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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Synergistic Inhibition of Lysophosphatidic Acid Signaling by Charged and Uncharged Local Anesthetics

Lisa M. Sullivan, MD^*, Christian W. Hönemann, MD^*,, John A. Arledge, BS^*, and Marcel E. Durieux, MD^*

*Department of Anesthesiology, University of Virginia Health System Charlottesville, Virginia; and Department of Anesthesiology, Wilhelms-Universität Muenster, Muenster, Germany

Address correspondence and reprint requests to Dr. Durieux, Department of Anesthesiology, University of Virginia HSC, PO Box 10010, Charlottesville, VA 22906-0010. Address e-mail to med2p{at}virginia.edu

We investigated the mechanism of benzocaine (permanently uncharged) and QX314 (permanently charged) inhibition of lysophosphatidic acid (LPA) signaling. To determine their site of action, we studied effects of these drugs, alone and in combination, on LPA-induced Ca^{2 +}-dependent Cl currents (I_Cl(Ca)) in Xenopus oocytes. After 10 min exposure to benzocaine, QX314 (10^-6–10^-2 M), or both, we measured effects on I_Cl(Ca) induced by LPA (with and without protein kinase [PKC] activation/inhibition) and on I_Cl(Ca) induced by the intracellular injection of IP₃ and GTPS. LPA application to oocytes resulted in I_Cl(Ca) (50% effective concentration approximately 10^-8 M). Both anesthetics inhibited LPA signaling concentration-dependently (50% inhibitory concentration [IC₅₀] benzocaine 0.9 mM, QX314 0.66 mM). The combination acted synergistically (IC₅₀ benzocaine 0.097 mM/QX314 0.048 mM). Intracellular signaling pathways were not affected. This study shows that benzocaine and QX314 inhibit LPA signaling and act synergistically, which is most easily explained by the existence of two different binding sites. Lack of inhibition of IP₃ or GTPS-induced I_Cl(Ca) identifies the receptor as a target. Activation of PKC can be excluded as a potential mechanism.

Implications: Lysophosphatidic acid may play a role in wound healing, and its signaling is inhibited by local anesthetics. We identified the membrane receptor as the local anesthetic site of action and showed that charged (QX314) and uncharged (benzocaine) local anesthetics inhibit lysophosphatidic acid signaling synergistically, which can be explained by the presence of different binding sites.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999