{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:03:23Z","timestamp":1784901803606,"version":"3.55.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Patients with early stage tongue cancer do not frequently complain of tongue pain. Endothelin-1 signaling is upregulated in the cancerous tongue at the early stage. We tested the hypothesis that endothelin-1 signaling contributes to the modulation of tongue nociception.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Squamous cell carcinoma cells were inoculated into the tongue under general anesthesia. Lingual mechanical sensitivity under light anesthesia using forceps from days 1 to 21 (n = 8) and the amounts of endothelin-1 and \u03b2-endorphin in the tongue on days 6, 14, and 21 (n = 5 to 7) were examined after the inoculation. The effect of endothelin-A or \u00b5-opioid receptor antagonism on the mechanical sensitivity was examined (n = 5 to 7).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Lingual mechanical sensitivity did not change at the early stage (days 5 to 6) but increased at the late stage (days 13 to 14). The amount of endothelin-1 increased (25.4\u2009\u00b1\u20094.8 pg\/ml\n                      <jats:italic toggle=\"yes\">vs.<\/jats:italic>\n                      15.0\u2009\u00b1\u20095.2 pg\/ml;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.008), and endothelin-A receptor antagonism in the tongue induced mechanical hypersensitivity at the early stage (51\u2009\u00b1\u20099\u2009g\n                      <jats:italic toggle=\"yes\">vs.<\/jats:italic>\n                      81\u2009\u00b1\u20096\u2009g;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = 0.0001). The \u00b5-opioid receptor antagonism enhanced mechanical hypersensitivity (39\u2009\u00b1\u20097\u2009g\n                      <jats:italic toggle=\"yes\">vs.<\/jats:italic>\n                      81\u2009\u00b1\u20096\u2009g;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; 0.0001), and the amount of \u03b2-endorphin increased at the early stage.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      \u03b2-Endorphin released from the cancer cells\n                      <jats:italic toggle=\"yes\">via<\/jats:italic>\n                      endothelin-1 signaling is involved in analgesic action in mechanical hypersensitivity at the early stage.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/aln.0000000000002139","type":"journal-article","created":{"date-parts":[[2018,2,15]],"date-time":"2018-02-15T11:09:00Z","timestamp":1518692940000},"page":"1207-1219","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":13,"title":["Endothelin Signaling Contributes to Modulation of Nociception in Early-stage Tongue Cancer in Rats"],"prefix":"10.1097","volume":"128","author":[{"given":"Akihiko","family":"Furukawa","sequence":"first","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamichi","family":"Shinoda","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Kubo","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuniya","family":"Honda","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Akasaka","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Yonehara","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Iwata","sequence":"additional","affiliation":[{"name":"From the Department of Clinical Medicine (A.F., R.A., Y.Y.) and the Department of Physiology (M.S., A.K., K.H., K.I.), Nihon University School of Dentistry, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20241223","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1002\/ijc.25516","article-title":"Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008.","volume":"127","year":"2010","journal-title":"Int J Cancer"},{"key":"R2-20241223","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.tripleo.2005.10.041","article-title":"Pain complaint as the first symptom of oral cancer: A descriptive study.","volume":"102","year":"2006","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod"},{"key":"R3-20241223","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1368-8375(98)00101-8","article-title":"Primary oral squamous cell carcinoma: An analysis of 703 cases in southern Taiwan.","volume":"35","year":"1999","journal-title":"Oral Oncol"},{"key":"R4-20241223","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.oraloncology.2010.03.009","article-title":"Oral cancer: Clinical features.","volume":"46","year":"2010","journal-title":"Oral Oncol"},{"key":"R5-20241223","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1254\/jphs.FP0072051","article-title":"Involvement of endothelin and ET(A) endothelin receptor in mechanical allodynia in mice given orthotopic melanoma inoculation.","volume":"106","year":"2008","journal-title":"J Pharmacol Sci"},{"key":"R6-20241223","first-page":"1757","article-title":"A role for endothelin in neuropathic pain after chronic constriction injury of the sciatic nerve.","volume":"101","year":"2005","journal-title":"Anesth Analg"},{"key":"R7-20241223","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pain.2006.02.010","article-title":"Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: Reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs.","volume":"123","year":"2006","journal-title":"Pain"},{"key":"R8-20241223","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S0026-895X(24)12544-8","article-title":"Endothelin B receptor modulates inflammatory pain and cutaneous inflammation.","volume":"56","year":"1999","journal-title":"Mol Pharmacol"},{"key":"R9-20241223","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1124\/pr.115.011833","article-title":"Endothelin.","volume":"68","year":"2016","journal-title":"Pharmacol Rev"},{"key":"R10-20241223","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.neulet.2007.03.008","article-title":"Neurosensory changes in a human model of endothelin-1 induced pain: A behavioral study.","volume":"418","year":"2007","journal-title":"Neurosci Lett"},{"key":"R11-20241223","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.jpain.2007.04.002","article-title":"Age- and sex-specific nociceptive response to endothelin-1.","volume":"8","year":"2007","journal-title":"J Pain"},{"key":"R12-20241223","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ejpain.2007.06.001","article-title":"Effect of peripheral endothelin-1 concentration on carcinoma-induced pain in mice.","volume":"12","year":"2008","journal-title":"Eur J Pain"},{"key":"R13-20241223","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.ejpain.2006.05.007","article-title":"Peripheral endothelin A receptor antagonism attenuates carcinoma-induced pain.","volume":"11","year":"2007","journal-title":"Eur J Pain"},{"key":"R14-20241223","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/nm885","article-title":"Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury.","volume":"9","year":"2003","journal-title":"Nat Med"},{"key":"R15-20241223","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals.","volume":"16","year":"1983","journal-title":"Pain"},{"key":"R16-20241223","first-page":"75","article-title":"Involvement of peripheral ionotropic glutamate receptors in orofacial thermal hyperalgesia in rats.","volume":"7","year":"2011","journal-title":"Mol Pain"},{"key":"R17-20241223","first-page":"258","article-title":"Metabotropic glutamate receptor 5 contributes to inflammatory tongue pain via extracellular signal-regulated kinase signaling in the trigeminal spinal subnucleus caudalis and upper cervical spinal cord.","volume":"9","year":"2012","journal-title":"J Neuroinflammation"},{"key":"R18-20241223","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.hrthm.2012.08.043","article-title":"Obesity results in progressive atrial structural and electrical remodeling: Implications for atrial fibrillation.","volume":"10","year":"2013","journal-title":"Heart Rhythm"},{"key":"R19-20241223","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1152\/jn.00295.2009","article-title":"Muscarinic acetylcholine receptor modulation of mu (mu) opioid receptors in adult rat sphenopalatine ganglion neurons.","volume":"103","year":"2010","journal-title":"J Neurophysiol"},{"key":"R20-20241223","doi-asserted-by":"crossref","first-page":"e34227","DOI":"10.1371\/journal.pone.0034227","article-title":"Repeated methamphetamine administration differentially alters fos expression in caudate-putamen patch and matrix compartments and nucleus accumbens.","volume":"7","year":"2012","journal-title":"PLoS One"},{"key":"R21-20241223","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1097\/j.pain.0000000000000973","article-title":"Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity.","volume":"158","year":"2017","journal-title":"Pain"},{"key":"R22-20241223","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/j.pain.0000000000000808","article-title":"Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia.","volume":"158","year":"2017","journal-title":"Pain"},{"key":"R23-20241223","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1097\/j.pain.0000000000000322","article-title":"Involvement of peripheral artemin signaling in tongue pain: Possible mechanism in burning mouth syndrome.","volume":"156","year":"2015","journal-title":"Pain"},{"key":"R24-20241223","first-page":"30","article-title":"Released lipids regulate transient receptor potential channel (TRP)-dependent oral cancer pain.","volume":"11","year":"2015","journal-title":"Mol Pain"},{"key":"R25-20241223","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.neuroscience.2011.02.007","article-title":"Central glial activation mediates cancer-induced pain in a rat facial cancer model.","volume":"180","year":"2011","journal-title":"Neuroscience"},{"key":"R26-20241223","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/j.1601-0825.2009.01563.x","article-title":"Oral squamous cell carcinoma: Overview of current understanding of aetiopathogenesis and clinical implications.","volume":"15","year":"2009","journal-title":"Oral Dis"},{"key":"R27-20241223","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1097\/00000542-200202000-00023","article-title":"Isoflurane and nociception: Spinal alpha2A adrenoceptors mediate antinociception while supraspinal alpha1 adrenoceptors mediate pronociception.","volume":"96","year":"2002","journal-title":"Anesthesiology"},{"key":"R28-20241223","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1096\/fj.10-161612","article-title":"Endothelin-1 gene regulation.","volume":"25","year":"2011","journal-title":"FASEB J"},{"key":"R29-20241223","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrc990","article-title":"The endothelin axis: Emerging role in cancer.","volume":"3","year":"2003","journal-title":"Nat Rev Cancer"},{"key":"R30-20241223","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1002\/hed.20615","article-title":"Role of activated nuclear factor-\u03baB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck.","volume":"29","year":"2007","journal-title":"Head Neck"},{"key":"R31-20241223","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1196\/annals.1352.026","article-title":"Transcription factor NF-\u03baB: A sensor for smoke and stress signals.","volume":"1056","year":"2005","journal-title":"Ann N Y Acad Sci"},{"key":"R32-20241223","doi-asserted-by":"crossref","first-page":"37570","DOI":"10.1074\/jbc.M112.398925","article-title":"Activation of nuclear factor \u03baB (NF-\u03baB) in prostate cancer is mediated by protein kinase C epsilon (PKCepsilon).","volume":"287","year":"2012","journal-title":"J Biol Chem"},{"key":"R33-20241223","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1158\/1078-0432.CCR-08-1383","article-title":"Constitutive NF-\u03baB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth.","volume":"15","year":"2009","journal-title":"Clin Cancer Res"},{"key":"R34-20241223","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1471-2121-9-6","article-title":"Phosphatidylinositol 3-kinase signaling in proliferating cells maintains an anti-apoptotic transcriptional program mediated by inhibition of FOXO and non-canonical activation of NF\u03baB transcription factors.","volume":"9","year":"2008","journal-title":"BMC Cell Biol"},{"key":"R35-20241223","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.bbrc.2016.10.085","article-title":"TAp73 upregulates IL-1\u03b2 in cancer cells: Potential biomarker in lung and breast cancer?","volume":"482","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"R36-20241223","doi-asserted-by":"crossref","first-page":"F446","DOI":"10.1152\/ajprenal.00095.2008","article-title":"Interleukin-1\u03b2, but not interleukin-6, enhances renal and systemic endothelin production in vivo.","volume":"295","year":"2008","journal-title":"Am J Physiol Renal Physiol"},{"key":"R37-20241223","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1158\/1535-7163.MCT-07-0151","article-title":"ZD4054, a specific antagonist of the endothelin A receptor, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo.","volume":"6","year":"2007","journal-title":"Mol Cancer Ther"},{"key":"R38-20241223","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1165\/ajrcmb.22.4.3795","article-title":"Studies on the expression of endothelin, its receptor subtypes, and converting enzymes in lung cancer and in human bronchial epithelium.","volume":"22","year":"2000","journal-title":"Am J Respir Cell Mol Biol"},{"key":"R39-20241223","doi-asserted-by":"crossref","first-page":"269","DOI":"10.2310\/7750.2006.00062","article-title":"Expression of endothelins and their receptors in nonmelanoma skin cancers.","volume":"10","year":"2006","journal-title":"J Cutan Med Surg"},{"key":"R40-20241223","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.jpain.2009.10.011","article-title":"Endothelin-A receptor antagonism attenuates carcinoma-induced pain through opioids in mice.","volume":"11","year":"2010","journal-title":"J Pain"},{"key":"R41-20241223","doi-asserted-by":"crossref","first-page":"5761","DOI":"10.1038\/onc.2010.352","article-title":"MicroRNA dysregulation in gastric cancer: A new player enters the game.","volume":"29","year":"2010","journal-title":"Oncogene"},{"key":"R42-20241223","doi-asserted-by":"crossref","first-page":"G275","DOI":"10.1152\/ajpgi.00344.2009","article-title":"TGF-\u03b2 downregulates PTEN via activation of NF-\u03baB in pancreatic cancer cells.","volume":"298","year":"2010","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R43-20241223","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0168-0102(00)00144-9","article-title":"Involvement of G-protein\u2013activated inwardly rectifying K (GIRK) channels in opioid-induced analgesia.","volume":"38","year":"2000","journal-title":"Neurosci Res"},{"key":"R44-20241223","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/FBP.0b013e32834eafbc","article-title":"The peripheral l-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K+ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats.","volume":"23","year":"2012","journal-title":"Behav Pharmacol"},{"key":"R45-20241223","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1073\/pnas.0308382101","article-title":"Peripheral analgesic blockade of hypernociception: Activation of arginine\/NO\/cGMP\/protein kinase G\/ATP-sensitive K+ channel pathway.","volume":"101","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"R46-20241223","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1523\/JNEUROSCI.21-03-00999.2001","article-title":"Expression and localization of endothelin receptors: Implications for the involvement of peripheral glia in nociception.","volume":"21","year":"2001","journal-title":"J Neurosci"},{"key":"R47-20241223","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.brainresbull.2009.04.012","article-title":"Endothelin-1 raises excitability and reduces potassium currents in sensory neurons.","volume":"79","year":"2009","journal-title":"Brain Res Bull"},{"key":"R48-20241223","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1177\/0022034513478428","article-title":"Endothelin receptor-mediated responses in trigeminal ganglion neurons.","volume":"92","year":"2013","journal-title":"J Dent Res"},{"key":"R49-20241223","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.neuroscience.2011.01.043","article-title":"Mechanical stimulation enhances endothelin-1 hyperalgesia.","volume":"178","year":"2011","journal-title":"Neuroscience"},{"key":"R50-20241223","doi-asserted-by":"crossref","first-page":"9426","DOI":"10.1158\/0008-5472.CAN-05-0826","article-title":"A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone.","volume":"65","year":"2005","journal-title":"Cancer Res"},{"key":"R51-20241223","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/j.neuroscience.2010.08.056","article-title":"Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain.","volume":"171","year":"2010","journal-title":"Neuroscience"},{"key":"R52-20241223","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.yexcr.2005.12.024","article-title":"Trypsins and their role in carcinoma growth.","volume":"312","year":"2006","journal-title":"Exp Cell Res"},{"key":"R53-20241223","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.pain.2010.02.010","article-title":"Serine proteases and protease-activated receptor 2-dependent allodynia: A novel cancer pain pathway.","volume":"149","year":"2010","journal-title":"Pain"}],"container-title":["Anesthesiology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/pubs.asahq.org\/anesthesiology\/article-pdf\/128\/6\/1207\/381921\/20180600_0-00030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/anesthesiology.pubs.asahq.org\/article.aspx?volume=128&page=1207","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:16:29Z","timestamp":1784898989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/ALN.0000000000002139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6]]},"references-count":53,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1097\/aln.0000000000002139","relation":{},"ISSN":["0003-3022"],"issn-type":[{"value":"0003-3022","type":"print"}],"subject":[],"published":{"date-parts":[[2018,6]]}}}