Article

Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors.

Department of Medical Chemistry, Kansai Medical University, 10-15 Fumizono, Moriguchi 570-8506, Japan.
Nitric Oxide (impact factor: 3.55). 09/2007; 17(1):18-24. DOI:10.1016/j.niox.2007.04.004 pp.18-24
Source: PubMed

ABSTRACT We have recently demonstrated that nitric oxide (NO) produced by neuronal NO synthase (nNOS) in the spinal cord is involved in the maintenance of neuropathic pain. To clarify whether NO itself affected nNOS activity in the spinal cord as a retrograde messenger, we examined the involvement of the NO/cGMP signaling pathway in the regulation of nNOS activity by NADPH-diaphorase histochemistry. NO-generating agents NOR3 (t(1/2)=30min) and SNAP (t(1/2)=5h), but not NOR1 (t(1/2)=1.8min), significantly enhanced NADPH-diaphorase staining in the spinal cord. 8-Br-cGMP also enhanced it similar to that by NOR3, and 8-Br-cAMP and forskolin, an activator of adenylate cyclase, enhanced it moderately. NOR1 and NOR3 markedly increased the cGMP level in the spinal cord. The enhancement of NADPH-diaphorase staining by NOR3 was significantly inhibited by CPTIO, an NO scavenger, ODQ, a soluble guanylate cyclase inhibitor, and KT5823, an inhibitor of cGMP-dependent protein kinase. Additionally, the NOR3-enhanced nNOS activity was completely inhibited by NMDA antagonists MK-801 and d-AP5, partially by the GluRepsilon2-selective antagonist CP-101,606, and was attenuated in GluRepsilon1(-/-) and GluRepsilon1(-/-)/epsilon4(-/-) mice. These results suggest that NO may regulate nNOS activity as a retrograde messenger in the spinal cord via activation of NMDA receptor containing GluRepsilon1 and GluRepsilon2 subunits.

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Keywords

attenuated
 
cGMP level
 
cGMP-dependent protein kinase
 
clarify
 
d-AP5
 
GluRepsilon2 subunits
 
GluRepsilon2-selective antagonist CP-101,606
 
NADPH-diaphorase histochemistry
 
NADPH-diaphorase staining
 
neuropathic pain
 
nitric oxide
 
NMDA antagonists MK-801
 
NMDA receptor
 
nNOS activity
 
NO/cGMP signaling pathway
 
NOR3-enhanced nNOS activity
 
retrograde messenger
 
scavenger
 
soluble guanylate cyclase inhibitor
 
spinal cord