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.

Effect of the T-type channel blocker KYS-05090S in mouse models of acute and neuropathic pain

ONNIS, VALENTINA;BALBONI, GIANFRANCO;
2016

Abstract

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.
Calcium channels; KYS-05090S; Nociception; Pain; T-type
File in questo prodotto:
File Dimensione Formato  
2015 KYS-05090S Pflugers Arch.pdf

Solo gestori archivio

Descrizione: articolo principale
Tipologia: versione editoriale
Dimensione 760.19 kB
Formato Adobe PDF
760.19 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/115187
Citazioni
  • ???jsp.display-item.citation.pmc??? 8
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 14
social impact