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Therapeutic Potential of RQ-00311651, a Novel T-Type Ca

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Therapeutic Potential of RQ-00311651, a Novel T-Type Ca Research Paper Therapeutic potential of RQ-00311651, a novel T-type Ca21 channel blocker, in distinct rodent models for neuropathic and visceral pain Fumiko Sekiguchia, Yuma Kawaraa, Maho Tsubotaa, Eri Kawakamia, Tomoka Ozakia, Yudai Kawaishia, Shiori Tomitaa, Daiki Kanaokaa, Shigeru Yoshidab, Tsuyako Ohkuboc, Atsufumi Kawabataa,* Abstract 21 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 21 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 265 ; 260 mV, but not 280 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K1-induced Ca21 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. Keywords: T-type calcium channel, Neuropathic pain, Visceral pain, Colonic pain, Pancreatic pain, Bladder pain, Analgesia 1. Introduction visceral pain/referred hyperalgesia accompanying cerulein- 33 21 induced pancreatitis or cyclophosphamide (CPA)-induced Among the 3 isoforms of T-type Ca channels (T channels), 29 cystitis. The involvement of Cav3.2 in diabetic neuropathy and Cav3.2 is most abundantly expressed in the primary sensory butyrate-induced colonic hypersensitivity has also been demon- neurons and plays a crucial role in peripheral pain process- 27,37,46,50 ing.40,41,46 We have reported that intraplantar (i.pl.) and intra- strated by independent groups. Thus, T channels appear to participate in a variety of pain signals, and T-channel colonic (i.col.) administration of NaHS, an H2S donor, evokes mechanical hyperalgesia and colonic pain/referred hyperalgesia, blockers are considered promising medicines for treatment of intractable and persistent pain including neuropathic and respectively, through the enhancement of Cav3.2 channel activity in rats and mice.18,26,30,34,48 A series of our studies have shown visceral pain. the involvement of the enhanced activity of Cav3.2 in the Various T-channel blockers have been developed so far, 28 4 20 neuropathic pain induced by L5 spinal nerve injury43 or repeated including mibefradil, NNC 55-0396 (NNC), TTA-A2, 7 25 23 13 treatment with paclitaxel, an anticancer drug,36 in the mechanical TTA-P2, KYS05090S, Z944, Z123212, neuroactive ste- 39 1 1,22 hyperalgesia induced by i.pl. prostaglandin E2 and in the roids ([ ]-ECN, epipregnanolone), cannabinoid ligand-based compounds,3 a novel class dihydropyridine compound (M4),11 etc. These T-channel blockers show significant effects on a range Sponsorships or competing interests that may be relevant to content are disclosed 7,13,22,23,26,36 at the end of this article. of rat or mouse models for neuropathic, inflamma- 3,11 10,29,33 a Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai tory, and visceral pain. Some of the blockers, such as University (formerly known as Kinki University), Higashi-Osaka, Japan, b Department NNC, TTA-A2, and Z944, penetrate the central nervous system of Life Science, Faculty of Science and Engineering, Kindai University (formerly (CNS) through the blood–brain barrier (BBB) and suppress the c known as Kinki University), Higashi-Osaka, Japan, Department of Physiological tremor in a parkinsonian model,31 seizures in the maximal Science and Molecular Biology, Fukuoka Dental College, Fukuoka, Japan electroshock seizure model,38 or the burst firing in the thala- *Corresponding author. Address: Laboratory of Pharmacology and Pathophysiol- 23 ogy, Faculty of Pharmacy, Kindai University (formerly known as Kinki University), mus. The central effects of BBB-permeable T-channel blockers 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. Tel.: 181 6 4307 3631; fax: 181 might also contribute to their potency as analgesics, considering 6 6730 1394. E-mail address: [email protected] (A. Kawabata). the roles of Cav3.2 T channels in the pain sensory pathways in the PAIN 157 (2016) 1655–1665 spinal dorsal horn and the thalamus.6,15,24 Nonetheless, the © 2016 International Association for the Study of Pain inhibition of T channels in the CNS might also cause intolerable http://dx.doi.org/10.1097/j.pain.0000000000000565 central side effects such as severe sedation, motor dysfunction, August 2016· Volume 157· Number 8 www.painjournalonline.com 1655 Copyright Ó 2016 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited. 1656 F. Sekiguchi et al.·157 (2016) 1655–1665 PAIN® 20,31 or impaired wake activity. To date, there are no T-channel– (mM) 97 N-methyl-D-glucamine, 10 BaCl2, 10 HEPES, 40 targeting analgesics for clinical application because of problems tetraethylammonium-Cl, and 5.6 glucose (pH 7.4). The such as poor potency or selectivity, drug–drug interactions, composition of the intracellular solution was (mM) 140 CsCl, 4,10,16,31,40,51 central side effects, and so on. 4MgCl2, 5 ethylene glycol tetraacetic acid, and 10 HEPES (pH RQ-00311651 (Fig. 1) is a novel T-channel blocker developed 7.2). The resistance of patch electrodes ranged from 3 to 5 MV. by RaQualia Pharma Inc. In this study, we characterized the Series resistance was compensated by 80%, and currents inhibitory effects of RQ on T-channel currents (T currents) or Ca21 were low-pass filtered at 5 Hz. T currents were measured as the influx in HEK293 cells transfected with human Cav3.1 or Cav3.2 difference between currents at the peak and 150 milliseconds and evaluated the analgesic or antiallodynic/antihyperalgesic after the beginning of the test pulse at 220 mV from holding effects of RQ in various pain models in which Cav3.2 is involved, potentials at 260 (Cav3.1) or 265 mV (Cav3.2) and 280 mV 29,30,33,34,36,43,48 as reported previously. Our data suggest that (Cav3.1 and Cav3.2). In the preliminary experiments, 40% to RQ is a state-dependent blocker of Cav3.1 and Cav3.2 and may serve as an orally available analgesic for treatment of painful neuropathy and visceral pain, without producing remarkable sedation or motor dysfunction. 2. Methods 2.1. Chemicals RQ-00311651 (CJ-042794) was synthesized in RaQualia Pharma Inc (Nagoya, Japan). NNC 55-0396, mibefradil, Na2S, and CPA were purchased from Sigma-Aldrich (St Louis, MO), and cerulein and NaHS were from Wako Pure Chemical Industries Ltd (Osaka, Japan) and Kishida Chemical Co Ltd (Osaka, Japan), respectively. Paclitaxel (Taxol) was obtained from Bristol-Myers Co Ltd (Tokyo, Japan). RQ-00311651 was dissolved in dimethyl sulfoxide (Sigma- Aldrich) for in vitro experiments and suspended in 0.5% methylcellulose (Wako Pure Chemical Industries Ltd) for in vivo experiments. Paclitaxel was dissolved in a mixture of 17% Cremophor EL (Sigma-Aldrich), 17% ethanol (Wako Pure Chemical Industries Ltd), and 66% saline. Other chemicals were dissolved in saline. 2.2. Cell culture HEK293 cells stably expressing human Cav3.1 or Cav3.2 T channels were cultured in high-glucose Dulbecco’s modified Eagle’s medium with L-glutamine (Wako Pure Chemical In- dustries Ltd) supplemented with 10% fetal calf serum (Nichirei Biosci. Inc, Tokyo, Japan), 50 U/mL penicillin, and 50 mg/mL streptomycin (Gibco, Carlsbad, CA), and G418 (Sigma-Aldrich) at 21 250 mg/mL. Human Cav2.2 (N-type) Ca channel–transfected HEK293 cells14 were also used in Ca21 influx experiments. 2.3. Whole-cell patch-clamp recording Whole-cell patch-clamp recordings were performed in HEK293 18 cells expressing Cav3.1 or Cav3.2, as described previously. The cells (1 3 104 cells) were seeded in plastic dishes (35 mm in diameter) and cultured for a day in the medium mentioned above containing 1% fetal calf serum. Ba21 currents were recorded from randomly chosen cells. The composition of the extracellular solution for patch-clamp experiments was Figure 2. Inhibitory effects of RQ-00311651 (RQ) on T-channel–dependent 21 Ba currents (T currents) in HEK293 cells transfected with Cav3.1 (A, B) and Cav3.2 (C, D). Cells were held at 280 mV (A, C) or 260 ; 265 mV (B, C) and stepped for 200 milliseconds to a test voltage of 220 mV. In the preliminary experiments, 5% to 20% and 40% to 60% T channels were in an inactivated state at holding potentials of 280 mV and 260 ; 265 mV, respectively. Data show the mean 6 SEM for 10 to 20 (A), 4 to 13 (B), 2 to 12 (C), or 4 to 10 (D) Figure 1.
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