Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain. Issue 8 (August 2016)

• Record Type: Journal Article
• Authors: Sekiguchi, Fumiko; Kawara, Yuma; Tsubota, Maho; Kawakami, Eri; Ozaki, Tomoka; Kawaishi, Yudai; Tomita, Shiori; Kanaoka, Daiki; Yoshida, Shigeru; Ohkubo, Tsuyako; Kawabata, Atsufumi
• Is Part Of: Pain. Volume 157:Issue 8(2016)
• Publication Date: 2016-08
• Subjects: T-type calcium channel -- Neuropathic pain -- Visceral pain -- Colonic pain -- Pancreatic pain -- Bladder pain -- Analgesia; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000000565
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: T-type Ca 2+ channels (T channels), particularly Cav 3.2 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 Cav 3.1 or Cav 3.2 by electrophysiological and fluorescent Ca 2+ 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 Cav 3.1- or Cav 3.2-expressing cells. RQ-00311651 also inhibited high K + -induced Ca 2+ 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 Na2 S, H2 S donors, respectively, which involve the enhanced activity of Cav 3.2 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 Cav 3.1/Cav 3.2 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. Abstract : RQ-00311651, a novel state-dependent T-type calcium channel blocker, is an orally available analgesic for treatment of neuropathic and visceral pain with minimum central side effects.