Peripheral inflammation modifies the effect of intrathecal IL-1β on spinal PGE2 production mainly through cyclooxygenase-2 activity. A spinal microdialysis study in freely moving rats

Acute inflammation induces upregulation of IL-1β both at the site of the peripheral inflammation and in the cerebrospinal fluid (CSF). The central increase of IL-1β mainly contributes to the development of hypersensitivity. However, the spinal mechanisms for the effects of IL-1β in nociceptive transmission are incompletely understood. It is also unknown whether previous sensitization changes IL-1β activity. We therefore investigated the dose-effect relationship of intrathecal (i.t.) IL-1β on spinal PGE2 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-1β-mediated spinal PGE2 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-1β, with doses of 1, 2, 8, or 16 ng, increased PGE2 levels in CSF in a dose-related fashion. This IL-1β-evoked PGE2 release occurred within 30 min after IL-1β administration, peaked at 30-60 min interval, and returned gradually to the baseline level within 4 h. Peripheral formalin inflammation in the paw induced a more prolonged effect of spinal IL-1β with larger PGE2 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-1β-mediated PGE2 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-1β-induced increase in spinal PGE2 in the presence of peripheral formalin inflammation.