title: p38 stress-activated protein kinase inhibitor reverses bradykinin B(1) receptor-mediated component of inflammatory hyperalgesia.
abstract: The effects of a p38 stress-activated protein kinase inhibitor, 4-(4-fluorophenyl)-2-(-4-methylsulfonylphenyl)-5-(4-pyridynyl) imidazole (SB203580), were evaluated in a rat model of inflammatory hyperalgesia. Oral, but not intrathecal, administration of SB203580 significantly reversed inflammatory mechanical hyperalgesia induced by injection of complete Freund's adjuvant into the hindpaw. SB203580 did not, however, affect the increased levels of interleukin-1beta and cyclo-oxygenase 2 protein observed in the hindpaw following complete Freund's adjuvant injection. Intraplantar injection of interleukin-1beta into the hindpaw elicited mechanical hyperalgesia in the ipsilateral paw, as well as in the contralateral paw, following intraplantar injection of the bradykinin B(1) receptor agonist des-Arg(9)-bradykinin. Oral administration of SB203580 1 h prior to interleukin-1beta administration prevented the development of hyperalgesia in the ipslateral paw and the contralateral bradykinin B(1) receptor-mediated hyperalgesia. In addition, following interleukin-1beta injection into the ipsilateral paw, co-administration of SB203580 with des-Arg(9)-bradykinin into the contralateral paw inhibited the bradykinin B(1) receptor-mediated hyperalgesia. In human embryonic kidney 293 cells expressing the human bradykinin B(1) receptor, its agonist des-Arg(10)-kallidin produced a rapid phosphorylation of endogenous p38 stress-activated protein kinase. Our data suggest that p38 stress-activated protein kinase is involved in the development of inflammatory hyperalgesia in the rat, and that its pro-inflammatory effects involve the induction of the bradykinin B(1) receptor as well as functioning as its downstream effector.
authors.affiliation: Novartis Institute for Medical Sciences, 5 Gower Place, WC1E 6BN, London, UK. pam.ganju@pharma.novartis.com
authors.forename: P
authors.initials: P
authors.lastname: Ganju
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: X
authors.initials: X
authors.lastname: Núñez
authors.forename: A
authors.initials: A
authors.lastname: Fox
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006614:Hindlimb / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007609:Kallidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin; D014409:Tumor Necrosis Factor-alpha; D007609:Kallidin; C052787:kallidin, des-Arg(10)-; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580