title: Role of interleukin-1beta and tumor necrosis factor-alpha-dependent expression of cyclooxygenase-2 mRNA in thermal hyperalgesia induced by chronic inflammation in mice.
abstract: The present study investigated whether the endogenous pro-inflammatory cytokines [interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha)]-dependent expression of cyclooxygenase-2 (COX-2) mRNA within the spinal cord could be involved in the development of chronic inflammatory pain-like behaviors in mice. We demonstrated that the expression of COX-2 mRNA on the ipsilateral side of the spinal cord was significantly increased 6 h and 3 days after intraplantar injection of complete Freund's adjuvant (CFA), compared with the expression in saline-treated mice. In addition, the chronic pain-like behaviors following CFA injection were markedly suppressed by repeated intrathecal (i.t.) pre-treatment with the COX-2 inhibitor etodolac, but not with the COX-1 inhibitor mofezolac. The cytosolic level of the activated form of nuclear factor-kappa B (NF-kappaB), which is a major contributor to the induction of COX-2, on the ipsilateral side of the mouse spinal cord was also increased compared with that in the saline-treated mice. The key finding in the present study was that a single i.t. injection with either IL-1beta or TNF-alpha induced a marked increase in spinal COX-2 mRNA and persistent thermal hyperalgesia in mice. Furthermore, CFA-induced hypersensitivity to inflammatory pain was significantly reduced by repeated i.t. pre-injection of the recombinant Fc chimera of IL-1 receptor I or soluble TNF receptor I, which sequesters endogenous IL-1beta or TNF-alpha, respectively. In contrast, the expression of spinal COX-2 mRNA in CFA-treated mice was similar to that in saline-treated mice at 7 days after CFA injection. The present findings strongly indicate the early intrathecal use of the COX-2 inhibitor for the relief of chronic inflammatory pain. Furthermore, together with the result in a previous study that pro-inflammatory cytokines lead to stimulation of a NF-kappaB-dependent transcriptional pathway, these findings suggest that a spinal cytokine/NF-kappaB/COX-2 pathway may play an important role in the development, but not maintenance, of chronic pain following peripheral tissue inflammation.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. narita@hoshi.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Narita
authors.forename: M
authors.initials: M
authors.lastname: Shimamura
authors.forename: S
authors.initials: S
authors.lastname: Imai
authors.forename: C
authors.initials: C
authors.lastname: Kubota
authors.forename: Y
authors.initials: Y
authors.lastname: Yajima
authors.forename: T
authors.initials: T
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Shiokawa
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017308:Etodolac / Q000627:therapeutic use; D005620:Freund's Adjuvant; D007839:Functional Laterality; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism*; D011930:Reaction Time / Q000187:drug effects; D013116:Spinal Cord / Q000201:enzymology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000502:physiology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017308:Etodolac; D005620:Freund's Adjuvant; D051546:Cyclooxygenase 2