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: Yuka Terada, Mayuko Fujimura, Sachiyo Nishimura, Maho Tsubota, Fumiko Sekiguchi, Atsufumi Kawabata
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 93 Issue 2 Pg. 361-9 (Feb 2015) ISSN: 1097-4547 [Electronic] United States
• PMID: 25267397 (Publication Type: Journal Article)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Benzimidazoles
• Cacna1h protein, mouse
• Calcium Channel Blockers
• Calcium Channels, T-Type
• Cyclopropanes
• Isothiocyanates
• Naphthalenes
• Oligodeoxyribonucleotides, Antisense
• Proto-Oncogene Proteins c-fos
• TRPA1 Cation Channel
• Transient Receptor Potential Channels
• Trpa1 protein, mouse
• NNC 55-0396
• 2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate
• Ceruletide
• Hydrogen Sulfide

Topics

• Analysis of Variance
• Animals
• Benzimidazoles (therapeutic use)
• Calcium Channel Blockers (therapeutic use)
• Calcium Channels, T-Type (metabolism)
• Ceruletide (toxicity)
• Cyclopropanes (therapeutic use)
• Disease Models, Animal
• Hydrogen Sulfide (therapeutic use)
• Hyperalgesia (drug therapy, physiopathology)
• Isothiocyanates (pharmacology)
• Male
• Mice
• Naphthalenes (therapeutic use)
• Oligodeoxyribonucleotides, Antisense (therapeutic use)
• Pancreatitis (chemically induced, complications, pathology)
• Posterior Horn Cells (drug effects, metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• TRPA1 Cation Channel
• Transient Receptor Potential Channels (antagonists & inhibitors, metabolism)
• Visceral Pain (drug therapy, etiology)