Ethosuximide inhibits acute histamine- and chloroquine-induced scratching behavior in mice

Abstract

We have recently reported that the Cav3.2 T-type calcium channel which is well known for its key role in pain signalling, also mediates a critical function in the transmission of itch/pruritus. Here, we evaluated the effect of the clinically used anti-seizure medication ethosuximide, a well known inhibitor of T-type calcium channels, on male and female mice subjected to histaminergic- and non-histaminergic itch. When delivered intraperitoneally ethosuximide significantly reduced scratching behavior of mice of both sexes in response to subcutaneous injection of either histamine or chloroquine. When co-delivered subcutaneously together with either pruritogenic agent ethosuximide was also effective in inhibiting scratching responses in both male and female animals. Overall, our results are consistent with an important role of Cav3.2 T-type calcium channels in modulating histamine-dependent and histamine-independent itch transmission in the primary sensory pathway. Our findings also suggest that ethosuximide could be explored further as a possible therapeutic for the treatment of itch.

Putative Synthetic Cannabinoids MEPIRAPIM, 5F-BEPIRAPIM (NNL-2), and Their Analogues Are T-Type Calcium Channel (CaV3) Inhibitors

“…46 Finally, there is emerging evidence that Ca V 3.2 channels may be a potential target for treating pruritus. 47,48 Hence, T-type channel inhibitors have considerable therapeutic potential, and it is important to identify novel pharmacophores that act on these channels for further optimization and development. 43 Activation of CB 1 and CB 2 receptors produces analgesia in many animal models of nociception, through actions at sites in the central and peripheral nervous systems, as well as the immune system.…”

“…Indeed, Ca V 3 inhibition is thought to be the key mechanism of action for the approved antiepileptic drugs zonisamide and ethosuximide, and Ca V 3 inhibitors Z944 and ACT-709,478 are currently in phase II clinical trials. , Ca V 3.2 T-type calcium channels are also considered as potential targets for chronic pain, although the inhibitor ABT-639 has failed in a phase II trial . Finally, there is emerging evidence that Ca V 3.2 channels may be a potential target for treating pruritus. , Hence, T-type channel inhibitors have considerable therapeutic potential, and it is important to identify novel pharmacophores that act on these channels for further optimization and development …”

Sensitive determination of ethosuximide in human fluids by electromembrane extraction coupled with high performance liquid chromatography ultraviolet spectroscopy

“…Ethosuximide (3‐ethyl‐3‐methylpyrrolidine‐2, 5‐dione, ETX) is a succinimide antiepileptic drug licensed as a first‐line treatment for absence epilepsy. It has been proven that it is capable of reducing the abdominal pain related to Irritable Bowel Syndrome, [ 1 ] preventing histaminergic itch, [ 2 ] improving depressive‐like behavior, [ 3 ] and inhibition of oxidative stress. [ 4 ] Long‐term therapy with ETX may induce adverse effects, for example, anorexia, gastrointestinal upset, dizziness, ataxia, aplastic anemia, and lupus erythematosus.…”