{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:13:41Z","timestamp":1787066021544,"version":"build-2736575974"},"reference-count":64,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_19047"],"award-info":[{"award-number":["MC_PC_19047"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R011338\/1"],"award-info":[{"award-number":["MR\/R011338\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and purpose<\/jats:title>\n                    <jats:p>In this study, we applied an induced pluripotent stem cell (iPSC)\u2010based model of inherited erythromelalgia (IEM) to screen a library of 281 small molecules, aiming to identify candidate pain\u2010modulating compounds.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental approach<\/jats:title>\n                    <jats:p>Human iPSC\u2010derived sensory neuron\u2010like cells, which exhibit action potentials in response to noxious stimulation, were evaluated using whole\u2010cell patch\u2010clamp and microelectrode array (MEA) techniques.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key results<\/jats:title>\n                    <jats:p>\n                      Sensory neuron\u2010like cells derived from individuals with IEM showed spontaneous electrical activity characteristic of genetic pain disorders. The drug screen identified four compounds (AZ106, AZ129, AZ037 and AZ237) that significantly decreased spontaneous firing with minimal toxicity. The calculated IC\n                      <jats:sub>50<\/jats:sub>\n                      values indicate the potential efficacy of these compounds. Electrophysiological analysis confirmed the compounds\u2019 ability to reduce action potential generation in IEM patient\u2010specific iPSC\u2010derived sensory neuron\u2010like cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>Our screening approach demonstrates the reproducibility and effectiveness of human neuronal disease modelling offering a promising avenue for discovering new analgesics. These findings address a critical gap in current therapeutic strategies for both general and neuropathic pain, warranting further investigation. This study highlights the innovative use of patient\u2010derived iPSC sensory neuronal models in pain research and emphasises the potential for personalised medicine in developing targeted analgesics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Utilisation of human iPSCs for efficient differentiation into sensory neuron\u2010like cells offers a novel strategy for studying pain mechanisms.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>IEM sensory neuron\u2010like cells exhibit key biomarkers and generate action potentials in response to noxious stimulation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>IEM sensory neuron\u2010like cells display spontaneous electrical activity, providing a relevant nociceptive model.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Screening of 281 compounds identified four candidates that significantly reduced spontaneous firing with low cytotoxicity.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Electrophysiological profiling of selected compounds revealed promising insights into their mechanisms of action, specifically modulating the Na\n                            <jats:sub>V<\/jats:sub>\n                            1.7 channel for targeted analgesia.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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