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17. While two-pore potassium channels are widely expressed in both neural and nonneural cells, hyrdroxyl-alpha-sanshool excites only a particular subset of two-pore channels: those formed by the products of the genes KCNK3, KCNK9, and KCNK18. D. M. Bautista, Y. M. Sigal, A. D. Milstein, J. L. Garrison, J. A. Zorn, P. R. Tsuruda, R. A. Nicoll, and D. Julius, “Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels,” Nature Neuroscience 11 (2008): 772–79; and R. C. Lennertz, M. Tsunozaki, D. M. Bautista, and C. L. Stucky, “Physiological basis of tingling paresthesia evoked by hydroxyl-alpha-sanshool,” Journal of Neuroscience 30 (2010): 4353–61. This paper claims that the sensation produced by Szechuan peppercorn extract on the lips resembles a 50-hertz vibration and is carried by Meissner fibers: N. Hagura, H. Barber, and P. Haggard, “Food vibrations: Asian spice sets lips trembling,” Proceedings of the Royal Society B: Biological Sciences 280 (2013): 20131680.

18. Yes, there are cases of vampire bats preying upon sleeping humans. However, this is quite rare. All three species of vampire bat much prefer ungulates.

19. L. Kürten and U. Schmidt, “Thermoperception in the common vampire bat ( Desmodus rotundus ),” Journal of Comparative Physiology 146 (1982): 223–28.

20. E. O. Gracheva, J. F. Cordero-Morales, J. A. Gonzales-Carcacia, N. T. Ingolia, C. Manno, C. I. Aranguren, J. S. Weissman, and D. Julius, “Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats,” Nature 476 (2011): 88–91. In the trigeminal ganglia of vampire bats, about 45 percent of the messenger RNA molecules directing translation of TRPV1 protein [were of the alternatively spliced short form], while this value was only about 5 percent in fruit bats. Not all of the neurons in the trigeminal ganglion of the vampire bat innervate the nasal pits, so the value of 45 percent short transcripts makes sense: We wouldn’t expect it to be higher.

21. A nice summary of the early years of the work on snake infrared sensing can be found here: E. A. Newman and P. H. Hartline, “The infrared ‘vision’ of snakes,” Scientific American 246 (1982): 116–27.

22. P. H. Hartline, L. Kass, and M. S. Loop, “Merging of modalities in the optic tectum: infrared and visual integration in rattlesnakes,” Science 199 (1978): 1225–29; E. A. Newman and P. H. Hartline, “Integration of visual and infrared information in bimodal neurons of the rattlesnake optic tectum,” Science 213 (1981): 789–91; and C. Moon, “Infrared-sensitive pit-organ and trigeminal ganglion in the crotaline snakes,” Anatomy & Cell Biology (2011), doi:10.5115/acb.2011.44.1.8.

23. Both human and rattlesnake TRPA1 are sensitive to AITC, the pungent chemical from wasabi, but human TRPA1 is much more sensitive. There appears to have been a molecular trade-off between thermal and wasabi sensitivity. E. O. Gracheva, N. T. Ingolia, Y. M. Kelly, J. F. Cordero-Morales, G. Hollopeter, A. T. Chesler, E. E. Sánchez, J. C. Perez, J. S. Weissman, and D. Julius, “Molecular basis of infrared detection by snakes,” Nature 464 (2010): 1006–11; and J. F. Cordero-Morales, E. O. Gracheva, and D. Julius, “Cytoplasmic ankyrin repeats of transient receptor potential A1 (TRPA1) dictate sensitivity to thermal and chemical stimuli,” Proceedings of the National Academy of Sciences of the USA 108 (2011): 1184–91.

24. S. Yokoyama, A. Altun, and D. F. Denardo, “Molecular convergence of infrared vision in snakes,” Molecular Biology and Evolution 28 (2011): 45–48; and J. Geng, D. Liang, K. Jiang, and P. Zhang, “Molecular evolution of the infrared sensory gene TRPA1 in snakes and implications for functional studies,” PLOS One 6 (2011): e28644.

25. H. Schmitz and H. Bousack, “Modelling a historic oil-tank fire allows an estimate of the sensitivity of the infrared receptors in pyrophilous Melanophila beetles,” PLOS One 7 (2012): e37627. There is a species of forest-fire-seeking beetle living in Australia ( Merimna atrata ) that also lays its eggs in freshly charred trees. The Australian fire beetle has four infrared sensors on each side of its body, toward the rear end. South American blood-sucking bugs called vinchuca ( Triatoma infestans ) are thought to sense infrared radiation from warm prey as well. A. L. Campbell, R. R. Naik, L. Sowards, and M. O. Stone, “Biological infrared imaging and sensing,” Micron 33 (2002): 211–25; and H. Bleckmann, H. Schmitz, and G. von der Emde, “Nature as a model for technical sensors,” Journal of Comparative Physiology A 190 (2004): 971–81.

26. B. R. Myers, Y. M. Sigal, and D. Julius, “Evolution of thermal response properties in a cold-activated TRP channel,” PLOS One 4 (2009): e5741. It should be noted that TRPV1 and TRPM8 are not just present in the neurons that innervate the skin. They are also present in neurons that carry signals from deep tissues in the abdomen and so are likely to be important in sensing core temperature as well. In addition, TRPV1 (but not TRPM8) is present in the brain and may also have a role in the central processing of thermal information.

27. M. L. Loggia, M. C. Bushnell, M. Tétreault, I. Thiffault, C. Bhérer, N. K. Mohammed, A. A. Kuchinad, A. Laferrière, M.-J. Dicaire, L. Loisel, J. S. Mogil, and B. Brais, “Carriers of recessive WNK1/HSN2 mutations for hereditary sensory and autonomic neuropathy type 2 (HSAN2) are more sensitive to thermal stimuli,” Journal of Neuroscience 29 (2009): 2162–66. There are more robust genetic links to pain perception, both thermal and other types of pain. We’ll discuss these in the next chapter.

CHAPTER SIX: PAIN AND EMOTION

1. J. J. Cox, F. Reimann, A. K. Nicholas, G. Thornton, E. Roberts, K. Springell, G. Karbani, H. Jafri, J. Mannan, Y. Raashid, L. Al-Gazali, H. Mamamy, E. Valente, S. Gorman, R. Williams, D. P. McHale, J. N. Wood, F. M. Gribble, and C. G. Woods, “An SCN9A channelopathy causes congenital inability to experience pain,” Nature 444 (2006): 894–98.

2. Ashlyn Blocker is a teenage girl living in Georgia who has congenital insensitivity to pain produced by a similar genetic mutation to that found in the British-Pakistani families. Her parents struggle to help her avoid injury. They have bought extra-thick carpet for the floors and furniture with rounded corners and edges. They struggle to balance their desire to protect her with the need for a teenager to have autonomy in her actions. Some people with congenital insensitivity to pain, like Ashlyn, have defects in sweating while others do not. The SCN9A gene is also expressed in the neurons that send messages to the skin to trigger sweating and flushing (vasodilation). The story of Ashlyn and her family was told by Justin Heckert in the New York Times Magazine : “The hazards of growing up painlessly,” November 15, 2012.

3. C. R. Fertleman, C. D. Ferrie, J. Aicardi, N. A. F. Bednarek, O. Eeg-Olofsson, F. V. Elmslie, D. A. Griesemer, F. Goutières, M. Kirkpatrick, I. N. O. Malmros, M. Pollitzer, M. Rossiter, E. Roulet-Perez, R. Schubert, V. V. Smith, H. Testard, V. Wong, J. B. P. Stephenson, “Paroxysmal extreme pain disorder (previously familial rectal pain syndrome),” Neurology 69 (2007): 586–95; and R. Hayden and M. Grossman, “Rectal, ocular and submaxillary pain,” A.M.A. Journal of Diseases of Children 97 (1959): 479–82. It’s not clear why the jaw, anus, and eyes are the most common trigger zones for painful attacks in this disorder.

4. C. R. Fertleman, M. D. Baker, K. A. Parker, S. Moffat, F. V. Elmslie, B. Abrahamsen, J. Ostman, N. Klugbauer, J. N. Wood, R. M. Gardiner, and M. Rees, “ SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes,” Neuron 52 (2006): 767–74; and J.-S. Choi, F. Boralevi, O. Brissaud, J. Sánchez-Martín, R. H. M. Te Morsche, S. D. Dib-Hajj, J. P. H. Drenth, and S. G. Waxman, “Paroxysmal extreme pain disorder: a molecular lesion of peripheral neurons,” Nature Reviews Neurology 7 (2011): 51–55. As in congenital insensitivity to pain, sufferers of paroxysmal extreme pain disorder have normal brain and nerve structure. It’s the function that’s changed. There’s an important lesson here: Many diseases are not associated with obvious structural changes to organs or cells.