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The Journal of Neuroscience, July 29, 2009, 29(30):9500-9509; doi:10.1523/JNEUROSCI.5803-08.2009

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Cellular/Molecular
Molecular Mechanisms of Lipoic Acid Modulation of T-Type Calcium Channels in Pain Pathway

Woo Yong Lee,^1,2 * Peihan Orestes,^2,5 * Janelle Latham,² Ajit K. Naik,² Michael T. Nelson,^2,5 Iuliia Vitko,^4,5 Edward Perez-Reyes,^4,5 Vesna Jevtovic-Todorovic,^2,3,5 and Slobodan M. Todorovic^2,3,5

¹Department of Anesthesiology and Pain Medicine InJe University, Sanggyepaik Hospital, Seoul 139-707, South Korea, Departments of ²Anesthesiology, ³Neuroscience, and ⁴Pharmacology, and ⁵Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0710

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

-Lipoic acid (1,2-dithiolane-3-pentanoic acid; lipoic acid) is an endogenous compound used to treat pain disorders in humans, but its mechanisms of analgesic action are not well understood. Here, we show that lipoic acid selectively inhibited native Ca_V3.2 T-type calcium currents (T-currents) and diminished T-channel-dependent cellular excitability in acutely isolated rat sensory neurons. Lipoic acid locally injected into peripheral receptive fields of pain-sensing sensory neurons (nociceptors) in vivo decreased sensitivity to noxious thermal and mechanical stimuli in wild-type but not Ca_V3.2 knock-out mice. Ensuing molecular studies demonstrated that lipoic acid inhibited recombinant Ca_V3.2 channels heterologously expressed in human embryonic kidney 293 cells by oxidating specific thiol residues on the cytoplasmic face of the channel. This study provides the first mechanistic demonstration of a nociceptive ion channel modulation that may contribute to the documented analgesic properties of lipoic acid in vivo.

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Received Dec. 5, 2008; revised May 27, 2009; accepted June 19, 2009.

Correspondence should be addressed to Slobodan M. Todorovic, Department of Anesthesiology, University of Virginia Health System, Mail Box 800710, Charlottesville, VA 22908-0710. Email: st9d{at}virginia.edu

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