Journal
NEUROPHARMACOLOGY
Volume 125, Issue -, Pages 156-165Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2017.07.023
Keywords
Synaptic plasticity; Synaptic transmission; Signal transduction; Ion channel; Neuropathic pain; Dorsal horn neurons
Categories
Funding
- National Institutes of Health [R01 GM120844]
- N.G. and Helen T. Hawkins Endowment
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The role of nitric oxide (NO) in nociceptive transmission at the spinal cord level remains uncertain. Increased activity of spinal N-methyl-o-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 precursor L-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 of L-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 of L-arginine on spinal NMDA receptor activity. Furthermore, knockdown of nNOS with siRNA abolished the inhibitory effects of L-arginine, but not SNAP, on spinal NMDA receptor activity in both groups of rats. Additionally, intrathecal injection of L-arginine significantly attenuated mechanical or thermal hyperalgesia induced by nerve injury, and the L-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. (C) 2017 Elsevier Ltd. All rights reserved.
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