{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:25:06Z","timestamp":1790799906936,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["20K16342"],"award-info":[{"award-number":["20K16342"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["20K09896"],"award-info":[{"award-number":["20K09896"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["19K10049"],"award-info":[{"award-number":["19K10049"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["19K19178"],"award-info":[{"award-number":["19K19178"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["18K09732"],"award-info":[{"award-number":["18K09732"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["17K11654"],"award-info":[{"award-number":["17K11654"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nihon University Multidisciplinary Research Grant","award":["18-014"],"award-info":[{"award-number":["18-014"]}]},{"DOI":"10.13039\/100007854","name":"Nihon University School of Dentistry","doi-asserted-by":"publisher","award":["Sato Fund"],"award-info":[{"award-number":["Sato Fund"]}],"id":[{"id":"10.13039\/100007854","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007854","name":"Nihon University School of Dentistry","doi-asserted-by":"publisher","award":["Uemura Fund"],"award-info":[{"award-number":["Uemura Fund"]}],"id":[{"id":"10.13039\/100007854","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007854","name":"Nihon University School of Dentistry","doi-asserted-by":"publisher","award":["Dental Research Center"],"award-info":[{"award-number":["Dental Research Center"]}],"id":[{"id":"10.13039\/100007854","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nihon University Chairman of the Board of Trustees Grant","award":["2019\u20132020"],"award-info":[{"award-number":["2019\u20132020"]}]},{"name":"Nihon University Chairman of the Board of Trustees Grant","award":["2020-2021"],"award-info":[{"award-number":["2020-2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pain is one of the most severe concerns in tongue cancer patients. However, the underlying mechanisms of tongue cancer pain are not fully understood. We investigated the molecular mechanisms of tongue cancer-induced mechanical allodynia in the tongue by squamous cell carcinoma (SCC) inoculation in rats. The head-withdrawal threshold of mechanical stimulation (MHWT) to the tongue was reduced following SCC inoculation, which was inhibited by intracisternal administration of 10Panx, an inhibitory peptide for pannexin 1 (PANX1) channels. Immunohistochemical analyses revealed that the expression of PANX1 was upregulated in the trigeminal spinal subnucleus caudalis (Vc) following SCC inoculation. The majority of PANX1 immunofluorescence was merged with ionized calcium-binding adapter molecule 1 (Iba1) fluorescence and a part of it was merged with glial fibrillary acidic protein (GFAP) fluorescence. Spike frequencies of Vc nociceptive neurons to noxious mechanical stimulation were significantly enhanced in SCC-inoculated rats, which was suppressed by intracisternal 10Panx administration. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons increased significantly in the Vc after SCC inoculation, which was inhibited by intracisternal 10Panx administration. SCC inoculation-induced MHWT reduction and increased pERK-IR Vc neuron numbers were inhibited by P2X7 purinoceptor (P2X7R) antagonism. Conversely, these effects were observed in the presence of P2X7R agonist in SCC-inoculated rats with PANX1 inhibition. SCC inoculation-induced MHWT reduction was significantly recovered by intracisternal interleukin-1 receptor antagonist administration. These observations suggest that SCC inoculation causes PANX1 upregulation in Vc microglia and adenosine triphosphate released through PANX1 sensitizes nociceptive neurons in the Vc, resulting in tongue cancer pain.<\/jats:p>","DOI":"10.3390\/ijms222111404","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T09:18:09Z","timestamp":1634894289000},"page":"11404","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pannexin 1-Mediated ATP Signaling in the Trigeminal Spinal Subnucleus Caudalis Is Involved in Tongue Cancer Pain"],"prefix":"10.3390","volume":"22","author":[{"given":"Ryo","family":"Koyama","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5859-9237","authenticated-orcid":false,"given":"Koichi","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7750-0674","authenticated-orcid":false,"given":"Yoshinori","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzuro","family":"Hitomi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Shibuta","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadayoshi","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Yonehara","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery II, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0965-6498","authenticated-orcid":false,"given":"Masamichi","family":"Shinoda","sequence":"additional","affiliation":[{"name":"Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku, Tokyo 101-8310, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.coms.2014.01.001","article-title":"Epidemiologic trends in head and neck cancer and aids in diagnosis","volume":"26","author":"Vigneswaran","year":"2014","journal-title":"Oral Maxillofac. Surg. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1177\/0022034511424156","article-title":"Biologic mechanisms of oral cancer pain and implications for clinical therapy","volume":"91","author":"Viet","year":"2012","journal-title":"J. Dent. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1158\/1535-7163.MCT-11-0123","article-title":"Nerve growth factor links oral cancer progression, pain, and cachexia","volume":"10","author":"Ye","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_4","first-page":"1011","article-title":"Role of endothelin receptor signalling in squamous cell carcinoma","volume":"40","author":"Ishimoto","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_5","first-page":"1136","article-title":"Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain","volume":"231","author":"Chichorro","year":"2006","journal-title":"Exp. Biol. Med. (Maywood)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1177\/0022034516647713","article-title":"Involvement of Microglial P2Y12 Signaling in Tongue Cancer Pain","volume":"95","author":"Tamagawa","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1111\/jnc.15004","article-title":"Pannexin-1 in the CNS: Emerging concepts in health and disease","volume":"154","author":"Yeung","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaas9846","DOI":"10.1126\/sciadv.aas9846","article-title":"Microglial pannexin-1 channel activation is a spinal determinant of joint pain","volume":"4","author":"Mousseau","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nm.4281","article-title":"Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents","volume":"23","author":"Burma","year":"2017","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1038\/sj.emboj.7601378","article-title":"Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor","volume":"25","author":"Pelegrin","year":"2006","journal-title":"EMBO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/nm.2710","article-title":"Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity","volume":"18","author":"Sorge","year":"2012","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.immuni.2017.06.020","article-title":"The P2X7 Receptor in Infection and Inflammation","volume":"47","author":"Sarti","year":"2017","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1002\/cne.21620","article-title":"Organization of pERK-immunoreactive cells in trigeminal spinal nucleus caudalis and upper cervical cord following capsaicin injection into oral and craniofacial regions in rats","volume":"507","author":"Noma","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nakaya, Y., Tsuboi, Y., Okada-Ogawa, A., Shinoda, M., Kubo, A., Chen, J.Y., Noma, N., Batbold, D., Imamura, Y., and Sessle, B.J. (2016). ERK-GluR1 phosphorylation in trigeminal spinal subnucleus caudalis neurons is involved in pain associated with dry tongue. Mol. Pain, 12.","DOI":"10.1177\/1744806916641680"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Asano, S., Hayashi, Y., Iwata, K., Okada-Ogawa, A., Hitomi, S., Shibuta, I., Imamura, Y., and Shinoda, M. (2020). Microglia-Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186834"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7667","DOI":"10.1523\/JNEUROSCI.4968-12.2013","article-title":"Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation","volume":"33","author":"Kiyomoto","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tins.2004.12.002","article-title":"Neuropathic pain and spinal microglia: A big problem from molecules in \u201csmall\u201d glia","volume":"28","author":"Tsuda","year":"2005","journal-title":"Trends Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6436","DOI":"10.1073\/pnas.0611280104","article-title":"The role of pannexin 1 hemichannels in ATP release and cell-cell communication in mouse taste buds","volume":"104","author":"Huang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.4049\/jimmunol.156.4.1531","article-title":"Mouse microglial cells express a plasma membrane pore gated by extracellular ATP","volume":"156","author":"Ferrari","year":"1996","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.brainres.2012.02.023","article-title":"Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain","volume":"1451","author":"Shibuta","year":"2012","journal-title":"Brain Res."},{"key":"ref_21","first-page":"3061","article-title":"Neuraxial Cytokines in Pain States","volume":"10","author":"Delay","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8692","DOI":"10.1523\/JNEUROSCI.23-25-08692.2003","article-title":"Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases","volume":"23","author":"Viviani","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1523\/JNEUROSCI.3338-07.2008","article-title":"Cytokine mechanisms of central sensitization: Distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord","volume":"28","author":"Kawasaki","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1002\/jnr.22103","article-title":"N-methyl-D-aspartate-stimulated ERK1\/2 signaling and the transcriptional up-regulation of plasticity-related genes are developmentally regulated following in vitro neuronal maturation","volume":"87","author":"Zhou","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jneuroim.2006.03.001","article-title":"Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons","volume":"175","author":"Lai","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/nn.4053","article-title":"Different immune cells mediate mechanical pain hypersensitivity in male and female mice","volume":"18","author":"Sorge","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_27","unstructured":"El-Naggar, A.K., Chan, J.C.K., Grandis, J.R., Takata, T., and Slootweg, P.J. (2017). WHO Classification of Head and Neck Tumours, IARC. [4th ed.]."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0885-3924(96)00302-8","article-title":"Monitoring of opioid therapy in advanced cancer pain patients","volume":"13","author":"Mercadante","year":"1997","journal-title":"J. Pain Symptom Manag."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1097\/ALN.0000000000002139","article-title":"Endothelin Signaling Contributes to Modulation of Nociception in Early-stage Tongue Cancer in Rats","volume":"128","author":"Furukawa","year":"2018","journal-title":"Anesthesiology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11404\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:03Z","timestamp":1760167263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11404"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":29,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111404"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111404","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,22]]}}}