Nitric Oxide Inhibits Nociceptive Transmission by Differentially Regulating Glutamate and Glycine Release to Spinal Dorsal Horn Neurons

• Published in: The Journal of biological chemistry 2011-09, Vol.286 (38), p.33190-33202
• Main Authors: Jin, Xiao-Gao, Chen, Shao-Rui, Cao, Xue-Hong, Li, Li, Pan, Hui-Lin
• Format: Article
• Language: English
• Subjects: Animals; Calcium Channels; Calcium Channels - metabolism; Cell Line; Cyclic GMP (cGMP); Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - metabolism; gamma-Aminobutyric Acid - metabolism; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Glutamic Acid - metabolism; Glycine - metabolism; Guanylate Cyclase - metabolism; Ion Channel Gating - drug effects; Male; Neurobiology; Nitric Oxide; Nitric Oxide - pharmacology; Nitrosation - drug effects; Nitrosylation; Nociceptors - metabolism; Posterior Horn Cells - drug effects; Posterior Horn Cells - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Synapses - drug effects; Synapses - metabolism; Synaptic Plasticity; Synaptic Transmission - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.270967

Nitric oxide (NO) is involved in many physiological functions, but its role in pain signaling remains uncertain. Surprisingly, little is known about how endogenous NO affects excitatory and inhibitory synaptic transmission at the spinal level. Here we determined how NO affects excitatory and inhibitory synaptic inputs to dorsal horn neurons using whole-cell recordings in rat spinal cord slices. The NO precursor l-arginine or the NO donor SNAP significantly increased the frequency of glycinergic spontaneous and miniature inhibitory postsynaptic currents (IPSCs) of lamina II neurons. However, neither l-arginine nor SNAP had any effect on GABAergic IPSCs. l-arginine and SNAP significantly reduced the amplitude of monosynaptic excitatory postsynaptic currents (EPSCs) evoked from the dorsal root with an increase in paired-pulse ratio. Inhibition of the soluble guanylyl cyclase abolished the effect of l-arginine on glycinergic IPSCs but not on evoked monosynaptic EPSCs. Also, inhibition of protein kinase G blocked the increase in glycinergic sIPSCs by the cGMP analog 8-bromo-cGMP. The inhibitory effects of l-arginine on evoked EPSCs and high voltage-activated Ca2+ channels expressed in HEK293 cells and dorsal root ganglion neurons were abolished by blocking the S-nitrosylation reaction with N-ethylmaleimide. Intrathecal injection of l-arginine and SNAP significantly increased mechanical nociceptive thresholds. Our findings suggest that spinal endogenous NO enhances inhibitory glycinergic input to dorsal horn neurons through sGC-cGMP-protein kinase G. Furthermore, NO reduces glutamate release from primary afferent terminals through S-nitrosylation of voltage-activated Ca2+ channels. Both of these actions probably contribute to inhibition of nociceptive transmission by NO at the spinal level. The role of nitric oxide (NO) in pain regulation remains controversial. It is unclear how NO affects spinal synaptic transmission. NO increases glycine release but inhibits glutamate release in the spinal cord through distinct mechanisms. NO inhibits nociceptive transmissions at the spinal level. To learn how NO controls spinal synaptic transmission is critical for understanding the role of NO in pain processing.