{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:32:34Z","timestamp":1790659954860,"version":"4.1.0"},"reference-count":47,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2020,3,1]],"date-time":"2020-03-01T00:00:00Z","timestamp":1583020800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81728013"],"award-info":[{"award-number":["81728013"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671101"],"award-info":[{"award-number":["81671101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009377","name":"Education Department Foundation of Hunan Province","doi-asserted-by":"publisher","award":["19A354"],"award-info":[{"award-number":["19A354"]}],"id":[{"id":"10.13039\/100009377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2019JJ40204"],"award-info":[{"award-number":["2019JJ40204"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research and Development Programs from Hunan Province","award":["2018DK2010"],"award-info":[{"award-number":["2018DK2010"]}]},{"name":"Key Research and Development Programs from Hunan Province","award":["2018DK2013"],"award-info":[{"award-number":["2018DK2013"]}]},{"DOI":"10.13039\/501100012476","name":"Fundamental Research Funds for the Central Universities of Central South University","doi-asserted-by":"publisher","award":["2018zzts398"],"award-info":[{"award-number":["2018zzts398"]}],"id":[{"id":"10.13039\/501100012476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Neuropharmacology"],"published-print":{"date-parts":[[2020,3]]},"DOI":"10.1016\/j.neuropharm.2019.107816","type":"journal-article","created":{"date-parts":[[2019,12,23]],"date-time":"2019-12-23T17:18:25Z","timestamp":1577121505000},"page":"107816","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":24,"special_numbering":"C","title":["Hyperactive Akt-mTOR pathway as a therapeutic target for pain hypersensitivity in Cntnap2-deficient mice"],"prefix":"10.1016","volume":"165","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8328-8692","authenticated-orcid":false,"given":"Xiaoliang","family":"Xing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunyang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufan","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1870-325X","authenticated-orcid":false,"given":"Wang-Ping","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Da","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.neuropharm.2019.107816_bib1","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.ajhg.2007.09.005","article-title":"Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene","volume":"82","author":"Alarcon","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.neuropharm.2019.107816_bib2","doi-asserted-by":"crossref","first-page":"18120","DOI":"10.1073\/pnas.1216398109","article-title":"Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development","volume":"109","author":"Anderson","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.neuropharm.2019.107816_bib3","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ajhg.2007.09.015","article-title":"A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism","volume":"82","author":"Arking","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"10.1016\/j.neuropharm.2019.107816_bib4","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1158\/0008-5472.CAN-10-1769","article-title":"Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1","volume":"71","author":"Ben Sahra","year":"2011","journal-title":"Cancer Res."},{"key":"10.1016\/j.neuropharm.2019.107816_bib5","doi-asserted-by":"crossref","first-page":"602","DOI":"10.7326\/0003-4819-154-9-201105030-00336","article-title":"Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations","volume":"154","author":"Bennett","year":"2011","journal-title":"Ann. Intern. Med."},{"key":"10.1016\/j.neuropharm.2019.107816_bib6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mce.2016.11.011","article-title":"Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms","volume":"440","author":"Chen","year":"2017","journal-title":"Mol. Cell. Endocrinol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuron.2008.10.055","article-title":"Translational control of long-lasting synaptic plasticity and memory","volume":"61","author":"Costa-Mattioli","year":"2009","journal-title":"Neuron"},{"key":"10.1016\/j.neuropharm.2019.107816_bib8","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/157015912804499537","article-title":"mTOR inhibitors in tuberous sclerosis complex","volume":"10","author":"Curatolo","year":"2012","journal-title":"Curr. Neuropharmacol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib9","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.neuron.2018.01.033","article-title":"Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability","volume":"97","author":"Dawes","year":"2018","journal-title":"Neuron"},{"key":"10.1016\/j.neuropharm.2019.107816_bib10","doi-asserted-by":"crossref","DOI":"10.1177\/1744806918769426","article-title":"Involvement of pro-inflammation signal pathway in inhibitory effects of rapamycin on oxaliplatin-induced neuropathic pain","volume":"14","author":"Duan","year":"2018","journal-title":"Mol. Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/sj.mp.4002049","article-title":"CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy","volume":"13","author":"Friedman","year":"2008","journal-title":"Mol. Psychiatry"},{"key":"10.1016\/j.neuropharm.2019.107816_bib12","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nm.4335","article-title":"Metformin ameliorates core deficits in a mouse model of fragile X syndrome","volume":"23","author":"Gantois","year":"2017","journal-title":"Nat. Med."},{"key":"10.1016\/j.neuropharm.2019.107816_bib13","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.cmet.2016.12.009","article-title":"Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex","volume":"25","author":"Howell","year":"2017","journal-title":"Cell Metabol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2018.10.027","article-title":"The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice","volume":"139","author":"Inyang","year":"2019","journal-title":"Pharmacol. Res."},{"key":"10.1016\/j.neuropharm.2019.107816_bib15","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1002\/ijc.29927","article-title":"Blocking mammalian target of rapamycin alleviates bone cancer pain and morphine tolerance via micro-opioid receptor","volume":"138","author":"Jiang","year":"2016","journal-title":"Int. J. Cancer"},{"key":"10.1016\/j.neuropharm.2019.107816_bib16","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0001961","article-title":"Local translation in primary afferent fibers regulates nociception","volume":"3","author":"Jimenez-Diaz","year":"2008","journal-title":"PLoS One"},{"key":"10.1016\/j.neuropharm.2019.107816_bib17","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1073\/pnas.0503224102","article-title":"The NF1 tumor suppressor critically regulates TSC2 and mTOR","volume":"102","author":"Johannessen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.neuropharm.2019.107816_bib18","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","article-title":"Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner","volume":"11","author":"Kalender","year":"2010","journal-title":"Cell Metabol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib19","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tins.2017.11.006","article-title":"Translational control mechanisms in persistent pain","volume":"41","author":"Khoutorsky","year":"2018","journal-title":"Trends Neurosci."},{"key":"10.1016\/j.neuropharm.2019.107816_bib20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.7326\/0003-4819-137-1-200207020-00009","article-title":"Metformin: an update","volume":"137","author":"Kirpichnikov","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"10.1016\/j.neuropharm.2019.107816_bib21","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1212\/WNL.0b013e3182698cab","article-title":"Chronic pain as a manifestation of potassium channel-complex autoimmunity","volume":"79","author":"Klein","year":"2012","journal-title":"Neurology"},{"key":"10.1016\/j.neuropharm.2019.107816_bib22","doi-asserted-by":"crossref","DOI":"10.1177\/1744806917713907","article-title":"Differential involvement of reactive oxygen species in a mouse model of capsaicin-induced secondary mechanical hyperalgesia and allodynia","volume":"13","author":"La","year":"2017","journal-title":"Mol. Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib23","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1124\/jpet.113.208421","article-title":"Pharmacologic profiling of phosphoinositide 3-kinase inhibitors as mitigators of ionizing radiation-induced cell death","volume":"347","author":"Lazo","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"10.1016\/j.neuropharm.2019.107816_bib24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/YPG.0b013e32833a216f","article-title":"Association analysis of CNTNAP2 polymorphisms with autism in the Chinese Han population","volume":"20","author":"Li","year":"2010","journal-title":"Psychiatr. Genet."},{"key":"10.1016\/j.neuropharm.2019.107816_bib25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.brainres.2013.04.003","article-title":"mTOR and its downstream pathway are activated in the dorsal root ganglion and spinal cord after peripheral inflammation, but not after nerve injury","volume":"1513","author":"Liang","year":"2013","journal-title":"Brain Res."},{"key":"10.1016\/j.neuropharm.2019.107816_bib26","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ejphar.2015.06.010","article-title":"Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin","volume":"764","author":"Ma","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib27","doi-asserted-by":"crossref","first-page":"740","DOI":"10.7326\/M15-2650","article-title":"Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis","volume":"164","author":"Maruthur","year":"2016","journal-title":"Ann. Intern. Med."},{"key":"10.1016\/j.neuropharm.2019.107816_bib28","doi-asserted-by":"crossref","first-page":"6829","DOI":"10.1523\/JNEUROSCI.2663-18.2019","article-title":"Differences between dorsal root and trigeminal ganglion nociceptors in mice revealed by translational profiling","volume":"39","author":"Megat","year":"2019","journal-title":"J. Neurosci."},{"key":"10.1016\/j.neuropharm.2019.107816_bib29","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/1744-8069-7-70","article-title":"Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain","volume":"7","author":"Melemedjian","year":"2011","journal-title":"Mol. Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib30","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1097\/j.pain.0000000000000197","article-title":"Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice","volume":"156","author":"Obara","year":"2015","journal-title":"Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.cell.2011.08.040","article-title":"Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits","volume":"147","author":"Penagarikano","year":"2011","journal-title":"Cell"},{"key":"10.1016\/j.neuropharm.2019.107816_bib32","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1083\/jcb.200305018","article-title":"Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1","volume":"162","author":"Poliak","year":"2003","journal-title":"J. Cell Biol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib33","doi-asserted-by":"crossref","first-page":"13958","DOI":"10.1523\/JNEUROSCI.4383-07.2007","article-title":"Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1\/5 and mTOR","volume":"27","author":"Price","year":"2007","journal-title":"J. Neurosci."},{"key":"10.1016\/j.neuropharm.2019.107816_bib34","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1126\/science.1131693","article-title":"Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites","volume":"314","author":"Raab-Graham","year":"2006","journal-title":"Science"},{"key":"10.1016\/j.neuropharm.2019.107816_bib35","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1038\/ncomms2295","article-title":"Rapamycin reverses impaired social interaction in mouse models of tuberous sclerosis complex","volume":"3","author":"Sato","year":"2012","journal-title":"Nat. Commun."},{"key":"10.1016\/j.neuropharm.2019.107816_bib36","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0039152","article-title":"Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy","volume":"7","author":"Sha","year":"2012","journal-title":"PLoS One"},{"key":"10.1016\/j.neuropharm.2019.107816_bib37","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1523\/JNEUROSCI.3696-09.2010","article-title":"Dysregulation of mTOR signaling in fragile X syndrome","volume":"30","author":"Sharma","year":"2010","journal-title":"J. Neurosci."},{"key":"10.1016\/j.neuropharm.2019.107816_bib38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jpain.2011.12.006","article-title":"Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats","volume":"13","author":"Shih","year":"2012","journal-title":"J. Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib39","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrm3757","article-title":"Making new contacts: the mTOR network in metabolism and signalling crosstalk","volume":"15","author":"Shimobayashi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"10.1016\/j.neuropharm.2019.107816_bib40","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0057289","article-title":"Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells","volume":"8","author":"Soares","year":"2013","journal-title":"PLoS One"},{"key":"10.1016\/j.neuropharm.2019.107816_bib41","doi-asserted-by":"crossref","first-page":"6176","DOI":"10.1073\/pnas.1423205112","article-title":"Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2\/Caspr2 knockout neurons","volume":"112","author":"Varea","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.neuropharm.2019.107816_bib42","doi-asserted-by":"crossref","first-page":"88","DOI":"10.4161\/cc.8.1.7499","article-title":"The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells","volume":"8","author":"Vazquez-Martin","year":"2009","journal-title":"Cell Cycle"},{"key":"10.1016\/j.neuropharm.2019.107816_bib43","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1111\/jcmm.14033","article-title":"Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation","volume":"23","author":"Weng","year":"2019","journal-title":"J. Cell Mol. Med."},{"key":"10.1016\/j.neuropharm.2019.107816_bib44","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1038\/s41598-019-39434-5","article-title":"Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice","volume":"9","author":"Xing","year":"2019","journal-title":"Sci. Rep."},{"key":"10.1016\/j.neuropharm.2019.107816_bib45","doi-asserted-by":"crossref","DOI":"10.1177\/1744806918767549","article-title":"Resveratrol enhances IL-4 receptor-mediated anti-inflammatory effects in spinal cord and attenuates neuropathic pain following sciatic nerve injury","volume":"14","author":"Xu","year":"2018","journal-title":"Mol. Pain"},{"key":"10.1016\/j.neuropharm.2019.107816_bib47","doi-asserted-by":"crossref","DOI":"10.1080\/10408398.2010.500245","article-title":"Cross-talk between AMPK and mTOR in regulating energy balance.","author":"Xu","year":"2012","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"10.1016\/j.neuropharm.2019.107816_bib46","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.pbb.2013.07.017","article-title":"Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice","volume":"111","author":"Zhang","year":"2013","journal-title":"Pharmacol. Biochem. Behav."}],"container-title":["Neuropharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002839081930382X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002839081930382X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T07:47:30Z","timestamp":1665301650000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S002839081930382X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3]]},"references-count":47,"alternative-id":["S002839081930382X"],"URL":"https:\/\/doi.org\/10.1016\/j.neuropharm.2019.107816","relation":{},"ISSN":["0028-3908"],"issn-type":[{"value":"0028-3908","type":"print"}],"subject":[],"published":{"date-parts":[[2020,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Hyperactive Akt-mTOR pathway as a therapeutic target for pain hypersensitivity in Cntnap2-deficient mice","name":"articletitle","label":"Article Title"},{"value":"Neuropharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.neuropharm.2019.107816","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"107816"}}