Analgesic effect of a broad-spectrum dihydropyridine inhibitor of voltage-gated calcium channels.
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.
Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive, NW, Calgary, Canada.
Vinicius M
VM
Gadotti
Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive, NW, Calgary, Canada.
Chris
C
Bladen
Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive, NW, Calgary, Canada.
Fang Xiong
FX
Zhang
Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive, NW, Calgary, Canada.
Lina
L
Chen
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
Miyase Gözde
MG
Gündüz
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
Rahime
R
Şimşek
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
Cihat
C
Şafak
Department of Physiology and Pharmacology, Cumming School of Medicine, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive, NW, Calgary, Canada. zamponi@ucalgary.ca.
Gerald W
GW
Zamponi
D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D002460:Cell Line; D004095:Dihydropyridines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats
D000700:Analgesics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; C038806:1,4-dihydropyridine
Dihydropyridine analogues; Electrophysiology; N-type calcium channel; Neuropathic pain; T-type calcium channel