title: Roles of Cav3.2 and TRPA1 channels targeted by hydrogen sulfide in pancreatic nociceptive processing in mice with or without acute pancreatitis.
abstract: 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.
authors.affiliation: Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Terada
authors.forename: Mayuko
authors.initials: M
authors.lastname: Fujimura
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Nishimura
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002108:Ceruletide / Q000633:toxicity; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D006862:Hydrogen Sulfide / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000627:therapeutic use; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059265:Visceral Pain / Q000188:drug therapy* / Q000209:etiology*
chemical_list: D001562:Benzimidazoles; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D003521:Cyclopropanes; D017879:Isothiocyanates; D009281:Naphthalenes; D020319:Oligodeoxyribonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C484287:NNC 55-0396; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D002108:Ceruletide; D006862:Hydrogen Sulfide
keywords: Cav3.2 T-type calcium channel; TRPA1; hydrogen sulfide; pancreatic pain; pancreatitis