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Inhibition of T\u2010type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T\u2010type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T\u2010type channels alone may be insufficient for pain relief.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We utilized the selective and CNS\u2010penetrant T\u2010type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Voltage\u2010clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T\u2010type current, which was blocked by Z944. Due to this highly prevalent T\u2010type current, Z944 potently blocked action\u2010potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I\/II neurons. Finally, we found that intraperitoneal injection of Z944 (1\u201310\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>) dose\u2010dependently reversed mechanical allodynia in the complete Freund's adjuvant model of persistent inflammatory pain, with a similar magnitude and time course of analgesic effects between male and female rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>T\u2010type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15498","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T20:01:19Z","timestamp":1618862479000},"page":"3517-3532","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["The T\u2010type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3941-3411","authenticated-orcid":false,"given":"Erika K.","family":"Harding","sequence":"first","affiliation":[{"name":"Department of Comparative Biology and Experimental Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"Program in Neurosciences and Mental Health The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-4928","authenticated-orcid":false,"given":"Annemarie","family":"Dedek","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Carleton University  Ottawa Ontario Canada"},{"name":"Neuroscience Program Ottawa Hospital Research Institute  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3287-6803","authenticated-orcid":false,"given":"Robert P.","family":"Bonin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy University of Toronto  Toronto Ontario Canada"},{"name":"University of Toronto Centre for the Study of Pain University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6897-6585","authenticated-orcid":false,"given":"Michael W.","family":"Salter","sequence":"additional","affiliation":[{"name":"Program in Neurosciences and Mental Health The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Department of Physiology University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5182-1296","authenticated-orcid":false,"given":"Terrance P.","family":"Snutch","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories University of British Columbia  Vancouver British Columbia Canada"},{"name":"Djavad Mowafaghian Center for Brain Health University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6845-8013","authenticated-orcid":false,"given":"Michael E.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Carleton University  Ottawa Ontario Canada"},{"name":"Neuroscience Program Ottawa Hospital Research Institute  Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,22]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S142","article-title":"the Concise Guide to PHARMACOLOGY 2019\/20: Ion channels","volume":"176","author":"Alexander S. 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