Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain.

Abstract

T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 ∼ -60 mV, but not -80 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K-induced Ca signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Cav3.1/Cav3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects.

• Authors: Fumiko Sekiguchi, Yuma Kawara, Maho Tsubota, Eri Kawakami, Tomoka Ozaki, Yudai Kawaishi, Shiori Tomita, Daiki Kanaoka, Shigeru Yoshida, Tsuyako Ohkubo, Atsufumi Kawabata
• Journal: Pain (Pain) Vol. 157 Issue 8 Pg. 1655-1665 (08 2016) ISSN: 1872-6623 [Electronic] United States
• PMID: 27023424 (Publication Type: Journal Article)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, T-Type
• Paclitaxel
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology, therapeutic use)
• Calcium Channels, T-Type (metabolism)
• Disease Models, Animal
• Female
• HEK293 Cells
• Humans
• Hyperalgesia (chemically induced, drug therapy)
• Male
• Mice
• Neuralgia (chemically induced, drug therapy)
• Nociception (drug effects)
• Paclitaxel
• Rats
• Rats, Wistar
• Visceral Pain (chemically induced, drug therapy)