Roles of Ca v 3.2 and TRPA1 channels targeted by hydrogen sulfide in pancreatic nociceptive processing in mice with or without acute pancreatitis

• Published in: Journal of neuroscience research 2015-02, Vol.93 (2), p.361-369
• Main Authors: Terada, Yuka, Fujimura, Mayuko, Nishimura, Sachiyo, Tsubota, Maho, Sekiguchi, Fumiko, Kawabata, Atsufumi
• Format: Article
• Language: English
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.23490

Hydrogen sulfide (H 2 S), formed by multiple enzymes, including cystathionine‐γ‐lyase (CSE), targets Ca v 3.2 T‐type Ca 2+ channels (T channels) and transient receptor potential ankyrin‐1 (TRPA1), facilitating somatic pain. Pancreatitis‐related pain also appears to involve activation of T channels by H 2 S formed by the upregulated CSE. Therefore, this study investigates the roles of the Ca v 3.2 isoform and/or TRPA1 in pancreatic nociception in the absence and presence of pancreatitis. In anesthetized mice, AP18, a TRPA1 inhibitor, abolished the Fos expression in the spinal dorsal horn caused by injection of a TRPA1 agonist into the pancreatic duct. As did mibefradil, a T‐channel inhibitor, in our previous report, AP18 prevented the Fos expression following ductal NaHS, an H 2 S donor. In the mice with cerulein‐induced acute pancreatitis, the referred hyperalgesia was suppressed by NNC 55‐0396 (NNC), a selective T‐channel inhibitor; zinc chloride; or ascorbic acid, known to inhibit Ca v 3.2 selectively among three T‐channel isoforms; and knockdown of Ca v 3.2. In contrast, AP18 and knockdown of TRPA1 had no significant effect on the cerulein‐induced referred hyperalgesia, although they significantly potentiated the antihyperalgesic effect of NNC at a subeffective dose. TRPA1 but not Ca v 3.2 in the dorsal root ganglia was downregulated at a protein level in mice with cerulein‐induced pancreatitis. The data indicate that TRPA1 and Ca v 3.2 mediate the exogenous H 2 S‐induced pancreatic nociception in naïve mice and suggest that, in the mice with pancreatitis, Ca v 3.2 targeted by H 2 S primarily participates in the pancreatic pain, whereas TRPA1 is downregulated and plays a secondary role in pancreatic nociceptive signaling. © 2014 Wiley Periodicals, Inc.