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The Journal of Neuroscience, September 1, 2000, 20(17):6714-6720
Suppressed Injury-Induced Rise in Spinal Prostaglandin
E2 Production and Reduced Early Thermal Hyperalgesia in
iNOS-Deficient Mice
Hans
Gühring1,
Manfred
Görig1,
Mehmet
Ates1,
Ovidiu
Coste1,
Hanns Ulrich
Zeilhofer1,
Andreas
Pahl1,
Klaus
Rehse2, and
Kay
Brune1
1 Department of Experimental and Clinical Pharmacology
and Toxicology, D-91054 Erlangen, Germany and 2 Department
of Pharmaceutical Chemistry, D-14195 Berlin, Germany
It is widely accepted that peripheral injury increases spinal
inducible cyclooxygenase (COX-2) expression and prostaglandin E2 (PGE2) 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 PGE2 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.
Key words:
nitric oxide; inducible nitric oxide synthase; zymosan; thermal hyperalgesia; paw edema; spinal microdialysis; L-NIL; RE-2047; prostaglandins; cyclooxygenase
Copyright © 2000 Society for Neuroscience 0270-6474/00/20176714-07$05.00/0
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