Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca²⁺ Channels, on Visceral Pain in Mice

Abstract

T-Type Ca 2 channels (T-channels), particularly Ca v 3.2, are now considered as therapeutic targets for treatment of intractable pain including visceral pain. Among existing medicines, bepridil, a multi-channel blocker, used for treatment of arrhythmia and angina, and pimozide, a dopamine D 2 receptor antagonist, known as a typical antipsychotic, have potent T-channel blocking activity. We thus tested whether bepridil and pimozide could suppress visceral pain in mice. Colonic and bladder pain were induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and systemic administration of cyclophosphamide (CPA), respectively. Referred hyperalgesia was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load with intracolonic water injection and spontaneous bladder pain were evaluated by observing nociceptive behaviors in conscious mice. The mice exhibited referred hyperalgesia and colonic hypersensitivity to distension on day 6 after TNBS treatment. Systemic administration of bepridil at 10-20 mg/kg or pimozide at 0.1-0.5 mg/kg strongly reduced the referred hyperalgesia on the TNBS-induced referred hyperalgesia and colonic hypersensitivity to distension. CPA treatment caused bladder pain-like nociceptive behavior and referred hyperalgesia, which were reversed by bepridil at 10-20 mg/kg or pimozide at 0.5-1 mg/kg. Our data thus suggest that bepridil and pimozide, existing medicines capable of blocking Tchannels, are useful for treatment of colonic and bladder pain, and serve as seeds for the development of new medicines for visceral pain treatment.

Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

“…As shown in Fig. 6 C, ZD7288 had no effect on mIPSC frequency in the presence of T-type Ca 2+ channel blocker pimozide (1 µM) ( Tsubota et al, 2021 ) ( Fig. 6 B; P <0.01 for pimozide+ZD versus pimozide, unpaired t -test).…”

Current Drug Development Overview: Targeting Voltage-Gated Calcium Channels for the Treatment of Pain

“…Dihydropiperidines are considered L-type VGCC blockers, but their derivatives have been described as Cav3.x inhibitors, being able to reduce pain in mice [132,133], as well as dihydropyrimidine derivatives [134]. Clinically existing medicines such as bepridil (a diamine used as anti-arrhythmic) and pimozine (diphenylbutylpiperidine used as antipsychotic) were also shown to block T-type VGCCs and decrease nociception in animals with colonic and bladder pain [135]. Still regarding piperidine derivatives, TTA-P2 is a recently synthesized selective and potent Cav3 inhibitor that was demonstrated to reduce pain responses in mice in acute inflammatory pain and diabetic neuropathy [136][137][138].…”

Effects of bepridil on early cardiac development of zebrafish

“…Additionally, bepridil inhibits leukemic cell infiltration via regulation of the NOTCH1 pathway and induces cell apoptosis (Baldoni et al 2018 ). Tsubota et al ( 2021 ) described a novel effect of bepridil on colonic hypersensitivity and anticipated its application in the treatment of visual pain. Additionally, bepridil is an alkalescent reagent that inhibits both beta- and gamma-secretase generation in primary neurons of mice.…”