title: Tacrolimus Triggers Transient Receptor Potential Vanilloid-1-Dependent Relapse of Pancreatitis-Related Pain in Mice.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Terada
authors.forename: Maho
authors.initials: M
authors.lastname: Tsubota
authors.forename: Hiiragi
authors.initials: H
authors.lastname: Sugo
authors.forename: Kohei
authors.initials: K
authors.lastname: Wakitani
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Wada
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Takada
authors.forename: Akira
authors.initials: A
authors.lastname: Oita
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002108:Ceruletide / Q000009:adverse effects; D002934:Cinnamates / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D010146:Pain / Q000150:complications / Q000503:physiopathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications; D012008:Recurrence; D050916:TRPV Cation Channels / Q000502:physiology*; D016559:Tacrolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D000813:Anilides; D001562:Benzimidazoles; D002934:Cinnamates; D003521:Cyclopropanes; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009281:Naphthalenes; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C484287:NNC 55-0396; D002108:Ceruletide; D016559:Tacrolimus