title: Upregulation of bradykinin receptors is implicated in the pain associated with caerulein-induced acute pancreatitis.
abstract: Although the way for pain management associated with acute pancreatitis has been searched for, there are not enough medications available for it. The aim of the present study was to investigate the role of bradykinin (BK) in pain related to acute pancreatitis. After repeated injections of caerulein (50 μg/kg and 6 times), mice showed edema in the pancreas, and blood concentrations of pancreatic enzymes (amylase and lipase) were clearly elevated. A histopathological study demonstrated that caerulein caused tissue damage characterized by edema, acinar cell necrosis, interstitial hemorrhage, and inflammatory cell infiltrates. Furthermore, the mRNA levels of interleukin-1β and monocyte chemotactic protein (MCP)-1 were significantly increased in the pancreas of caerulein-treated mice. The sensitivity of abdominal organs as measured by abdominal balloon distension was enhanced in caerulein-injected mice, suggesting that caerulein caused pancreatic hyperalgesia. Moreover, repeated treatment with caerulein resulted in cutaneous tactile allodynia of the upper abdominal region as demonstrated by the use of von Frey filaments, indicating that caerulein-treated mice exhibited referred pain. Under this condition, the mRNA levels of bradykinin B1 receptor (BKB1R) and bradykinin B2 receptor (BKB2R) were significantly increased in the dorsal root ganglion (DRG). Finally, we found that des-Arg⁹-(Leu⁸)-bradykinin (BKB1R antagonist) and HOE-140 (BKB2R antagonist) attenuated the acute pancreatitis pain-like state in caerulein-treated mice. These findings suggest that the upregulation of BK receptors in the DRG may, at least in part, contribute to the development of the acute pancreatitis pain-like state in mice.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takemura
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Furuta
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Miyashita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Yoshi
authors.initials: Y
authors.lastname: Tsukiyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
mesh_terms: D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D005727:Ganglia, Spinal / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018002:Receptors, Bradykinin / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D018002:Receptors, Bradykinin; D002108:Ceruletide