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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Angela R. Evans, Heidi Junger, Michael D. Southall, Grant D. Nicol, Linda S. Sorkin, James T. Broome, Timothy W. Bailey and Michael R. Vasko
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 912-920;
Angela R. Evans
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Heidi Junger
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Michael D. Southall
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Grant D. Nicol
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Linda S. Sorkin
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James T. Broome
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Timothy W. Bailey
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Michael R. Vasko
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Abstract

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 F2α (8-iso PGF2α) 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 PGF2α 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 PGF2α augmented the number of action potentials elicited by a ramp of depolarizing current. In contrast, 8-iso PGE2 but not 8-iso PGF2α 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.

Footnotes

  • Send reprint requests to: Michael R. Vasko, Ph.D., Dept. of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202-5120. E-mail: vaskom{at}iupui.edu

  • ↵1 This work was supported by National Institutes of Health Grants F32 NS 09733 (to A.R.E.), NS35630 (to L.S.S.), NS30527 (to G.D.N.), and NS34159 (to M.R.V.).

  • ↵2 These authors contributed equally to the work.

  • Abbreviations:
    8-iso PGF2α
    8-iso prostaglandin F2α
    8-iso PGE2
    8-iso prostaglandin E2
    SP
    substance P
    iSP
    immunoreactive substance P
    CGRP
    calcitonin gene-related peptide
    iCGRP
    immunoreactive calcitonin gene-related peptide
    NSAIDs
    nonsteroidal anti-inflammatory drugs
    SRT
    sustained response threshold
    LSD
    least significant difference
    • Received December 8, 1999.
    • Accepted February 24, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Angela R. Evans, Heidi Junger, Michael D. Southall, Grant D. Nicol, Linda S. Sorkin, James T. Broome, Timothy W. Bailey and Michael R. Vasko
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 912-920;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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

Angela R. Evans, Heidi Junger, Michael D. Southall, Grant D. Nicol, Linda S. Sorkin, James T. Broome, Timothy W. Bailey and Michael R. Vasko
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 912-920;
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