Formation of 6-nitro-norepinephrine from nitric oxide and norepinephrine in the spinal cord and its role in spinal analgesia.
Spinally released norepinephrine is thought to produce analgesia in part by stimulating alpha(2)-adrenergic receptors, which in turn leads to nitric oxide synthesis. Also, nitric oxide is known to react with norepinephrine in vivo in the brain to form 6-nitro-norepinephrine, which inhibits neuronal norepinephrine reuptake. In the present study, we tested the hypothesis that formation of 6-nitro-norepinephrine occurs in the spinal cord and that intrathecal administration of 6-nitro-norepinephrine produces analgesia by stimulating norepinephrine release. 6-Nitro-norepinephrine was present in rat spinal cord tissue and microdialysates of the dorsal horn and intrathecal space. Intrathecal norepinephrine injection increased 6-nitro-norepinephrine. 6-Nitro-norepinephrine also stimulated norepinephrine release in dorsal spinal cord in vitro. Intrathecal injection of 6-nitro-norepinephrine produced antinociception and interacted additively with norepinephrine for antinociception. Spinal noradrenergic nerve destruction increased antinociception from intrathecally injected norepinephrine, but decreased antinociception from 6-nitro-norepinephrine. These results suggest a functional interaction between spinal nitric oxide and norepinephrine in analgesia, mediated in part by formation of 6-nitro-norepinephrine. Stimulation of auto-inhibitory alpha(2)-adrenergic receptors at noradrenergic synapses decreases norepinephrine release. Paradoxically, alpha(2)-adrenergic agonist injection increases and alpha(2)-adrenergic antagonist injection decreases norepinephrine release in the spinal cord. 6-Nitro-norepinephrine may be an important regulator of spinal norepinephrine release and could explain the positive feedback on norepinephrine release after activation of spinal alpha(2)-adrenergic receptors.
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Pain Mechanisms Laboratory of the Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157-1009, USA.
Li
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Xu
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Pan
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Eisenach
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JC
D000698:Analgesia / Q000379:methods*; D000818:Animals; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D008297:Male; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology; D010146:Pain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
C100495:6-nitronorepinephrine; D018341:Receptors, Adrenergic, alpha-2; D009569:Nitric Oxide; D009638:Norepinephrine