Painful Channels in Sensory Neurons

  • Lee, Yunjong (Sensory Research Center, CRI, College of Pharmacy, Seoul National University) ;
  • Lee, Chang-Hun (Sensory Research Center, CRI, College of Pharmacy, Seoul National University) ;
  • Oh, Uhtaek (Sensory Research Center, CRI, College of Pharmacy, Seoul National University)
  • Received : 2005.12.19
  • Accepted : 2005.12.21
  • Published : 2005.12.31


Pain is an unpleasant sensation experienced when tissues are damaged. Thus, pain sensation in some way protects body from imminent threat or injury. Peripheral sensory nerves innervated to peripheral tissues initially respond to multiple forms of noxious or strong stimuli, such as heat, mechanical and chemical stimuli. In response to these stimuli, electrical signals for conducting the nociceptive neural signals through axons are generated. These action potentials are then conveyed to specific areas in the spinal cord and in the brain. Sensory afferent fibers are heterogeneous in many aspects. For example, sensory nerves are classified as $A{\alpha}$, $-{\beta}$, $-{\delta}$ and C-fibers according to their diameter and degree of myelination. It is widely accepted that small sensory fibers tend to respond to vigorous or noxious stimuli and related to nociception. Thus these fibers are specifically called nociceptors. Most of nociceptors respond to noxious mechanical stimuli and heat. In addition, these sensory fibers also respond to chemical stimuli [Davis et al. (1993)] such as capsaicin. Thus, nociceptors are considered polymodal. Recent advance in research on ion channels in sensory neurons reveals molecular mechanisms underlying how various types of stimuli can be transduced to neural signals transmitted to the brain for pain perception. In particular, electrophysiological studies on ion channels characterize biophysical properties of ion channels in sensory neurons. Furthermore, molecular biology leads to identification of genetic structures as well as molecular properties of ion channels in sensory neurons. These ion channels are expressed in axon terminals as well as in cell soma. When these channels are activated, inward currents or outward currents are generated, which will lead to depolarization or hyperpolarization of the membrane causing increased or decreased excitability of sensory neurons. In order to depolarize the membrane of nerve terminals, either inward currents should be generated or outward currents should be inhibited. So far, many cationic channels that are responsible for the excitation of sensory neurons are introduced recently. Activation of these channels in sensory neurons is evidently critical to the generation of nociceptive signals. The main channels responsible for inward membrane currents in nociceptors are voltage-activated sodium and calcium channels, while outward current is carried mainly by potassium ions. In addition, activation of non-selective cation channels is also responsible for the excitation of sensory neurons. Thus, excitability of neurons can be controlled by regulating expression or by modulating activity of these channels.


Analgesics;Channels;Dorsal Root Ganglion;Nociceptor;Pain


  1. Acosta, C. G. and Lopez, H. S. (1999) delta opioid receptor modulation of several voltage-dependent Ca(2+) currents in rat sensory neurons. J. Neurosci. 19, 8337-8348
  2. Akopian, A. N., Sivilotti, L., and Wood, J. N. (1996) A tetrodotoxin- resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379, 257-262
  3. Babes, A., Amuzescu, B., Krause, U., Scholz, A., Flonta, M. L., et al. (2002) Cooling inhibits capsaicin-induced currents in cultured rat dorsal root ganglion neurones. Neurosci. Lett. 317, 131-134
  4. Babinski, K., Le, K. T., and Seguela, P. (1999) Molecular cloning and regional distribution of a human proton receptor subunit with biphasic functional properties. J. Neurochem. 72, 51-57
  5. Burnstock, G. and Wood, J. N. (1996) Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr. Opin. Neurobiol. 6, 526-532
  6. Caterina, M. J. and Julius, D. (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487-517
  7. Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J., and Julius, D. (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436-441
  8. Cockayne, D. A., Hamilton, S. G., Zhu, Q. M., Dunn, P. M., Zhong, Y., et al. (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407, 1011-1015
  9. Coutts, A. A., Jorizzo, J. L., Eady, R. A., Greaves, M. W., and Burnstock, G. (1981) Adenosine triphosphate-evoked vascular changes in human skin: mechanism of action. Eur. J. Pharmacol. 76, 391-401
  10. Davis, K. D., Meyer, R. A., and Campbell, J. N. (1993) Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J. Neurophysiol. 69, 1071-1081
  11. Evans, A. R., Nicol, G. D., and Vasko, M. R. (1996) Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res. 712, 265-273
  12. Goldin, A. L., Barchi, R. L., Caldwell, J. H., Hofmann, F., Howe, J. R., et al. (2000) Nomenclature of voltage-gated sodium channels. Neuron 28, 365-368
  13. Gudermann, T. and Flockerzi, V. (2005) TRP channels as new pharmacological targets. Naunyn. Schmiedebergs Arch. Pharmacol. 371, 241-244
  14. Hamilton, S. G., McMahon, S. B., and Lewin, G. R. (2001) Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin. J. Physiol. 534, 437-445
  15. Hatakeyama, S., Wakamori, M., Ino, M., Miyamoto, N., Takahashi, E., et al. (2001) Differential nociceptive responses in mice lacking the alpha(1B) subunit of N-type Ca(2+) channels. Neuroreport 12, 2423-2427
  16. Holz, G. G. 4th, Shefner, S. A., and Anderson, E. G. (1985) Serotonin depolarizes type A and C primary afferents: an intracellular study in bullfrog dorsal root ganglion. Brain Res 327, 71-79
  17. Honma, Y., Yamakage, M., and Ninomiya, T. (1999) Effects of adrenergic stimulus on the activities of $Ca^{2+}$ and $K^+$ channels of dorsal root ganglion neurons in a neuropathic pain model. Brain Res. 832, 195-206
  18. Hu, H. Z., Gu, Q., Wang, C., Colton, C. K., Tang, J., et al. (2004) 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J. Biol. Chem. 279, 35741-35748
  19. Inoue, K., Tsuda, M., and Koizumi, S. (2004) ATP receptors in pain sensation. Nippon Yakurigaku Zasshi 124, 228-233
  20. Jia, Y., Wang, X., Varty, L., Rizzo, C. A., Yang, R., et al. (2004) Functional TRPV4 channels are expressed in human airway smooth muscle cells. Am. J. Physiol. Lung Cell Mol. Physiol. 287, L272-278
  21. Kang, M. G., Chen, C. C., Felix, R., Letts, V. A., Frankel, W. N., et al. (2001) Biochemical and biophysical evidence for gamma 2 subunit association with neuronal voltage-activated $Ca^{2+}$ channels. J. Biol. Chem. 276, 32917-32924
  22. Kim, Y., Bang, H., and Kim, D. (2000) TASK-3, a new member of the tandem pore K(+) channel family. J. Biol. Chem. 275, 9340-9347
  23. Liedtke, W., Choe, Y., Marti-Renom, M. A., Bell, A. M., Denis, C. S., et al. (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525-535
  24. McCleane, G. J., Suzuki, R., and Dickenson, A. H. (2003) Does a single intravenous injection of the 5HT3 receptor antagonist ondansetron have an analgesic effect in neuropathic pain? A double-blinded, placebo-controlled cross-over study. Anesth. Analg. 97, 1474-1478
  25. Montell, C. (2001) An end in sight to a long TRP. Neuron 30, 3-5
  26. Moqrich, A., Hwang, S. W., Earley, T. J., Petrus, M. J., Murray, A. N., et al. (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468-1472
  27. Nicholas, R. S., Winter, J., Wren, P., Bergmann, R., and Woolf, C. J. (1999) Peripheral inflammation increases the capsaicin sensitivity of dorsal root ganglion neurons in a nerve growth factor-dependent manner. Neuroscience 91, 1425-1433
  28. Nilius, B., Prenen, J., Vennekens, R., Hoenderop, J. G., Bindels, R. J., et al. (2001) Pharmacological modulation of monovalent cation currents through the epithelial $Ca^{2+}$ channel ECaC1. Br. J. Pharmacol. 134, 453-462
  29. Nilius, B., Vriens, J., Prenen, J., Droogmans, G., and Voets, T. (2004) TRPV4 calcium entry channel: a paradigm for gating diversity. Am. J. Physiol. Cell Physiol. 286, C195-205
  30. Numazaki, M. and Tominaga, M. (2004) Nociception and TRP Channels. Curr. Drug Targets CNS Neurol. Disord. 3, 479-485
  31. Peier, A. M., Reeve, A. J., Andersson, D. A., Moqrich, A., Earley, T. J., et al. (2002a) A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046-2049
  32. Perez-Reyes, E. (2003) Molecular physiology of low-voltageactivated t-type calcium channels. Physiol. Rev. 83, 117-161
  33. Premkumar, L. S. and Ahern, G. P. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985-990
  34. Reid, G. and Flonta, M. L. (2001) Physiology. Cold current in thermoreceptive neurons. Nature 413, 480
  35. Scott, K. and Zuker, C. (1998) TRP, TRPL and trouble in photoreceptor cells. Curr. Opin. Neurobiol. 8, 383-388
  36. Sluka, K. A. (1998) Blockade of N- and P/Q-type calcium channels reduces the secondary heat hyperalgesia induced by acute inflammation. J. Pharmacol. Exp. Ther. 287, 232-237
  37. Smart, D. and Jerman, J. C. (2000) Anandamide: an endogenous activator of the vanilloid receptor. Trends Pharmacol. Sci. 21, 134
  38. Strotmann, R., Harteneck, C., Nunnenmacher, K., Schultz, G., and Plant, T. D. (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat. Cell Biol. 2, 695-702
  39. Suzuki, M., Watanabe, Y., Oyama, Y., Mizuno, A., Kusano, E., et al. (2003a) Localization of mechanosensitive channel TRPV4 in mouse skin. Neurosci. Lett. 353, 189-192
  40. Suzuki, M., Mizuno, A., Kodaira, K., and Imai, M. (2003b) Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664-22668
  41. Takahashi, T. and Momiyama, A. (1993) Different types of calcium channels mediate central synaptic transmission. Nature 366, 156-158
  42. Wang, Y. X., Bezprozvannaya, S., Bowersox, S. S., Nadasdi, L., Miljanich, G., et al. (1998) Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers. Naunyn. Schmiedebergs Arch. Pharmacol. 357, 159-168
  43. Wood, J. N., Abrahamsen, B., Baker, M. D., Boorman, J. D., Donier, E., et al. (2004) Ion channel activities implicated in pathological pain. Novartis. Found. Symp. 261, 32-40; discussion 40-54
  44. Yoshimura, N. and de Groat, W. C. (1999) Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J. Neurosci. 19, 4644-4653
  45. Zheng, J. H. and Chen, J. (2000) Modulatory roles of the adenosine triphosphate P2x-purinoceptor in generation of the persistent nociception induced by subcutaneous bee venom injection in the conscious rat. Neurosci. Lett. 278, 41-44
  46. Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., et al. (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849-857
  47. Heyman, I. and Rang, H. P. (1985) Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells. Neurosci. Lett. 56, 69-75
  48. Huang, S. M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., et al. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl. Acad. Sci. USA 99, 8400-8405
  49. Voilley, N., de Weille, J., Mamet, J., and Lazdunski, M. (2001) Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J. Neurosci. 21, 8026-8033
  50. Zhang, L., Jones, S., Brody, K., Costa, M., and Brookes, S. J. (2004) Thermosensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G983-991
  51. Catterall, W. A. (2000) Structure and regulation of voltage-gated $Ca^{2+}$ channels. Annu. Rev. Cell Dev. Biol. 16, 521-555
  52. Guler, A. D., Lee, H., Iida, T., Shimizu, I., Tominaga, M., et al. (2002) Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 6408-6414
  53. Tsien, R. W., Ellinor, P. T., and Horne, W. A. (1991) Molecular diversity of voltage-dependent $Ca^{2+}$ channels. Trends Pharmacol. Sci. 12, 349-354
  54. Kim, D., Park, D., Choi, S., Lee, S., Sun, M., et al. (2003) Thalamic control of visceral nociception mediated by T-type $Ca^{2+}$ channels. Science 302, 117-119
  55. Novakovic, S. D., Levinson, S. R., Schachner, M., and Shrager, P. (1998) Disruption and reorganization of sodium channels in experimental allergic neuritis. Muscle Nerve 21, 1019-1032<1019::AID-MUS6>3.0.CO;2-B
  56. Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., et al. (2002b) A TRP channel that senses cold stimuli and menthol. Cell 108, 705-715
  57. Tian, W., Salanova, M., Xu, H., Lindsley, J. N., Oyama, T. T., et al. (2004) Renal expression of osmotically responsive cation channel TRPV4 is restricted to water-impermeant nephron segments. Am. J. Physiol. Renal Physiol. 287, F17-24
  58. Xu, H., Ramsey, I. S., Kotecha, S. A., Moran, M. M., Chong, J. A., et al. (2002) TRPV3 is a calcium-permeable temperaturesensitive cation channel. Nature 418, 181-186
  59. Chuang, H. H., Prescott, E. D., Kong, H., Shields, S., Jordt, S. E., et al. (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957-962
  60. Gao, X., Wu, L., and O'Neil, R. G. (2003) Temperaturemodulated diversity of TRPV4 channel gating: activation by physical stresses and phorbol ester derivatives through protein kinase C-dependent and -independent pathways. J. Biol. Chem. 278, 27129-27137
  61. Gitterman, D. P., Wilson, J., and Randall, A. D. (2005) Functional properties and pharmacological inhibition of ASIC channels in the human SJ-RH30 skeletal muscle cell line. J. Physiol. 562, 759-769
  62. Kim, C. H., Oh, Y., Chung, J. M., and Chung, K. (2002) Changes in three subtypes of tetrodotoxin sensitive sodium channel expression in the axotomized dorsal root ganglion in the rat. Neurosci. Lett. 323, 125-128
  63. Abdi, S., Lee, D. H., and Chung, J. M. (1998) The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth. Analg. 87, 1360-1366
  64. Vedder, H. and Otten, U. (1991) Biosynthesis and release of tachykinins from rat sensory neurons in culture. J. Neurosci. Res. 30, 288-299
  65. Vellani, V., Zachrisson, O., and McNaughton, P. A. (2004) Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF. J. Physiol. 560, 391-401
  66. Cardenas, C. G., Del Mar, L. P., and Scroggs, R. S. (1995) Variation in serotonergic inhibition of calcium channel currents in four types of rat sensory neurons differentiated by membrane properties. J. Neurophysiol. 74, 1870-1879
  67. Cummins, T. R., Dib-Hajj, S. D., Black, J. A., Akopian, A. N., Wood, J. N., et al. (1999) A novel persistent tetrodotoxinresistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci. 19, RC43
  68. Shin, J., Cho, H., Hwang, S. W., Jung, J., Shin, C. Y., et al. (2002) Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc. Natl. Acad. Sci. USA 99, 10150-10155
  69. Trimmer, J. S. and Rhodes, K. J. (2004) Localization of voltagegated ion channels in mammalian brain. Annu. Rev. Physiol. 66, 477-519
  70. Muraki, K., Iwata, Y., Katanosaka, Y., Ito, T., Ohya, S., et al. (2003) TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ. Res. 93, 829-838
  71. Story, G. M., Peier, A. M., Reeve, A. J., Eid, S. R., Mosbacher, J., et al. (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819-829
  72. Gunthorpe, M. J., Harries, M. H., Prinjha, R. K., Davis, J. B., and Randall, A. (2000) Voltage- and time-dependent properties of the recombinant rat vanilloid receptor (rVR1). J. Physiol. 525, 747-759
  73. Hwang, J. H. and Yaksh, T. L. (1997) Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat. Reg. Anesth. 22, 249-256
  74. Corey, D. P., Garcia-Anoveros, J., Holt, J. R., Kwan, K. Y., Lin, S. Y., et al. (2004) TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432, 723-730
  75. Gothert, M. and Schlicker, E. (1987) Classification of serotonin receptors. J. Cardiovasc. Pharmacol. 10 (Suppl 3), S3?7
  76. Black, J. A., Dib-Hajj, S., McNabola, K., Jeste, S., Rizzo, M. A., et al. (1996) Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs. Brain Res. Mol. Brain Res. 43, 117-131
  77. Miller, R. J. (2001) Rocking and rolling with $Ca^{2+}$ channels. Trends Neurosci. 24, 445-449
  78. Chung, M. K., Lee, H., and Caterina, M. J. (2003) Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J. Biol. Chem. 278, 32037-32046
  79. Jordt, S. E., Bautista, D. M., Chuang, H. H., McKemy, D. D., Zygmunt, P. M., et al. (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260-265
  80. Nealen, M. L., Gold, M. S., Thut, P. D., and Caterina, M. J. (2003) TRPM8 mRNA is expressed in a subset of coldresponsive trigeminal neurons from rat. J. Neurophysiol. 90, 515-520
  81. Bleehen, T. and Keele, C. A. (1977) Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain 3, 367-377
  82. Santicioli, P., Del Bianco, E., Tramontana, M., and Maggi, C. A. (1992) Adenosine inhibits action potential-dependent release of calcitonin gene-related peptide- and substance P-like immunoreactivities from primary afferents in rat spinal cord. Neurosci. Lett. 144, 211-214
  83. Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., et al. (1997) The capsaicin receptor: a heatactivated ion channel in the pain pathway. Nature 389, 816-824
  84. Hwang, S. W., Cho, H., Kwak, J., Lee, S. Y., Kang, C. J., et al. (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl. Acad. Sci. USA 97, 6155-6160
  85. Minke, B. and Cook, B. (2002) TRP channel proteins and signal transduction. Physiol. Rev. 82, 429-472
  86. Oh, U., Hwang, S. W., and Kim, D. (1996) Capsaicin activates a nonselective cation channel in cultured neonatal rat dorsal root ganglion neurons. J. Neurosci. 16, 1659-1667
  87. Suh, B. C. and Kim, K. T. (1995) Inhibition of bradykinininduced cytosolic $Ca^{2+}$ elevation by muscarinic stimulation without attenuation of inositol 1,4,5-trisphosphate production in human neuroblastoma SK-N-BE(2)C cells. J. Neurochem. 65, 2124-2130
  88. Kim, C., Jun, K., Lee, T., Kim, S. S., McEnery, M. W., et al. (2001) Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel. Mol. Cell. Neurosci. 18, 235-245
  89. Todorovic, S. M., Meyenburg, A., and Jevtovic-Todorovic, V. (2002) Mechanical and thermal antinociception in rats following systemic administration of mibefradil, a T-type calcium channel blocker. Brain Res. 951, 336-340
  90. Bevan, S., Hothi, S., Hughes, G., James, I. F., Rang, H. P., et al. (1992) Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 107, 544-552
  91. Sakata, Y., Saegusa, H., Zong, S., Osanai, M., Murakoshi, T., et al. (2001) Analysis of Ca(2+) currents in spermatocytes from mice lacking Ca(v)2.3 (alpha(1E)) Ca(2+) channel. Biochem. Biophys. Res. Commun. 288, 1032-1036
  92. Souslova, V., Cesare, P., Ding, Y., Akopian, A. N., Stanfa, L., et al. (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407, 1015-1017
  93. Gee, N. S., Brown, J. P., Dissanayake, V. U., Offord, J., Thurlow, R., et al. (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J. Biol. Chem. 271, 5768-5776
  94. Iwata, Y., Katanosaka, Y., Arai, Y., Komamura, K., Miyatake, K., et al. (2003) A novel mechanism of myocyte degeneration involving the $Ca^{2+}$-permeable growth factor-regulated channel. J. Cell Biol. 161, 957-967
  95. Jaquemar, D., Schenker, T., and Trueb, B. (1999) An ankyrinlike protein with transmembrane domains is specifically lost after oncogenic transformation of human fibroblasts. J. Biol. Chem. 274, 7325-7333
  96. Thut, P. D., Wrigley, D., and Gold, M. S. (2003) Cold transduction in rat trigeminal ganglia neurons in vitro. Neuroscience 119, 1071-1083
  97. Ferreira, J., da Silva, G. L., and Calixto, J. B. (2004) Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Br. J. Pharmacol. 141, 787-794
  98. Gold, M. S., Shuster, M. J., and Levine, J. D. (1996) Characterization of six voltage-gated $K^+$ currents in adult rat sensory neurons. J. Neurophysiol. 75, 2629-2646
  99. McKemy, D. D., Neuhausser, W. M., and Julius, D. (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52-58
  100. North, R. A. (1996) Families of ion channels with two hydrophobic segments. Curr. Opin. Cell Biol. 8, 474-483
  101. Weizman, R., Getslev, V., Pankova, I. A., Schrieber, S., and Pick, C. G. (1999) Pharmacological interaction of the calcium channel blockers verapamil and flunarizine with the opioid system. Brain Res. 818, 187-195
  102. Hille, B. (2001) Ionic Channels of Excitable Membranes, Sinauer, Sunderland, MA
  103. Hofmann, F., Lacinova, L., and Klugbauer, N. (1999) Voltagedependent calcium channels: from structure to function. Rev. Physiol. Biochem. Pharmacol. 139, 33-87
  104. Kashiba, H., Uchida, Y., Takeda, D., Nishigori, A., Ueda, Y., et al. (2004) TRPV2-immunoreactive intrinsic neurons in the rat intestine. Neurosci. Lett. 366, 193-196
  105. Rane, S. G., Holz, G. G. 4th, and Dunlap, K. (1987) Dihydropyridine inhibition of neuronal calcium current and substance P release. Pflugers Arch. 409, 361-366
  106. Zygmunt, P. M., Petersson, J., Andersson, D. A., Chuang, H., Sorgard, M., et al. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452-457
  107. Gruner, W. and Silva, L. R. (1994) Omega-conotoxin sensitivity and presynaptic inhibition of glutamatergic sensory neurotransmission in vitro. J. Neurosci. 14, 2800-2808
  108. Todorovic, S. M., Pathirathna, S., Meyenburg, A., and Jevtovic- Todorovic, V. (2004) Mechanical and thermal anti-nociception in rats after systemic administration of verapamil. Neurosci. Lett. 360, 57-60
  109. Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C., and Lazdunski, M. (1997) A proton-gated cation channel involved in acid-sensing. Nature 386, 173-177
  110. Cummins, T. R. and Waxman, S. G. (1997) Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J. Neurosci. 17, 3503-3514
  111. Ma, Q. P. (2001) Vanilloid receptor homologue, VRL1, is expressed by both A- and C-fiber sensory neurons. Neuroreport 12, 3693-3695
  112. Maggi, C. A., Giuliani, S., Santicioli, P., Tramontana, M., and Meli, A. (1990) Effect of omega conotoxin on reflex responses mediated by activation of capsaicin-sensitive nerves of the rat urinary bladder and peptide release from the rat spinal cord. Neuroscience 34, 243-250
  113. Meuser, T., Pietruck, C., Gabriel, A., Xie, G. X., Lim, K. J., et al. (2002) 5-HT7 receptors are involved in mediating 5-HTinduced activation of rat primary afferent neurons. Life Sci. 71, 2279-2289
  114. Dib-Hajj, S. D., Tyrrell, L., Cummins, T. R., Black, J. A., Wood, P. M., et al. (1999) Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett. 462, 117-120
  115. Okazawa, M., Takao, K., Hori, A., Shiraki, T., Matsumura, K., et al. (2002) Ionic basis of cold receptors acting as thermostats. J. Neurosci. 22, 3994
  116. Toth, A., Kedei, N., Wang, Y., and Blumberg, P. M. (2003) Arachidonyl dopamine as a ligand for the vanilloid receptor VR1 of the rat. Life Sci. 73, 487-498
  117. Bleehen, T., Hobbiger, F., and Keele, C. A. (1976) Identification of algogenic substances in human erythrocytes. J. Physiol. 262, 131-149
  118. Chung, M. K., Lee, H., Mizuno, A., Suzuki, M., and Caterina, M. (2004) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J. Biol. Chem. 279, 21569-21575
  119. Holzer, P. (1991) Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev. 43, 143-201
  120. Watanabe, H., Davis, J. B., Smart, D., Jerman, J. C., Smith, G. D., et al. (2002) Activation of TRPV4 channels (hVRL- 2/mTRP12) by phorbol derivatives. J. Biol. Chem. 277, 13569-13577