title: 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.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Kawara
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Tomoka
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Kawaishi
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Kanaoka
authors.affiliation: Department of Life Science, Faculty of Science and Engineering, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Tsuyako
authors.initials: T
authors.lastname: Ohkubo
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), Higashi-Osaka, Japan.
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D059225:Nociception / Q000187:drug effects*; D017239:Paclitaxel; D051381:Rats; D017208:Rats, Wistar; D059265:Visceral Pain / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D017239:Paclitaxel; D002118:Calcium