Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from rat spinal cord slices

Inflammation enhances release of neuropeptides from sensory nerve terminals in the spinal cord, and this may contribute to the development of hyperalgesia. In a similar manner, proinflammatory prostaglandins also augment peptide release from sensory neurons. To ascertain whether the inflammation-induced increase in peptide release from spinal cord slices is mediated by production of these eicosanoids, we examined whether intrathecal administration of nonsteroidal antiinflammatory drugs (NSAIDS) could attenuate the effects of inflammation. Unilateral injection of 150 microl of complete Freund's adjuvant (CFA) into the hindpaw of adult Sprague-Dawley rats resulted in a lower threshold for paw withdrawal (hyperalgesia) on 1, 4, and 5 days after injection. Five days after the induction of inflammation, capsaicin-evoked release of immunoreactive substance P (iSP) and immunoreactive calcitonin gene-related peptide (iCGRP) was increased approximately 2-fold in slices of cord tissue from the side ipsilateral to CFA injection, compared to spinal cord slices from the non-inflamed side. Intrathecal administration of 1 microl/h of 10 nmol/microl solution of the NSAID, ketorolac, for 1 day prior to and throughout the inflammation significantly attenuated the inflammation-induced increase in capsaicin-evoked release of both peptides without altering release in cord tissue from the non-inflamed side. Systemic administration of the same amount of ketorolac did not attenuate the effect of inflammation on peptide release. Intrathecal administration of 16 nmol/h (S)-ibuprofen, before and throughout the inflammation, also significantly attenuated the increase in evoked neuropeptide release associated with inflammation, whereas (R)-ibuprofen was ineffective. These results suggest that inhibition of cyclooxygenase at the level of the spinal cord attenuates the augmentation of neuropeptide release induced by peripheral inflammation, and provide further evidence for an action of prostaglandins at central terminals of sensory neurons during inflammation.