Isoprostanes, novel eicosanoids that produce nociception and sensitize ratsensory neurons

Isoprostanes are a novel class of eicosanoids primarily formed by peroxidat ion of arachidonic acid. Because of their potential as inflammatory and/or hyperalgesic agents whose formation is largely independent of cyclooxygenas es, we examined whether 8-iso prostaglandin E-2(8-iso PGE(2)) or 8-iso pros taglandin F-2 alpha (8-iso PGF(2 alpha)) reduces mechanical and thermal wit hdrawal threshold in rats, and whether they sensitize rat sensory neurons. Injection of 1 mu g Of 8-iSO PGE(2) (in 2.5 mu l) into the hindpaw of rats significantly reduced mechanical and thermal withdrawal thresholds, whereas 1 mu g of 8-iso PGF(2 alpha) elicited a transient decrease in only the mec hanical withdrawal threshold. Both isoprostanes enhanced the firing of C-no ciceptors in a concentration-dependent manner when injected into peripheral receptive fields. Exposing sensory neurons grown in culture to 1 mu M 8-is o PGE(2) or 8iso PGF(2 alpha) augmented the number of action potentials eli cited by a ramp of depolarizing current. In contrast, 8-iso PGE(2) but not 8-iso PGF(2 alpha) enhanced the release of substance P- and calcitonin gene -related peptide-like immunoreactivity from isolated sensory neurons. Ten m icromolar 8-iso PGE(2) stimulated peptide release directly, whereas treatme nt with 1 mu M 8-iso PGE(2) augmented the release evoked by either bradykin in or capsaicin. Pretreating neuronal cultures with the nonsteroidal anti-i nflammatory drug ketorolac did not alter the sensitizing action of 8-iso PG E(2) on peptide release, suggesting that this action of the isoprostane was not secondary to the production of prostaglandins via the cyclooxygenase p athway. These data support the notion that isoprostanes are an important cl ass of inflammatory mediators that augment nociception.