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Anesth Analg 2008; 107:318-324
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31816d140a
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PAIN MECHANISMS

A High Concentration of Resiniferatoxin Inhibits Ion Channel Function in Clonal Neuroendocrine Cells

Kenji Sugimoto, MD, PhD, Igor Kissin, MD, PhD, and Gary Strichartz, PhD

From the Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Address correspondence and reprint requests to G. Strichartz, PhD, MRB 613/BWH, 75 Francis St., Boston, MA 02115-6110. Address e-mail to gstrichz{at}zeus.bwh.harvard.edu.

Abstract

BACKGROUND: Resiniferatoxin (RTX) is a potent agonist of the transient receptor potential vanilloid 1 channel (TRPV1) found in peripheral nociceptors. RTX causes cellular excitation first, followed by a long-lasting refractory state, which has suggested its therapeutic use for pain control. RTX's effect could result from specific actions on TRPV1 channels, but might also arise from previously reported TRPV1-independent effects. We have tested whether exposure to RTX compromises ion channels in a TRPV1-independent manner.

METHODS: Clonal rat anterior pituitary (GH3) cells, loaded with the Ca+2-sensitive fluorescent dye (fluo-4), were stimulated with the Na+ channel activator veratridine (VTD) or directly depolarized by 60 mM K+ solution. The physiological effects of exposure to RTX were evaluated by stimulated increases of fluorescence from raised intracellular [Ca2+].

RESULTS: The presence of 10 µM RTX acutely reduced the median fluorescence changes by VTD and 60 mM K+ to 45% and 50%, respectively (P = 0.018 and 0.043). Prolonged exposure (24 h) of cells to 10 µM RTX, followed by a 2 h washout, reduced the median fluorescence changes by VTD and 60 mM K+ to 5.6% and 42% of control changes, respectively (P = 0.027 and 0.011). Cell responses to VTD partially recovered, to 42% of control, after incubation in RTX-free medium for 24 h.

CONCLUSION: RTX at 10 µM directly and acutely inhibited voltage-dependent Ca2+ channels, in a TRPV1-independent manner. Prolonged exposure (24 h) to 10 µM RTX inhibited voltage-dependent Na+ channels in addition to the Ca2+ channels, in at least a partially reversible manner.







Lippincott, Williams & Wilkins 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 HighWire Press
Copyright © 2008 by the International Anesthesia Research Society.