis Research UK (grant 20200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":2,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}