Analgesic effect of a broad-spectrum dihydropyridine inhibitor of voltage-gated calcium channels

Vinicius M. Gadotti, Chris Bladen, Fang Xiong Zhang, Lina Chen, Miyase Gözde Gündüz, Rahime Şimşek, Cihat Şafak, Gerald W. Zamponi*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Voltage-activated calcium channels are important facilitators of nociceptive transmission in the primary afferent pathway. Consequently, molecules that block these channels are of potential use as pain therapeutics. Our group has recently reported on the identification of a novel class of dihydropyridines (DHPs) that included compounds with preferential selectivity for T-type over L-type channels. Among those compounds, M4 was found to be an equipotent inhibitor of both Cav1.2 L- and Cav3.2 T-type calcium channels. Here, we have further characterized the effects of this compound on other types of calcium channels and examined its analgesic effect when delivered either spinally (i.t.) or systemically (i.p.) to mice. Both delivery routes resulted in antinociception in a model of acute pain. Furthermore, M4 was able to reverse mechanical hyperalgesia produced by nerve injury when delivered intrathecally. M4 retained partial activity when delivered to Cav3.2 null mice, indicating that this compound acts on multiple targets. Additional whole-cell patch clamp experiments in transfected tsA-201 cells revealed that M4 also effectively blocks Cav3.3 (T-type) and Cav2.2 (N-type) currents. Altogether, our data indicate that broad-spectrum inhibition of multiple calcium channel subtypes can lead to potent analgesia in rodents.

Original languageEnglish
Pages (from-to)2485-2493
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume467
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015
Externally publishedYes

Keywords

  • Dihydropyridine analogues
  • Electrophysiology
  • N-type calcium channel
  • Neuropathic pain
  • T-type calcium channel

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