title: Peripheral inflammation modifies the effect of intrathecal IL-1beta on spinal PGE2 production mainly through cyclooxygenase-2 activity. A spinal microdialysis study in freely moving rats.
abstract: Acute inflammation induces upregulation of IL-1beta both at the site of the peripheral inflammation and in the cerebrospinal fluid (CSF). The central increase of IL-1beta mainly contributes to the development of hypersensitivity. However, the spinal mechanisms for the effects of IL-1beta in nociceptive transmission are incompletely understood. It is also unknown whether previous sensitization changes IL-1beta activity. We therefore investigated the dose-effect relationship of intrathecal (i.t.) IL-1beta on spinal PGE(2) production in the absence and presence of peripheral formalin inflammation with spinal microdialysis in freely moving rats. The possible involvement of cyclooxygenase (COX) isoforms in the IL-1beta-mediated spinal PGE(2) production on the background of peripheral formalin inflammation was further evaluated with the selective COX-1 and COX-2 inhibitors. We found that the i.t. administration of IL-1beta, with doses of 1, 2, 8, or 16 ng, increased PGE(2) levels in CSF in a dose-related fashion. This IL-1beta-evoked PGE(2) release occurred within 30min after IL-1beta administration, peaked at 30-60 min interval, and returned gradually to the baseline level within 4h. Peripheral formalin inflammation in the paw induced a more prolonged effect of spinal IL-1beta with larger PGE(2) releases in the CSF compared with the non-inflammatory state, suggesting that peripheral inflammation enhances central sensitization. The COX-2 inhibitor SC58236 (15 mg/kg) reduced the IL-1beta-mediated PGE(2) increase in CSF by 86% while the COX-1 inhibitor SC58560 (15 mg/kg) had less effect (28%). Our study suggests that mainly the COX-2 enzyme mediates the IL-1beta-induced increase in spinal PGE(2) in the presence of peripheral formalin inflammation.
authors.affiliation: Department of Anesthesiology, Academic Hospital of Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium Department of Physiology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Lin
authors.initials: L
authors.lastname: Shi
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.forename: Vincent
authors.initials: V
authors.lastname: Umbrain
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Lauwers
authors.forename: Sophie
authors.initials: S
authors.lastname: Sarre
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Martin
authors.initials: M
authors.lastname: Zizi
authors.forename: Frederic
authors.initials: F
authors.lastname: Camu
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007278:Injections, Spinal; D007375:Interleukin-1 / Q000008:administration & dosage*; D008297:Male; D017551:Microdialysis / Q000379:methods; D009068:Movement; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D005557:Formaldehyde; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone