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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,21]]},"abstract":"<jats:p>\n                    Neurotransmitters and neuromodulators can be released via either action potential (AP)\u2013evoked transient or AP-independent continuous neurotransmission. The elevated AP-evoked neurotransmission in the primary sensory neurons plays crucial roles in hyperalgesia. However, whether and how the AP-independent continuous neurotransmission contributes to hyperalgesia remains largely unknown. Here, we show that primary sensory dorsal root ganglion (DRG) neurons exhibit frequent spontaneous microdomain Ca\n                    <jats:sup>2+<\/jats:sup>\n                    (smCa) activities independent of APs across the cell bodies and axons, which are mediated by the spontaneous opening of TRPA1 channels and trigger continuous neurotransmission via the cyclic adenosine monophosphate-protein kinase A signaling pathway. More importantly, the frequency of smCa activity and its triggered continuous neurotransmission in DRG neurons increased dramatically in mice experiencing inflammatory pain, inhibition of which alleviates hyperalgesia. Collectively, this work revealed the AP-independent continuous neurotransmission triggered by smCa activities in DRG neurons, which may serve as a unique mechanism underlying the nociceptive sensitization in hyperalgesia and offer a potential target for the treatment of chronic pain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2406741122","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T13:35:51Z","timestamp":1737120951000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Action potential\u2013independent spontaneous microdomain Ca\n                    <sup>2+<\/sup>\n                    transients\u2013mediated continuous neurotransmission regulates hyperalgesia"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7427-2207","authenticated-orcid":false,"given":"Zhuoyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Neurological Department of Tongji Hospital, School of Medicine, Tongji University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0911-1363","authenticated-orcid":false,"given":"Jingyu","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxiao","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueting","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huadong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-2277","authenticated-orcid":false,"given":"Changhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, the Second Affiliated Hospital, Neuroscience Research Center, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi\u2019an Jiaotong University","place":["Xi\u2019an, China"]},{"name":"Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1449-9351","authenticated-orcid":false,"given":"Zuying","family":"Chai","sequence":"additional","affiliation":[{"name":"Solomon H. 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