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This Article Full Text Full Text (PDF) All Versions of this Article: 96/4/1848    most recent 00354.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sheets, P. L. Articles by Cummins, T. R. Search for Related Content PubMed PubMed Citation Articles by Sheets, P. L. Articles by Cummins, T. R.

Inhibition of Na_v1.7 and Na_v1.4 Sodium Channels by Trifluoperazine Involves the Local Anesthetic Receptor

¹Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana; ²Department of Anesthesiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ³Department of Biology, State University of New York, Albany, New York

Submitted 5 April 2006; accepted in final form 26 June 2006

The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Na_v1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 µM TFP induce major decreases in Na_v1.7 and Na_v1.4 current amplitudes and that 2 µM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na_v1.7 and Na_v1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Na_v1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.