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

Autor: Lina Chen, Hassan Pajouhesh, Cyrus Eduljee, Michael E. Hildebrand, Yongbao Zhu, Stephen P. Arneric, Molly Fee-Maki, Frank Porreca, Terrance P. Snutch, Paula L. Smith, Manjeet Parmar, Francesco Belardetti, Chris Bladen, David Parker, Clint J. Doering, Janette Mezeyova, Gerald W. Zamponi, Elizabeth Tringham, Jennifer Y. Xie
Rok vydání: 2011
Předmět:
Male
Patch-Clamp Techniques
P-type calcium channel
Sensory Receptor Cells
Biophysics
Tetrodotoxin
In Vitro Techniques
Transfection
Ion Channels
Piperazines
Sodium Channels
NAV1.8 Voltage-Gated Sodium Channel
Calcium Channels
T-Type
Ganglia
Spinal
Membrane Transport Modulators
Animals
Humans
Patch clamp
Rats
Wistar
Cell Line
Transformed
Pain Measurement
Analysis of Variance
Voltage-dependent calcium channel
Chemistry
Sodium channel
Calcium channel
NAV1.7 Voltage-Gated Sodium Channel
T-type calcium channel
Heart
Neural Inhibition
Electric Stimulation
Rats
Disease Models
Animal
Spinal Nerves
Anesthesiology and Pain Medicine
Acrylates
Animals
Newborn
Spinal Cord
Neurology
Hyperalgesia
Anesthesia
Neuropathic pain
Nociceptor
Neuralgia
Acetanilides
Rabbits
Neurology (clinical)
Neuroscience
Sodium Channel Blockers
Zdroj: Pain. 152:833-843
ISSN: 0304-3959
Popis: 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 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.
Databáze: OpenAIRE
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