{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T15:42:54Z","timestamp":1789054974032,"version":"build-2803163510"},"reference-count":69,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T00:00:00Z","timestamp":1760832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Fentanyl is widely used perioperatively and illicitly as a drug of abuse. As a potent \u03bc\u2010opioid receptor agonist, fentanyl canonically inhibits excitability through G\u03b1\n                      <jats:sub>i\/o<\/jats:sub>\n                      intracellular signalling pathways resulting in analgesia and respiratory depression. However, fentanyl also paradoxically activates respiratory muscles causing a potentially lethal effect termed wooden chest syndrome. Here we show that fentanyl, but not morphine, causes a persistent tonic component of diaphragmatic muscle activity. Voltage\u2010clamp studies reveal that fentanyl directly blocks a subset of\n                      <jats:italic>ether\u2010\u00e0\u2010go\u2010go<\/jats:italic>\n                      \u2010class potassium (K\n                      <jats:sup>+<\/jats:sup>\n                      ) channels. These channels are widely expressed in spinal motoneurons, including those innervating the diaphragm. A significant fraction of these motoneurons are excited by fentanyl, concomitant with blockade of K\n                      <jats:sup>+<\/jats:sup>\n                      currents. Taken together we identified a novel off\u2010target mechanism for fentanyl action, independent of \u03bc\u2010opioid receptor activation. Our findings may inform the design of safer analgesics and generalize beyond the activation of motoneurons to other neuronal circuits implicated in fentanyl\u2010related maladaptive behaviours.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70163-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            High doses of fentanyl can cause a lethal phenotype termed \u2018wooden chest syndrome\u2019 (WCS) resulting from tonic contractions of respiratory\u2010associated musculature, precluding the ability to mechanically inflate the lungs.\n                            <jats:italic>In vivo<\/jats:italic>\n                            murine diaphragmatic electromyograms reveal a tonic component of muscle activity elicited by fentanyl, but not morphine.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Fentanyl reversibly blocks a subset of\n                            <jats:italic>ether\u2010\u00e0\u2010go\u2010go<\/jats:italic>\n                            (EAG)\u2010class potassium channels (EAG\/Kv10 and ERG\/Kv11 subclasses) expressed in HEK293 cells. Computational docking of fentanyl into cryogenic electron microscopy structures of these potassium channels predicts a binding site beneath the K\n                            <jats:sup>+<\/jats:sup>\n                            selectivity filter.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            RT\u2010PCR and RNA\u2010scope\n                            <jats:italic>in situ<\/jats:italic>\n                            experiments reveal widespread expression of EAG\/Kv10 (\n                            <jats:italic>Kcnh1<\/jats:italic>\n                            ,\n                            <jats:italic>Kcnh5<\/jats:italic>\n                            ) and ERG\/Kv11 (\n                            <jats:italic>Kcnh2<\/jats:italic>\n                            ,\n                            <jats:italic>Kcnh6<\/jats:italic>\n                            ,\n                            <jats:italic>Kcnh7<\/jats:italic>\n                            ) transcripts in cervical motoneurons, including phrenic motoneurons retrogradely labelled from the diaphragm.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            <jats:italic>In vitro<\/jats:italic>\n                            patch\u2010clamp recordings from cervical spinal sections identifies a significant fraction of phrenic motoneurons (44%) electrically excited by fentanyl, concomitant with the blockade of a non\u2010inactivating voltage\u2010gated potassium current.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Direct block of EAG potassium channels by fentanyl may contribute to WCS.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp289107","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:50:22Z","timestamp":1760921422000},"page":"582-604","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Fentanyl blockade of K\n                    <sup>+<\/sup>\n                    channels contributes to wooden chest syndrome"],"prefix":"10.1113","volume":"604","author":[{"given":"Aguan D.","family":"Wei","sequence":"first","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Burgraff","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"},{"name":"Department of Comparative Biosciences University of Wisconsin\u2010Madison  Madison WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz M.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago S.","family":"Moreira","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"},{"name":"Department of Physiology and Biophysics, Institute of Biomedical Science University of Sao Paulo  Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan\u2010Marino","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research Seattle Children's Research Institute  Seattle WA USA"},{"name":"Department of Neurological Surgery University of Washington School of Medicine, University of Washington  Seattle WA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,19]]},"reference":[{"key":"e_1_2_5_2_1","volume-title":"Provisional drug overdose death counts","author":"Ahmad F. 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