• Dan Okura, Takafumi Horishita, Susumu Ueno, Nobuyuki Yanagihara, Yuka Sudo, Yasuhito Uezono, Tomoko Minami, Takashi Kawasaki, and Takeyoshi Sata.
• From the Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu, Fukuoka, Japan; Department of Occupational Toxicology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu, Fukuoka, Japan; Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu, Fukuoka, Japan; Department of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan; and Cancer Pathophysiology Division, National Cancer Center Research Institute, Chuouku, Tokyo, Japan.
• Anesth. Analg. 2015 Mar 1; 120 (3): 597-605.

BackgroundLidocaine has been widely used to relieve acute pain and chronic refractory pain effectively by both systemic and local administration. Numerous studies reported that lidocaine affects several pain signaling pathways as well as voltage-gated sodium channels, suggesting the existence of multiple mechanisms underlying pain relief by lidocaine. Some extracellular adenosine triphosphate (ATP) receptor subunits are thought to play a role in chronic pain mechanisms, but there have been few studies on the effects of lidocaine on ATP receptors. We studied the effects of lidocaine on purinergic P2X3, P2X4, and P2X7 receptors to explore the mechanisms underlying pain-relieving effects of lidocaine.MethodsWe investigated the effects of lidocaine on ATP-induced currents in ATP receptor subunits, P2X3, P2X4, and P2X7 expressed in Xenopus oocytes, by using whole-cell, two-electrode, voltage-clamp techniques.ResultsLidocaine inhibited ATP-induced currents in P2X7, but not in P2X3 or P2X4 subunits, in a concentration-dependent manner. The half maximal inhibitory concentration for lidocaine inhibition was 282 ± 45 μmol/L. By contrast, mepivacaine, ropivacaine, and bupivacaine exerted only limited effects on the P2X7 receptor. Lidocaine inhibited the ATP concentration-response curve for the P2X7 receptor via noncompetitive inhibition. Intracellular and extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) and benzocaine suppressed ATP-induced currents in the P2X7 receptor in a concentration-dependent manner. In addition, repetitive ATP treatments at 5-minute intervals in the continuous presence of lidocaine revealed that lidocaine inhibition was use-dependent. Finally, the selective P2X7 receptor antagonists Brilliant Blue G and AZ11645373 did not affect the inhibitory actions of lidocaine on the P2X7 receptor.ConclusionsLidocaine selectively inhibited the function of the P2X7 receptor expressed in Xenopus oocytes. This effect may be caused by acting on sites in the ion channel pore both extracellularly and intracellularly. These results help to understand the mechanisms underlying the analgesic effects of lidocaine when it is administered locally at least.

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