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

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.

KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

“…von Frey filament tests confirmed that mice whose hind paws were injected with shKLHL1 were less sensitive to pain than those injected with control EGFP-AAV (5.6 ± 0.5 g threshold compared to 3.5 ± 0.4 g, respectively at week 3 of treatment). These values are in line with the majority of data in the literature (Watanabe et al, 2015;Garcia-Caballero et al, 2016;M'Dahoma et al, 2016;Stemkowski et al, 2016;Ogawa et al, 2018); however, two groups have reported withdrawal threshold values around 1 g (Costigan et al, 2009;Chiu et al, 2013;Vicuna et al, 2015;Choi et al, 2016). It is no clear the reason for these differences, given that most studies were done using C57B/6 mice (6-14 weeks old).…”

Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential

“…Additionally, central blockade of CaV2.2 is effective in treatment of cases of chronic pain that are intractable to other interventions [11]. Other subtypes of calcium channels, such as CaV2.3 (R-type) [54; 72; 81] or CaV3 (T-type)[35; 51; 58], have also been indicated to play important roles in chronic pain. The CaV2.3-selective blocker, SNX-482, has been reported to block the C- and Aδ- fiber neurotransmission in animal models of chronic neuropathic pain [54] and reduce formalin induced paw-flinching and FOS-expression in the ipsilateral spinal cord [81].…”

Etiology and Pharmacology of Neuropathic Pain

“…The observation that T-type Ca 2+ channel blockers mibefradil and ethosuximide acutely increase withdrawal thresholds in rats subject to nerve injury further supports the suggestion that T-type channels are involved in neuropathic pain expression. Small-molecule T-channel blockers (KYS05090S or ABT-639) also showed promise in preclinical studies Zhang et al, 2015a;M'Dahoma et al, 2016). Unfortunately, preliminary clinical results with ABT-639 have been disappointing .…”