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Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 12, pp 2485–2493 | Cite as

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. ZamponiEmail author
Ion channels, receptors and transporters

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.

Keywords

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

Notes

Acknowledgments

This work was supported by operating grants to GWZ from the Canadian Institutes of Health Research and by the Vi Riddell Child Pain program of the Alberta Children’s Hospital Research Institute. GWZ is a Canada Research Chair. VG held a Canadian Diabetes Association fellowship. CB held a T. Chen Fong studentship and an Alberta Innovates-Health Solutions (AI-HS) studentship award. FXZ holds an AI-HS fellowship.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Vinicius M. Gadotti
    • 1
  • Chris Bladen
    • 1
  • Fang Xiong Zhang
    • 1
  • Lina Chen
    • 1
  • Miyase Gözde Gündüz
    • 2
  • Rahime Şimşek
    • 2
  • Cihat Şafak
    • 2
  • Gerald W. Zamponi
    • 1
    Email author
  1. 1.Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children’s Hospital Research InstituteUniversity of CalgaryCalgaryCanada
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyHacettepe UniversityAnkaraTurkey

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