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The structural and functional characteristics of synapses are highly dynamic, exhibiting extensive plasticity that is shaped by neural activity and regulated primarily by trans-synaptic cell-adhesion molecules (CAMs). Prototypical trans-synaptic CAMs, such as neurexins (Nrxs) and neuroligins (Nlgs), directly regulate the assembly of presynaptic and postsynaptic molecules, including synaptic vesicles, active zone proteins, and receptors. Therefore, the trans-synaptic adhesion mechanisms mediated by Nrx\u2013Nlg interaction can contribute to a range of synaptopathies in the context of pathological pain and other neurological disorders. The present review provides an overview of the current understanding of the roles of Nrx\u2013Nlg interaction in the regulation of trans-synaptic connections, with a specific focus on Nrx and Nlg structures, the dynamic shaping of synaptic function, and the dysregulation of Nrx\u2013Nlg in pathological pain. Additionally, we discuss a range of proteins capable of modulating Nrx\u2013Nlg interactions at the synaptic cleft, with the objective of providing a foundation to guide the future development of novel therapeutic agents for managing pathological pain.<\/jats:p>","DOI":"10.3390\/cells11121940","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T01:48:12Z","timestamp":1655430492000},"page":"1940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Modulation of Trans-Synaptic Neurexin\u2013Neuroligin Interaction in Pathological Pain"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9316-4087","authenticated-orcid":false,"given":"Huili","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0653-1059","authenticated-orcid":false,"given":"Ruijuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1321-6655","authenticated-orcid":false,"given":"Yun","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1930-9724","authenticated-orcid":false,"given":"Junfa","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0695-8861","authenticated-orcid":false,"given":"Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"779125","DOI":"10.3389\/fnins.2021.779125","article-title":"Neuron to oligodendrocyte precursor cell synapses: Protagonists in oligodendrocyte development and myelination, and targets for therapeutics","volume":"15","author":"Moura","year":"2022","journal-title":"Front. 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