A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain

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dc.contributor.authorHildebrand, Michael E.
dc.contributor.authorSmith, Paula L.
dc.contributor.authorBladen, Chris
dc.contributor.authorEduljee, Cyrus
dc.contributor.authorXie, Jennifer Yanhua
dc.contributor.authorChen, Lina
dc.contributor.authorFee-Maki, Molly
dc.contributor.authorDoering, Clinton J.
dc.contributor.authorMezeyova, Janette
dc.contributor.authorZhu, Yongbao
dc.contributor.authorBelardetti, Francesco
dc.contributor.authorPajouhesh, Hassan
dc.contributor.authorParker, David B.
dc.contributor.authorArnerić, Stephen Peter
dc.contributor.authorParmar, Manjeet
dc.contributor.authorPorreca, Frank
dc.contributor.authorTringham, Elizabeth W.
dc.contributor.authorZamponi, Gerald W.
dc.contributor.authorSnutch, Terrance Preston
dc.date.accessioned2018-05-29T21:14:13Z
dc.date.available2018-05-29T21:14:13Z
dc.date.issued2011-04-01
dc.description.abstractVoltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.en_US
dc.identifier.citationHildebrand, M. E., Smith, P. L., Bladen, C., Eduljee, C., Xie, J. Y., Chen, L., … Snutch, T. P. (2011). A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain. Pain, 152(4), 833–843. https://doi.org/10.1016/j.pain.2010.12.035en_US
dc.identifier.doihttp://dx.doi.org/10.1016/j.pain.2010.12.035en_US
dc.identifier.urihttp://hdl.handle.net/1880/106710
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.publisher.departmentPhysiology & Pharmacologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.titleA novel slow-inactivation-specific ion channel modulator attenuates neuropathic painen_US
dc.typejournal articleen_US
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