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Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels


In traditional folk medicine, Xanthoxylum plants are referred to as 'toothache trees' because their anesthetic or counter-irritant properties render them useful in the treatment of pain. Psychophysical studies have identified hydroxy-α-sanshool as the compound most responsible for the unique tingling and buzzing sensations produced by Szechuan peppercorns or other Xanthoxylum preparations. Although it is generally agreed that sanshool elicits its effects by activating somatosensory neurons, the underlying cellular and molecular mechanisms remain a matter of debate. Here we show that hydroxy-α-sanshool excites two types of sensory neurons, including small-diameter unmyelinated cells that respond to capsaicin (but not mustard oil) as well as large-diameter myelinated neurons that express the neurotrophin receptor TrkC. We found that hydroxy-α-sanshool excites neurons through a unique mechanism involving inhibition of pH- and anesthetic-sensitive two-pore potassium channels (KCNK3, KCNK9 and KCNK18), providing a framework for understanding the unique and complex psychophysical sensations associated with the Szechuan pepper experience.

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Figure 1: Hydroxy-α-sanshool excites a subset of presumptive nociceptors and mechanoreceptors.
Figure 2: Sanshool inhibits pH-sensitive background potassium channels in sensory neurons.
Figure 3: Sanshool inhibits KCNK3, KCNK9 and KCNK18.
Figure 4: TRPA1 and TRPV1 are not required for sanshool sensitivity.
Figure 5: Sanshool excites CNS neurons that express KCNK3, KCNK9 or KCNK18.
Figure 6: Sanshool excites sensory neurons that express KCNK3, KCNK9 or KCNK18.


  1. Meyer, R.A., Ringkamp, M., Campbell, J.N. & Raja, S.N. Peripheral mechanisms of cutaneous nociception. in Textbook of Pain (eds. McMahon, S.B. & Koltzenburg, M.) 3–34 (Elsevier, Philadelphia, 2006).

    Google Scholar 

  2. Julius, D. & Basbaum, A.I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001).

    Article  CAS  Google Scholar 

  3. Fields, H.L. Pain (McGraw-Hill, New York, 1987).

  4. Snyder, S.H. Opiate receptors and internal opiates. Sci. Am. 236, 44–56 (1977).

    Article  CAS  Google Scholar 

  5. Julius, D. From peppers to peppermints: natural products as probes of the pain pathway. Harvey Lect. 101, 89–115 (2005).

    CAS  PubMed  Google Scholar 

  6. Woolf, C.J. & Ma, Q. Nociceptors–noxious stimulus detectors. Neuron 55, 353–364 (2007).

    Article  CAS  Google Scholar 

  7. Foster, S. & Duke, J.A. Eastern/Central Medicinal Plants and Herbs (Houghton-Mifflin, New York, 2000).

    Google Scholar 

  8. McGee, H. On Food and Cooking: The Science and Lore of the Kitchen (Scribner, New York, 2004).

    Google Scholar 

  9. Sugai, E. et al. Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1. Biosci. Biotechnol. Biochem. 69, 1951–1957 (2005).

    Article  CAS  Google Scholar 

  10. Sugai, E., Morimitsu, Y. & Kubota, K. Quantitative analysis of sanshool compounds in Japanese pepper (Xanthoxylum piperitum DC.) and their pungent characteristics. Biosci. Biotechnol. Biochem. 69, 1958–1962 (2005).

    Article  CAS  Google Scholar 

  11. Bryant, B.P. & Mezine, I. Alkylamides that produce tingling paresthesia activate tactile and thermal trigeminal neurons. Brain Res. 842, 452–460 (1999).

    Article  CAS  Google Scholar 

  12. Koo, J.Y. et al. Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur. J. Neurosci. 26, 1139–1147 (2007).

    Article  Google Scholar 

  13. Kobayashi, K. et al. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with aδ/c-fibers and colocalization with trk receptors. J. Comp. Neurol. 493, 596–606 (2005).

    Article  CAS  Google Scholar 

  14. Ramsey, I.S., Delling, M. & Clapham, D.E. An introduction to TRP channels. Annu. Rev. Physiol. 68, 619–647 (2006).

    Article  CAS  Google Scholar 

  15. Bautista, D.M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).

    Article  CAS  Google Scholar 

  16. Delmas, P. & Brown, D.A. Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat. Rev. Neurosci. 6, 850–862 (2005).

    Article  CAS  Google Scholar 

  17. Goldstein, S.A., Bockenhauer, D., O'Kelly, I. & Zilberberg, N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nat. Rev. Neurosci. 2, 175–184 (2001).

    Article  CAS  Google Scholar 

  18. Lesage, F. & Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal Physiol. 279, F793–F801 (2000).

    Article  CAS  Google Scholar 

  19. Alloui, A. et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J. 25, 2368–2376 (2006).

    Article  CAS  Google Scholar 

  20. Kang, D. & Kim, D. TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. Am. J. Physiol. Cell Physiol. 291, C138–C146 (2006).

    Article  CAS  Google Scholar 

  21. Dobler, T.M. et al. TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine DRG neurones. J. Physiol. (Lond.) 585, 867–879 (2007).

    Article  CAS  Google Scholar 

  22. Duprat, F. et al. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 16, 5464–5471 (1997).

    Article  CAS  Google Scholar 

  23. Kim, Y., Bang, H. & Kim, D. TASK-3, a new member of the tandem pore K+ channel family. J. Biol. Chem. 275, 9340–9347 (2000).

    Article  CAS  Google Scholar 

  24. Sano, Y. et al. A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J. Biol. Chem. 278, 27406–27412 (2003).

    Article  CAS  Google Scholar 

  25. Liu, C., Au, J.D., Zou, H.L., Cotten, J.F. & Yost, C.S. Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth. Analg. 99, 1715–1722 (2004).

    Article  CAS  Google Scholar 

  26. Patel, A.J. et al. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat. Neurosci. 2, 422–426 (1999).

    Article  CAS  Google Scholar 

  27. Talley, E.M. & Bayliss, D.A. Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J. Biol. Chem. 277, 17733–17742 (2002).

    Article  CAS  Google Scholar 

  28. Kang, D., Han, J., Talley, E.M., Bayliss, D.A. & Kim, D. Functional expression of TASK-1/TASK-3 heteromers in cerebellar granule cells. J. Physiol. (Lond.) 554, 64–77 (2004).

    Article  CAS  Google Scholar 

  29. Caterina, M.J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).

    Article  CAS  Google Scholar 

  30. Kwan, K.Y. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).

    Article  CAS  Google Scholar 

  31. Brickley, S.G. et al. TASK-3 two-pore domain potassium channels enable sustained high-frequency firing in cerebellar granule neurons. J. Neurosci. 27, 9329–9340 (2007).

    Article  CAS  Google Scholar 

  32. Han, J., Truell, J., Gnatenco, C. & Kim, D. Characterization of four types of background potassium channels in rat cerebellar granule neurons. J. Physiol. (Lond.) 542, 431–444 (2002).

    Article  CAS  Google Scholar 

  33. Millar, J.A. et al. A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proc. Natl. Acad. Sci. USA 97, 3614–3618 (2000).

    Article  CAS  Google Scholar 

  34. Peters, H.C., Hu, H., Pongs, O., Storm, J.F. & Isbrandt, D. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat. Neurosci. 8, 51–60 (2005).

    Article  CAS  Google Scholar 

  35. Bargmann, C.I. Comparative chemosensation from receptors to ecology. Nature 444, 295–301 (2006).

    Article  CAS  Google Scholar 

  36. Chandrashekar, J., Hoon, M.A., Ryba, N.J. & Zuker, C.S. The receptors and cells for mammalian taste. Nature 444, 288–294 (2006).

    Article  CAS  Google Scholar 

  37. McMahon, S.B., Bennett, D.L.H. & Bevan, S. Inflammatory mediators and modulators of pain. in Textbook of Pain (eds. McMahon, S.B. & Koltzenburg, M.) 49–72 (Elsevier, Philadelphia, 2006).

    Google Scholar 

  38. Aller, M.I. et al. Modifying the subunit composition of TASK channels alters the modulation of a leak conductance in cerebellar granule neurons. J. Neurosci. 25, 11455–11467 (2005).

    Article  CAS  Google Scholar 

  39. Kato, A.S. et al. New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors. J. Neurosci. 27, 4969–4977 (2007).

    Article  CAS  Google Scholar 

  40. Almers, W. & Neher, E. The Ca signal from fura-2 loaded mast cells depends strongly on the method of dye-loading. FEBS Lett. 192, 13–18 (1985).

    Article  CAS  Google Scholar 

  41. Feliciangeli, S. et al. Does sumoylation control K2P1/TWIK1 background K+ channels? Cell 130, 563–569 (2007).

    Article  CAS  Google Scholar 

  42. Funfschilling, U. et al. TrkC kinase expression in distinct subsets of cutaneous trigeminal innervation and nonneuronal cells. J. Comp. Neurol. 480, 392–414 (2004).

    Article  CAS  Google Scholar 

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We are grateful to S. Yost (University of California, San Francisco) and D. Kim (Rosalind Franklin University) for providing KCNK6 and KCNK16 cDNAs, respectively; H. Haeberle and E. Lumpkin (University of California, San Francisco, and Baylor College of Medicine) for TrkC-GFP mice; A. Tzingounis and A. Priel for helpful discussion; and J. Poblete for expert technical assistance. This work was supported by grants from the NIH (D.J. and R.A.N.), a Burroughs Welcome Fund Career Award in Biomedical Sciences (D.M.B.) and an NSF Graduate Research Fellowship (A.D.M.).

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Authors and Affiliations



D.M.B. and Y.M.S. designed and carried out cellular physiology and histological studies involving native and cloned ion channels; D.M.B. designed and carried out behavioral experiments; D.M.B., Y.M.S. and A.D.M. carried out experiments involving analysis of CGNs; J.L.G. and J.A.Z. designed and effected purification procedures and chemical analysis of sanshool compounds; P.R.T. contributed to gene cloning and electrophysiological analysis; D.M.B., Y.M.S. and D.J. wrote the manuscript; R.A.N. and D.J. provided advice and guidance throughout.

Corresponding author

Correspondence to David Julius.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1 and 2 (PDF 1834 kb)

Supplementary Movie 1

Both wild type and TRPV1/TRPA1 double mutant mice display aversion to sanshool. The first segment shows a TRPV1/TRPA1 double mutant mouse drinking saccharine-containing water (vehicle). The second segment shows the same mouse drinking saccharine-containing water laced with sanshool (1 mM). Behavior did not differ from that of wild type littermates. The third segment shows the same TRPV1/TRPA1 double mutant mouse drinking saccharine-containing water laced with capsaicin (1 μM) and mustard oil (100 μM). As expected, no aversive response was observed. In contrast, the final segment shows robust aversion by a wild type littermate after briefly sampling saccharine-containing water laced with capsaicin (1 μM) and mustard oil (100 μM). Quantification of these behaviors is shown in Fig. 3d. (MOV 16637 kb)

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Bautista, D., Sigal, Y., Milstein, A. et al. Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci 11, 772–779 (2008).

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