Lidocaine Inhibits Hyperpolarization-activated Currents In Rat Spinal Substantia Gelatinosa Neurons

Objective: Lidocaine is one of the most widely used local anesthetics in surgical anesthesia and in the management of acute postoperative and chronic pain syndromes. However, besides of sodium channels, hyperpolarization–activated cyclic nucleotide-gated(HCN) channels have been also identified as a novel class of targets of lidocaine. Substantia gelatinosa(SG) neurons, Laminae II of Rexed in spinal dorsal horn, have been identified as the “central gate” of nociceptive information transmission and modulation. Moreover, hyperpolarization-activated current(Ih) mediated by HCN channels is widely expressed in SG neurons. However, the exact roles of lidocaine on HCN channels in SG neurons remain unclear. Thus, by using the whole-cell patchclamp recordings in this study, we aim to investigate the effect of lidocaine on Ih and burst firing in SG neurons and interpret another new probable mechanism of lidocaine in regulating pain and provide a new theoretical basis for clinical application of lidocaine.Methods: 3-5 weeks old male Spraueu-Dawley rats were deeply anesthetized with urethane intraperitoneally. After transcardial perfusion with anatomy solution, the lumbosacral spinal cords(L1-S3) were extracted. Parasagittal slices measuring 300 ?m in thickness were cut. Whole-cell patch clamp recordings were conducted to investigate the effect of lidocaine on Ih and firing in SG neurons.Results: 1. Inward currents could be recorded in about 56% SG neurons after the injection of hyperpolarization current. ZD7288(a selective inhibitor of HCN channels) obviously inhibited these currents; 2. Lidocaine significantly inhibited Ih in a rapid, reversible, and dose-dependent manner(IC50 = 80 ?M). Moreover, The inhibition rate of Ih was not significantly different with a second application of lidocaine of the same concentration to the same neuron;3. Lidocaine still inhibited Ih in the presence of tetrodotoxin(TTX, a sodium channel blocker), as the inhibition of Ih by lidocaine was not significantly different in the absence or presence of TTX; 4. Lidocaine shifted Ih activation curve to more hyperpolarized potential, decreased the current density and increased the time constant of Ih; 5. Lidocaine shifted the reversal potential of Ih towards more negative direction; 6. Lidocaine reduced the frequency of action potential and the rebound spikes, delayed the rebound depolarization latency, increased the resting membrane potential and input resistance of SG neurons.Conclusions: Lidocaine inhibits Ih in a rapid, reversible and concentration-dependent manner in substantial gelatinosa neurons, further to suppress the burst firing in SG neurons and to decrease the excitability of SG neurons. Our study may indicate that the inhibition of lidocaine on Ih in SG neurons may be one of the other mechanisms of lidocaine in regulating the analgesic effect.