Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain.
T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 μg/10 μl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada.
Saïd
S
M'Dahoma
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada.
Vinicius M
VM
Gadotti
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada.
Fang-Xiong
FX
Zhang
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 130-701, Republic of Korea.
Byeongyeon
B
Park
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 130-701, Republic of Korea.
Ji Hye
JH
Nam
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, 09124, Cagliari, Italy.
Valentina
V
Onnis
Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, 09124, Cagliari, Italy. gbalboni@unica.it.
Gianfranco
G
Balboni
Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, 130-701, Republic of Korea. ljy@khu.ac.kr.
Jae Yeol
JY
Lee
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, T2N 4N1, Canada. zamponi@ucalgary.ca.
Gerald W
GW
Zamponi
D000200:Action Potentials; D059787:Acute Pain / Q000188:drug therapy*; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000188:drug therapy*; D059225:Nociception; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use
D000700:Analgesics; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C549128:KYS 05090; D011799:Quinazolines
Calcium channels; KYS-05090S; Nociception; Pain; T-type