title: Alleviation of behavioral hypersensitivity in mouse models of inflammatory pain with two structurally different casein kinase 1 (CK1) inhibitors.
abstract: BACKGROUND
  The phylogenetically highly conserved CK1 protein kinases consisting of at least seven isoforms form a distinct family within the eukaryotic protein kinases. CK1 family members play crucial roles in a wide range of signaling activities. However, the functional role of CK1 in somatosensory pain signaling has not yet been fully understood. The aim of this study was to clarify the role of CK1 in the regulation of inflammatory pain in mouse carrageenan and complete Freund's adjuvant (CFA) models.
  
  
  RESULTS
  We have used two structurally different CK1 inhibitors, TG003 and IC261. TG003, which was originally identified as a cdc2-like kinase inhibitor, had potent inhibitory effects on CK1 isoforms in vitro and in cultured cells. Intrathecal injection of either TG003 (1-100 pmol) or IC261 (0.1-1 nmol) dose-dependently decreased mechanical allodynia and thermal hyperalgesia induced by carrageenan or CFA. Bath-application of either TG003 (1 μM) or IC261 (1 μM) had only marginal effects on spontaneous excitatory postsynaptic currents (sEPSCs) recorded in the substantia gelatinosa neurons of control mice. However, both compounds decreased the frequency of sEPSCs in both inflammatory pain models.
  
  
  CONCLUSIONS
  These results suggest that CK1 plays an important pathophysiological role in spinal inflammatory pain transmission, and that inhibition of the CK1 activity may provide a novel strategy for the treatment of inflammatory pain.
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima City, Kagoshima 890-8544, Japan. tkmphm10@m.kufm.kagoshima-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurihara
authors.forename: Eri
authors.initials: E
authors.lastname: Sakurai
authors.forename: Masayasu
authors.initials: M
authors.lastname: Toyomoto
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kawamoto
authors.forename: Toshihide
authors.initials: T
authors.lastname: Asada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanabe
authors.forename: Megumu
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Atsuro
authors.initials: A
authors.lastname: Miyata
mesh_terms: D000818:Animals; D002351:Carrageenan / Q000633:toxicity; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D021381:Protein Transport / Q000187:drug effects; D013116:Spinal Cord / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; C411652:IC 261; D007211:Indoles; C487497:TG 003; D013844:Thiazoles; D002351:Carrageenan; D010696:Phloroglucinol; D047389:Casein Kinase I