Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury. (October 2017)

• Record Type: Journal Article
• Authors: Chen, Shao-Rui; Jin, Xiao-Gao; Pan, Hui-Lin
• Is Part Of: Neuropharmacology. Volume 125(2017)
• Page Start: 156
• Page End: 165
• Publication Date: 2017-10
• Subjects: Synaptic plasticity -- Synaptic transmission -- Signal transduction -- Ion channel -- Neuropathic pain -- Dorsal horn neurons; NO nitric oxide -- nNOS neuronal nitric oxide synthase -- NMDAR N-methyl-d-aspartate receptor -- ODQ 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one -- sGC soluble guanylyl cyclase -- SNL spinal nerve ligation -- SNAP S-nitroso-N-acetylpenicillamine -- TRIM 1, 2-trifluoromethylphenyl imidazole; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.07.023
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: The role of nitric oxide (NO) in nociceptive transmission at the spinal cord level remains uncertain. Increased activity of spinal N -methyl-d -aspartate (NMDA) receptors contributes to development of chronic pain induced by peripheral nerve injury. In this study, we determined how endogenous NO affects NMDA receptor activity of spinal cord dorsal horn neurons in control and spinal nerve-ligated rats. Bath application of the NO precursorl -arginine or the NO donor S -nitroso- N -acetylpenicillamine (SNAP) significantly inhibited NMDA receptor currents of spinal dorsal horn neurons in both sham control and nerve-injured rats. Inhibition of neuronal nitric oxide synthase (nNOS) or blocking the S -nitrosylation reaction with N -ethylmaleimide abolished the inhibitory effects ofl -arginine on NMDA receptor currents recorded from spinal dorsal horn neurons in sham control and nerve-injured rats. However, bath application of the cGMP analog 8-bromo-cGMP had no significant effects on spinal NMDA receptor currents. Inhibition of soluble guanylyl cyclase also did not alter the inhibitory effect ofl -arginine on spinal NMDA receptor activity. Furthermore, knockdown of nNOS with siRNA abolished the inhibitory effects ofl -arginine, but not SNAP, on spinal NMDA receptor activity in both groups of rats. Additionally, intrathecal injection ofl -arginine significantly attenuated mechanical or thermal hyperalgesia induced by nerve injury, and thel -arginine effect was diminished in rats treated with a nNOS inhibitor or nNOS-specific siRNA. These findings suggest that endogenous NO inhibits spinal NMDA receptor activity through S -nitrosylation. NO derived from nNOS attenuates spinal nociceptive transmission and neuropathic pain induced by nerve injury. Highlights: Nitric oxide (NO) affects synaptic transmission but its role in neuropathic pain is unclear. Endogenous NO inhibits NMDA receptor activity in the spinal dorsal horn through S -nitrosylation. NO reduces spinal cord NMDA receptor activity and pain hypersensitivity caused by nerve injury. Understanding how NO controls pain transmission may improve treatments for neuropathic pain.