title: Suppressed injury-induced rise in spinal prostaglandin E2 production and reduced early thermal hyperalgesia in iNOS-deficient mice.
abstract: It is widely accepted that peripheral injury increases spinal inducible cyclooxygenase (COX-2) expression and prostaglandin E(2) (PGE(2)) formation as key mediators of nociceptive sensitization. Here, we used inducible nitric oxide synthase (iNOS) gene-deficient (iNOS-/-) mice to determine the contribution of iNOS-derived nitric oxide (NO) to this process. iNOS-/- mice exhibited reduced thermal hyperalgesia after zymosan injection. Spinal NO and PGE(2) formation both remained at baseline levels, in contrast to wild-type (wt) mice. In wt mice reduced hyperalgesia similar to that seen in iNOS-/- mice was induced by local spinal, but not by systemic treatment with the iNOS inhibitor l-NIL, suggesting that the reduced heat sensitization in iNOS-/- mice was attributable to the lack of spinal rather than peripheral iNOS. Two additional observations indicate that the antinociceptive effects of iNOS inhibition are dependent on a loss of stimulation of PG synthesis. First, intrathecal injection of the COX inhibitor indomethacin, which exerted pronounced antinociceptive effects in wt mice, was completely ineffective in iNOS-/- mice. Second, treatment with the NO donor RE-2047 not only completely restored spinal PG production and thermal sensitization in iNOS-/- mice but also its sensitivity to indomethacin. In both types of mice induction of thermal hyperalgesia was accompanied by similar increases in COX-1 and COX-2 mRNA expression. The stimulation of PG production by NO therefore involves an increase in enzymatic activity, rather than an alteration of COX gene expression. These results indicate that NO derived from spinal iNOS acts as a fast inductor of spinal thermal hyperalgesia.
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, D-91054 Erlangen, Germany. guehring@pharmakologie.uni-erlangen.de
authors.forename: H
authors.initials: H
authors.lastname: Gühring
authors.forename: M
authors.initials: M
authors.lastname: Görig
authors.forename: M
authors.initials: M
authors.lastname: Ates
authors.forename: O
authors.initials: O
authors.lastname: Coste
authors.forename: H U
authors.initials: HU
authors.lastname: Zeilhofer
authors.forename: A
authors.initials: A
authors.lastname: Pahl
authors.forename: K
authors.initials: K
authors.lastname: Rehse
authors.forename: K
authors.initials: K
authors.lastname: Brune
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006358:Hot Temperature; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010146:Pain / Q000503:physiopathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D013558:Sydnones / Q000494:pharmacology; D014158:Transcription, Genetic; D015054:Zymosan
chemical_list: C092610:3-methylsydnone-5-nitrosimine; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; C090663:N(6)-(1-iminoethyl)lysine; D020030:Nitric Oxide Donors; D013558:Sydnones; D009569:Nitric Oxide; D015054:Zymosan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D008239:Lysine; D015232:Dinoprostone; D007213:Indomethacin