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PAIN MECHANISMS

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

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.