6-NO(2)-norepinephrine increases norepinephrine release and inhibits norepinephrine uptake in rat spinal synaptosomes.
Nitric oxide has been shown to react under physiologic conditions with norepinephrine (NE) to produce 6-nitro-norepinephrine (6-NO(2)-NE), a compound that enhances NE release in the brain. Previous studies suggest that 6-NO(2)-NE is formed in the spinal cord and stimulates spinal NE release to produce analgesia. The purpose of the current studies was to examine the mechanisms by which 6-NO(2)-NE stimulates NE release in the spinal cord. Crude synaptosomes were prepared from spinal cords of male Sprague-Dawley rats and loaded with [(3)H]NE. Incubation of synaptosomes with 6-NO(2)-NE resulted in a release of NE, with a threshold of 1 microM 6-NO(2)-NE and a maximum effect of 30% fractional release. NE transporter inhibitors desipramine and nomifensine blocked NE release from 6-NO(2)-NE, and desipramine exhibited an IC(50) of 9.6 microM. NE release from 6-NO(2)-NE was dependent on external Na(+), but not Ca(2+) or the activity of guanylate cyclase. 6-NO(2)-NE also blocked uptake of [(3)H]NE into synaptosomes, with an IC(50) of 8.3 microM. These data are consistent with a direct action of 6-NO(2)-NE on noradrenergic terminals in the spinal cord to release NE. This action is independent of guanylate cyclase activation, and most likely shares a common mechanism with classic monoamine releasers such as amphetamine that cause direct release of NE from vesicles into the nerve terminal cytoplasm, leading to extracellular release by reverse transport.
Li
X
X
Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Rose
G
G
Chiari
A
A
Pan
H L
HL
Tobin
J R
JR
Eisenach
J C
JC
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
C100495:6-nitronorepinephrine; D009569:Nitric Oxide; D012964:Sodium; D002118:Calcium; D009638:Norepinephrine