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Anesth Analg 2009; 109:632-640
© 2009 International Anesthesia Research Society
doi: 10.1213/ane.0b013e3181a909a4
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ANALGESIA

The Effect of {kappa}-Opioid Receptor Agonists on Tetrodotoxin-Resistant Sodium Channels in Primary Sensory Neurons

Xin Su, MD, Neil A. Castle, PhD, Brett Antonio, BS, Rosemarie Roeloffs, PhD, James B. Thomas, PhD, Douglas S. Krafte, PhD, and Mark L. Chapman, PhD

From the Icagen, Inc, Durham, North Carolina.

Address correspondence and reprint requests to Xin Su, MD, Neuromodulation, Medtronic Inc, 7000 Central Avenue NE, RCE470, Minneapolis, MN 55432. Address e-mail to xin.su{at}medtronic.com.

Abstract

BACKGROUND: A non-opioid receptor-mediated inhibition of sodium channels in dorsal root ganglia (DRGs) by {kappa}-opioid receptor agonists ({kappa}-ORAs) has been reported to contribute to the antinociceptive actions in animals and humans. In this study, we examined structurally diverse {kappa}-ORAs for their abilities to inhibit tetrodotoxin-resistant (TTX-r) sodium channels in adult rat DRGs.

METHODS: Whole-cell recordings of TTX-r sodium currents were performed on cultured adult rat DRGs. Structurally diverse {kappa}-ORAs were studied for their abilities to inhibit TTX-r sodium channels.

RESULTS: The racemic {kappa}-ORA, (±)U50,488, inhibited TTX-r sodium currents in a voltage-dependent manner, yielding IC50 values of 49 and 8 µM, at prepulse potentials of –100 and –40 mV, respectively. Furthermore, we found that both the {kappa}-ORA U50,488 active enantiomer 1S,2S U50,488 and the inactive enantiomer 1R,2R U50,488 were equally potent inhibitors of TTX-r sodium currents. Structurally related {kappa}-ORAs, such as BRL 52537 and ICI 199,441 also inhibited TTX-r sodium currents. However, sodium channel inhibition and {kappa}-opioid receptor agonism have a distinct structure-activity relationship because another {kappa}-ORA (ICI 204,488) was inactive versus TTX-r sodium channels. We further investigated the sodium channel block of this class of compounds by studying (±)U50,488. (±)U50,488 was found to preferentially interact with the slow inactivated state of TTX-r sodium channels and to retard recovery from inactivation.

CONCLUSION: Our results suggest that TTX-r sodium channels can be inhibited by many {kappa}-ORAs via an opioid receptor-independent mechanism. Although the potency for sodium channel inhibition is typically much less than apparent affinity for opioid receptors, sodium channel block may still contribute to the antinociceptive effects of this class of compounds.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2009 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2009 by the International Anesthesia Research Society.