Vol. 293, Issue 3, 912-920, June 2000

Isoprostanes, Novel Eicosanoids That Produce Nociception and Sensitize Rat Sensory Neurons¹

Angela R. Evans² , Heidi Junger² , Michael D. Southall, Grant D. Nicol, Linda S. Sorkin, James T. Broome, Timothy W. Bailey and Michael R. Vasko

Department of Pharmacology and Toxicology (A.R.E., M.D.S., G.D.N., J.T.B., T.W.B., M.R.V.) and Department of Anesthesia (M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and Department of Anesthesiology, University of California at San Diego, La Jolla, California (H.J., L.S.S.)

Isoprostanes are a novel class of eicosanoids primarily formed by peroxidation of arachidonic acid. Because of their potential as inflammatory and/or hyperalgesic agents whose formation is largely independent of cyclooxygenases, we examined whether 8-iso prostaglandin E₂ (8-iso PGE₂) or 8-iso prostaglandin F₂ (8-iso PGF₂) reduces mechanical and thermal withdrawal threshold in rats, and whether they sensitize rat sensory neurons. Injection of 1 µg of 8-iso PGE₂ (in 2.5 µl) into the hindpaw of rats significantly reduced mechanical and thermal withdrawal thresholds, whereas 1 µg of 8-iso PGF₂ elicited a transient decrease in only the mechanical withdrawal threshold. Both isoprostanes enhanced the firing of C-nociceptors in a concentration-dependent manner when injected into peripheral receptive fields. Exposing sensory neurons grown in culture to 1 µM 8-iso PGE₂ or 8-iso PGF₂ augmented the number of action potentials elicited by a ramp of depolarizing current. In contrast, 8-iso PGE₂ but not 8-iso PGF₂ enhanced the release of substance P- and calcitonin gene-related peptide-like immunoreactivity from isolated sensory neurons. Ten micromolar 8-iso PGE₂ stimulated peptide release directly, whereas treatment with 1 µM 8-iso PGE₂ augmented the release evoked by either bradykinin or capsaicin. Pretreating neuronal cultures with the nonsteroidal anti-inflammatory drug ketorolac did not alter the sensitizing action of 8-iso PGE₂ on peptide release, suggesting that this action of the isoprostane was not secondary to the production of prostaglandins via the cyclooxygenase pathway. These data support the notion that isoprostanes are an important class of inflammatory mediators that augment nociception.