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Lidocaine Inhibits HCN Currents in Rat Spinal Substantia Gelatinosa Neurons

Hu, Tao MD; Liu, Nana MD; Lv, Minhua MD; Ma, Longxian MD; Peng, Huizhen MD; Peng, Sicong; Liu, Tao PhD, MD

doi: 10.1213/ANE.0000000000001140
Anesthetic Pharmacology: Research Report

BACKGROUND: Lidocaine, which blocks voltage-gated sodium channels, is widely used in surgical anesthesia and pain management. Recently, it has been proposed that the hyperpolarization-activated cyclic nucleotide (HCN) channel is one of the other novel targets of lidocaine. Substantia gelatinosa in the spinal dorsal horn, which plays key roles in modulating nociceptive information from primary afferents, comprises heterogeneous interneurons that can be electrophysiologically categorized by firing pattern. Our previous study demonstrated that a substantial proportion of substantia gelatinosa neurons reveal the presence of HCN current (I h); however, the roles of lidocaine and HCN channel expression in different types of substantia gelatinosa neurons remain unclear.

METHODS: By using the whole-cell patch-clamp technique, we investigated the effect of lidocaine on I h in rat substantia gelatinosa neurons of acute dissociated spinal cord slices.

RESULTS: We found that lidocaine rapidly decreased the peak I h amplitude with an IC50 of 80 μM. The inhibition rate on I h was not significantly different with a second application of lidocaine in the same neuron. Tetrodotoxin, a sodium channel blocker, did not affect lidocaine’s effect on I h. In addition, lidocaine shifted the half-activation potential of I h from −109.7 to −114.9 mV and slowed activation. Moreover, the reversal potential of I h was shifted by −7.5 mV by lidocaine. In the current clamp, lidocaine decreased the resting membrane potential, increased membrane resistance, delayed rebound depolarization latency, and reduced the rebound spike frequency. We further found that approximately 58% of substantia gelatinosa neurons examined expressed I h, in which most of them were tonically firing.

CONCLUSIONS: Our studies demonstrate that lidocaine strongly inhibits I h in a reversible and concentration-dependent manner in substantia gelatinosa neurons, independent of tetrodotoxin-sensitive sodium channels. Thus, our study provides new insight into the mechanism underlying the central analgesic effect of the systemic administration of lidocaine.

Published ahead of print January 11, 2016

From the Departments of *Pediatrics and Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; and Center for Laboratory Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China.

Accepted for publication November 17, 2015.

Published ahead of print January 11, 2016

Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81000480 and 81260175) and Natural Science Foundation of Jiangxi, China (No. 20151BAB204022).

The authors declare no conflicts of interest.

The first three authors are co-first authors.

Reprints will not be available from the authors.

Address correspondence to Tao Liu, PhD, MD, Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Yongwaizhengjie 17, Nanchang, Jiangxi, People’s Republic of China. Address e-mail to

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© 2016 International Anesthesia Research Society