Tacrolimus Triggers Transient Receptor Potential Vanilloid-1-Dependent Relapse of Pancreatitis-Related Pain in Mice

Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphoryl...

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Bibliographic Details
Published in:	Pharmacology Vol. 99; no. 5-6; p. 281
Main Authors:	Terada, Yuka, Tsubota, Maho, Sugo, Hiiragi, Wakitani, Kohei, Sekiguchi, Fumiko, Wada, Kyoichi, Takada, Mitsutaka, Oita, Akira, Kawabata, Atsufumi
Format:	Journal Article
Language:	English
Published:	Switzerland 01-01-2017
Subjects:	Anilides - pharmacology Animals Benzimidazoles - pharmacology Ceruletide - adverse effects Cinnamates - pharmacology Cyclopropanes - pharmacology Hyperalgesia - chemically induced Male Mice Naphthalenes - pharmacology Pain - complications Pain - physiopathology Pancreatitis - chemically induced Pancreatitis - complications Recurrence Tacrolimus - antagonists & inhibitors Tacrolimus - pharmacology TRPV Cation Channels - physiology
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Summary:	Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain.
ISSN:	1423-0313
DOI:	10.1159/000454816