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

Michael E. Hildebrand, Paula L. Smith, Chris Bladen, Cyrus Eduljee, Jennifer Y. Xie, Lina Chen, Molly Fee-Maki, Clint J. Doering, Janette Mezeyova, Yongbao Zhu, Francesco Belardetti, Hassan Pajouhesh, David Parker, Stephen P. Arneric, Manjeet Parmar, Frank Porreca, Elizabeth Tringham, Gerald W. Zamponi, Terrance P. Snutch

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Voltage-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 NaV1.7 and NaV1.8 sodium channels and CaV3.2 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. A novel organic compound stabilizes slow-inactivated sodium and calcium channels to reduce the excitability of nociceptors and dorsal horn neurons and attenuate neuropathic pain signaling.

Original languageEnglish (US)
Pages (from-to)833-843
Number of pages11
JournalPain
Volume152
Issue number4
DOIs
StatePublished - Apr 1 2011

Keywords

  • Calcium channel
  • Dorsal horn
  • Dorsal root ganglia
  • Neuropathic pain
  • Slow inactivation
  • Sodium channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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  • Cite this

    Hildebrand, M. E., Smith, P. L., Bladen, C., Eduljee, C., Xie, J. Y., Chen, L., Fee-Maki, M., Doering, C. J., Mezeyova, J., Zhu, Y., Belardetti, F., Pajouhesh, H., Parker, D., Arneric, S. P., Parmar, M., Porreca, F., Tringham, E., Zamponi, G. W., & 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.2010.12.035