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In this study we created a kinetic model of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> and used it, in combination with dynamic\u2010clamp, to study <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> function in DRG neurons. We show, for the first time, that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>. Our results show that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>, due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> reverses the hyperexcitability of DRG neurons expressing a gain\u2010of\u2010function Nav1.7 mutation that causes IEM. In the aggregate, our results show that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> unexpectedly has strikingly different effects in DRG neurons as compared to previously\u2010 and well\u2010studied cardiac cells. Within DRG neurons where Nav1.7 is present, <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain\u2010of\u2010function Nav1.7 mutation that causes IEM.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15771-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Hyperpolarization\u2010activated cyclic nucleotide\u2010gated (HCN) channels, the molecular determinants of hyperpolarization\u2010activated current (<jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>) have been characterized as a \u2018pain pacemaker\u2019, and thus considered to be a potential molecular target for pain therapeutics.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain\u2010of\u2010function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We found that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We also demonstrate that <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our results show that, in contrast to cardiac cells and CNS neurons, <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> acts to stabilize DRG neuron excitability and prevents excessive firing.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284999","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T11:58:58Z","timestamp":1697543938000},"page":"5341-5366","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["<i>I<\/i><sub>h<\/sub> current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain"],"prefix":"10.1113","volume":"601","author":[{"given":"Dmytro V.","family":"Vasylyev","sequence":"first","affiliation":[{"name":"Department of Neurology and Center for Neuroscience &amp; Regeneration Research Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Rehabilitation Research Center Veterans Affairs Connecticut Healthcare System  West Haven Connecticut 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