Essential role of Ca(v)3.2 T-type calcium channels in butyrate-induced colonic pain and nociceptor hypersensitivity in mice.

Given the role of Cav3.2 isoform among T-type Ca2+ channels (T-channels) in somatic and visceral nociceptive processing, we analyzed the contribution of Cav3.2 to butyrate-induced colonic pain and nociceptor hypersensitivity in mice, to evaluate whether Cav3.2 could serve as a target for treatment of visceral pain in irritable bowel syndrome (IBS) patients. Mice of ddY strain, and wild-type and Cav3.2-knockout mice of a C57BL/6J background received intracolonic administration of butyrate twice a day for 3 days. Referred hyperalgesia in the lower abdomen was assessed by von Frey test, and colonic hypersensitivity to distension by a volume load or chemicals was evaluated by counting nociceptive behaviors. Spinal phosphorylated ERK was detected by immunohistochemistry. Cav3.2 knockdown was accomplished by intrathecal injection of antisense oligodeoxynucleotides. Butyrate treatment caused referred hyperalgesia and colonic hypersensitivity to distension in ddY mice, which was abolished by T-channel blockers and/or Cav3.2 knockdown. Butyrate also increased the number of spinal phosphorylated ERK-positive neurons following colonic distension in the anesthetized ddY mice. The butyrate-treated ddY mice also exhibited T-channel-dependent colonic hypersensitivity to intracolonic Na2S, known to enhance Cav3.2 activity, and TRPV1, TRPA1 or proteinase-activated receptor 2 (PAR2) agonists. Wild-type, but not Cav3.2-knockout, mice of a C57BL/6J background, after treated with butyrate, mimicked the T-channel-dependent referred hyperalgesia and colonic hypersensitivity in butyrate-treated ddY mice. Our study provides definitive evidence for an essential role of Cav3.2 in the butyrate-induced colonic pain and nociceptor hypersensitivity, which might serve as a target for treatment of visceral pain in IBS patients.

Tsubota M ，Matsui K ，Nakano M ，Kajitani R ，Ishii Y ，Tomochika K ，Nishikawa Y ，Fukushi S ，Yamagata A ，Sekiguchi F ，Okada T ，Toyooka N ，Kawabata A ... -  《-》

Genetic deletion of Ca(v)3.2 T-type calcium channels abolishes H(2)S-dependent somatic and visceral pain signaling in C57BL/6 mice.

We tested whether genetic deletion of Cav3.2 T-type Ca2+ channels abolishes hydrogen sulfide (H2S)-mediated pain signals in mice. In Cav3.2-expressing HEK293 cells, Na2S, an H2S donor, at 100 μM clearly increased Ba2+ currents, as assessed by whole-cell patch-clamp recordings. In wild-type C57BL/6 mice, intraplantar and intracolonic administration of Na2S evoked mechanical allodynia and visceral nociceptive behavior, respectively, which were abolished by TTA-A2, a T-type Ca2+ channel blocker. In Cav3.2-knockout mice of a C57BL/6 background, Na2S caused neither somatic allodynia nor colonic nociception. Our study thus provides definitive evidence for an essential role of Cav3.2 in H2S-dependent somatic and colonic pain.

Matsui K ，Tsubota M ，Fukushi S ，Koike N ，Masuda H ，Kasanami Y ，Miyazaki T ，Sekiguchi F ，Ohkubo T ，Yoshida S ，Mukai Y ，Oita A ，Takada M ，Kawabata A ... -  《-》

Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca(2+) Channels, on Visceral Pain in Mice.

Tsubota M ，Matsui K ，Fukushi S ，Okazaki K ，Sekiguchi F ，Kawabata A ... -  《-》

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

Sekiguchi F ，Kawara Y ，Tsubota M ，Kawakami E ，Ozaki T ，Kawaishi Y ，Tomita S ，Kanaoka D ，Yoshida S ，Ohkubo T ，Kawabata A ... -  《-》

Colonic hydrogen sulfide-induced visceral pain and referred hyperalgesia involve activation of both Ca(v)3.2 and TRPA1 channels in mice.

Tsubota-Matsunami M ，Noguchi Y ，Okawa Y ，Sekiguchi F ，Kawabata A ... -  《-》