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

doi:10.1016/j.pain.2010.12.035

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.

Highlights

Voltage-gated sodium (NaV) and calcium (CaV) channels are crucially involved in nociceptive signaling pathways, in part by mediating ionic currents that contribute to the excitability of peripheral nociceptors in the dorsal root ganglia (DRG)
Synthesis and functional characterization of a novel small organic agent (Z123212) that uniquely stabilizes the slow-inactivated state of a subset of NaV and CaV channels
The data suggest that by enhancing the slow inactivation of a combination of TTX-sensitive and TTX-resistant NaV and T-type CaV currents, Z123212 reduces action potential (AP) firing in peripheral DRG and lamina I/II spinal cord neurons

Summary

Introduction

Voltage-gated sodium (NaV) and calcium (CaV) channels are crucially involved in nociceptive signaling pathways, in part by mediating ionic currents that contribute to the excitability of peripheral nociceptors in the dorsal root ganglia (DRG). A specific subtype of T-type CaV channel (CaV3.2) is highly expressed in DRG neurons and is involved in the initiation of action potential (AP) firing and the generation of burst firing [6,19,31,42]. Both tetrodotoxin (TTX)-sensitive NaV1.7 and TTX-resistant NaV1.8 channels are robustly expressed in DRGs and are important for setting the. Loss-of-function mutations in the NaV1.7 channel lead to complete abolition of pain sensation, while gain-of-function NaV1.7 mutations cause severe chronic pain syndromes [10]

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Results

Conclusion