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Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)\u2010derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG\u2010induced sensory neurons (iSNs) using a combined chemical and transcription factor\u2010driven approach via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABA\n                    <jats:sub>B<\/jats:sub>\n                    R and ion channels including Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.2 and GIRK1 in iSNs. Functional characterisation of GABA\n                    <jats:sub>B<\/jats:sub>\n                    R was conducted using whole\u2010cell patch clamp electrophysiology, assessing neuronal excitability under current\u2010clamp conditions in the absence and presence of GABA\n                    <jats:sub>B<\/jats:sub>\n                    R agonists baclofen and \u03b1\u2010conotoxin Vc1.1. Both baclofen (100\u2009\u03bcM) and Vc1.1 (1\u2009\u03bcM) significantly reduced membrane excitability by hyperpolarising the resting membrane potential and increasing the rheobase for action potential firing. In voltage\u2010clamp mode, baclofen and Vc1.1 inhibited HVA Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel currents, which were attenuated by the selective GABA\n                    <jats:sub>B<\/jats:sub>\n                    R antagonist CGP 55845. However, modulation of GIRK channels by GABA\n                    <jats:sub>B<\/jats:sub>\n                    Rs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1\/2 channels were not coupled to GABA\n                    <jats:sub>B<\/jats:sub>\n                    Rs in hPSC\u2010derived iSNs. This study is the first to report GABA\n                    <jats:sub>B<\/jats:sub>\n                    R modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70004-fig-0008-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70004","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T02:48:21Z","timestamp":1738032501000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>\n                      GABA\n                      <sub>B<\/sub>\n                    <\/scp>\n                    Receptor Modulation of Membrane Excitability in Human Pluripotent Stem Cell\u2010Derived Sensory Neurons by Baclofen and \u03b1\u2010Conotoxin Vc1.1"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8095-0927","authenticated-orcid":false,"given":"Mitchell","family":"St Clair\u2010Glover","sequence":"first","affiliation":[{"name":"Molecular Horizons, Faculty of Science, Medicine and Health University of Wollongong  Wollongong New South Wales 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