• Kenji Sugimoto, Igor Kissin, and Gary Strichartz.
• Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
• Anesth. Analg. 2008 Jul 1; 107 (1): 318-24.

BackgroundResiniferatoxin (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.MethodsClonal rat anterior pituitary (GH(3)) 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 [Ca(2+)].ResultsThe presence of 10 microM 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 microM 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.ConclusionRTX at 10 microM directly and acutely inhibited voltage-dependent Ca(2+) channels, in a TRPV1-independent manner. Prolonged exposure (24 h) to 10 microM RTX inhibited voltage-dependent Na(+) channels in addition to the Ca(2+) channels, in at least a partially reversible manner.

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