Lidocaine that is widely used as local anesthetics and anti-arrhythmia drugs inhibits voltage-gated Na channels by stabilizing inactivation, so that it blocks neurotransmission. Lidocaine passes through lipid cell membrane and binds Na channel protein from the inside of cell membrane. Recently, systemic continuous low-dose intravenous infusion of lidocaine has been shown to relieve cancer pain, chronic pain, pain due to adiposis dolorosa, and pain after surgery, although the precise mechanisms remain unclear. We examined the effects of lidocaine on respiratory rhythm generation in the brainstem-spinal cord preparations isolated from 0-3 day old Wistar rats. Preparations were superfused at a rate of 3.0 ml/min with the following artificial cerebrospinal fluid (in mM): 124 NaCl, 5.0 KCl, 1.24 KH2PO4, 2.4 CaCl2, 1.3 MgCl2, 26 NaHCO3 and 30 glucose, equilibrated with 95% O2 and 5% CO2, pH 7.4, at 26-27ºC. Inspiratory activity was monitored from the fourth cervical ventral root. Low dose (10-50 μM) of lidocaine has been shown to increase in the C4 burst rate, but high dose (100-400 μM) of lidocaine dose-dependently decreases C4 burst rate and then blocks the burst activity completely. Burst duration of inspiratory and pre-inspiratory (Pre-I) neurons decreased dose-dependently after application of 100-400 μM lidocaine. Effects of high dose of lidocaine were irreversible after washed out. Though high dose of lidocaine stops respiratory neuron burst activities, action potentials were induced when they were depolarized by the electric pulse current injection. We hypothesized that lidocaine depressed respiratory burst generation via blockade of persistent sodium channels before complete blockade of fast sodium channels.