Lipoxygenase inhibitors suppressed carrageenan-induced Fos-expression and inflammatory pain responses in the rat

Lipoxygenase (LO) metabolites are generated in inflamed tissues. However, it is unclear whether the inhibition of the LO activity regulates the expression of c-Fos protein, a pain marker in the spinal cord. Here we used a carrageenan-induced inflammation model to examine the role of LO in the development of c-Fos expression. Intradermally injected carrageenan caused elevated number of cells exhibiting Fos-like immunoreactivity (Fos-LI) in the spinal dorsal horn, and decreased the thermal and mechanical threshold in Hargreaves and von Frey tests. Pretreatment with an inhibitor of phospholipase A2, that generates the LO substrate, prior to the carrageenan injection significantly reduced the number of Fos-(+) cells. A general LO inhibitor NDGA, a 5-LO inhibitor AA-861 and a 12-LO inhibitor baicalein also exhibited the similar effects. Moreover, the LO inhibitors suppressed carrageenan-induced thermal and mechanical hyperalgesic behaviors, which inidcates that the changes in Fos expression correlates with those in the nociceptive behaviors in the inflamed rats. LO products are endogenous TRPV1 activators and pretreatment with BCTC, a TRPV1 antagonist inhibited the thermal but not the mechanical hypersensitivity. Overall, our results from the Fos-LI and behavior tests suggest that LO products released from inflamed tissues contribute to nociception during carrageenan-induced inflammation, indicating that the LO pathway is a possible target for modulating inflammatory pain.