The detection of noxious stimuli by nociceptors is mediated by high-threshold transducers expressed on their peripheral terminal membranes. These transducers are receptor/ion channels that convert thermal, mechanical and chemical stimuli into ion fluxes that excite the neuron to produce a sensory inflow.
Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins and encode thermal and chemical stimuli.
Among the TRP channels expressed by nociceptors, TRPV1 and TRPA1 have been the most extensively investigated, and represent validated targets for the development of novel analgesics.
In addition to detecting noxious stimuli, the density, threshold and kinetics of TRPV1 and TRPA1 are modulated by inflammatory mediators, and in this way sensitize nociceptors to increase pain sensitivity after tissue damage or on exposure to inflammation.
TRPV1 and TRPA1 are also expressed on the central terminals of sensory neurons where they seem to act as synaptic modulators. Antagonists acting at these two channels are promising candidates as analgesics by virtue of blocking the activation of the channels in response to noxious stimuli or inflammation.
TRP nociceptive transducer proteins may have adaptive actions beyond simply detecting noxious stimuli, including body temperature control, synaptic plasticity, and respiratory and cardiovascular function, which may produce adverse effects when blocked.
TRP channel agonists can also produce analgesia by either desensitizing the receptors or, at high doses, ablating them.
TRP channels can be used as a drug delivery system to target small cationic drugs selectively into nociceptors.
Overall, targeting nociceptive TRP channels, where the pain-pathway begins, represents a promising opportunity for the development of novel analgesics.
Pain results from the complex processing of neural signals at different levels of the central nervous system, with each signal potentially offering multiple opportunities for pharmacological intervention. A logical strategy for developing novel analgesics is to target the beginning of the pain pathway, and aim potential treatments directly at the nociceptors — the high-threshold primary sensory neurons that detect noxious stimuli. The largest group of receptors that function as noxious stimuli detectors in nociceptors is the transient receptor potential (TRP) channel family. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting drugs, and discusses the development pathways needed to test candidates as analgesics in humans.
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Woolf, C. J. & Ma, Q. Nociceptors-noxious stimulus detectors. Neuron 55, 353–364 (2007).
Hucho, T. & Levine, J. D. Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron 55, 365–376 (2007).
Baron, R. Mechanisms of disease: neuropathic pain — a clinical perspective. Nature Clin. Pract. Neurol. 2, 95–106 (2006).
Finnegan, T. F., Chen, S. R. & Pan, H. L. Effect of the μ opioid on excitatory and inhibitory synaptic inputs to periaqueductal gray-projecting neurons in the amygdala. J. Pharmacol. Exp. Ther. 312, 441–448 (2005).
Mico, J. A., Ardid, D., Berrocoso, E. & Eschalier, A. Antidepressants and pain. Trends Pharmacol. Sci. 27, 348–354 (2006).
Wood, J. N. Ion channels in analgesia research. Handb. Exp. Pharmacol. 177, 329–358 (2007).
Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).
Dhaka, A., Viswanath, V. & Patapoutian, A. TRP ion channels and temperature sensation. Annu. Rev. Neurosci. 29, 135–161 (2006).
Julius, D. & Basbaum, A. I. Molecular mechanisms of nociception. Nature 413, 203–210 (2001).
Montell, C. & Rubin, G. M. Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2, 1313–1323 (1989).
Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997). The first cloning of a nociceptive TRP ion channel, TRPV1, and the demonstration that it is both the capsaicin receptor and a noxious heat detector.
Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441 (1999).
Peier, A. M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).
Smith, G. D. et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418, 186–190 (2002).
Xu, H. et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418, 181–186 (2002).
Guler, A. D. et al. Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 6408–6414 (2002).
Watanabe, H. et al. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J. Biol. Chem. 277, 47044–47051 (2002).
McKemy, D. D., Neuhausser, W. M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002).
Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002). By annotating novel TRP ion channels within the genome and determining their expression and function, the authors cloned TRPM8, the first channel shown to be activated by cool temperatures (15–25 °C) and menthol.
Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003).
Clapham, D. E., Runnels, L. W. & Strubing, C. The TRP ion channel family. Nature Rev. Neurosci. 2, 387–396 (2001).
Talavera, K. et al. Heat activation of TRPM5 underlies thermal sensitivity of sweet taste. Nature 438, 1022–1025 (2005).
Togashi, K. et al. TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J. 25, 1804–1815 (2006).
Caterina, M. J. et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313 (2000).
Davis, J. B. et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187 (2000).
Philip, G., Baroody, F. M., Proud, D., Naclerio, R. M. & Togias, A. G. The human nasal response to capsaicin. J. Allergy Clin. Immunol. 94, 1035–1045 (1994).
Green, B. G. & Shaffer, G. S. The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency. Pain 53, 323–334 (1993).
Siemens, J. et al. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature 444, 208–212 (2006).
Macpherson, L. J. et al. The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15, 929–934 (2005).
Bautista, D. M. et al. Pungent products from garlic activate the sensory ion channel TRPA1. Proc. Natl Acad. Sci. USA 102, 12248–12252 (2005).
Jordt, S. E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004).
Bandell, M. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849–857 (2004).
Macpherson, L. J. et al. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445, 541–545 (2007). This paper shows that TRPA1 is activated through covalent cysteine modification, and that it is the reactivity of these pungent chemicals (not necessarily their shape) that leads to TRPA1 activation.
Hinman, A., Chuang, H. H., Bautista, D. M. & Julius, D. TRP channel activation by reversible covalent modification. Proc. Natl Acad. Sci. USA 103, 19564–19568 (2006).
Bang, S., Kim, K. Y., Yoo, S., Kim, Y. G. & Hwang, S. W. Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur. J. Neurosci. 26, 2516–2523 (2007).
Trevisani, M. et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc. Natl Acad. Sci. USA 104, 13519–13524 (2007).
McNamara, C. R. et al. TRPA1 mediates formalin-induced pain. Proc. Natl Acad. Sci. USA 104, 13525–13530 (2007).
Macpherson, L. J. et al. An ion channel essential for sensing chemical damage. J. Neurosci. 27, 11412–11415 (2007).
Sawada, Y., Hosokawa, H., Matsumura, K. & Kobayashi, S. Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur. J. Neurosci. 27, 1131–1142 (2008).
Takahashi, N. et al. Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. Channels (Austin) 2, 287–298 (2008).
Yoshida, T. et al. Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nature Chem. Biol. 2, 596–607 (2006).
Uchida, K. 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog. Lipid Res. 42, 318–343 (2003).
Chen, J. et al. Molecular determinants of species-specific activation or blockade of TRPA1 channels. J. Neurosci. 28, 5063–5071 (2008).
Conaway, C. C., Krzeminski, J., Amin, S. & Chung, F. L. Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome p450 enzymes. Chem. Res. Toxicol. 14, 1170–1176 (2001).
Salazar, H. et al. A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic. Nature Neurosci. 11, 255–261 (2008).
Zurborg, S., Yurgionas, B., Jira, J. A., Caspani, O. & Heppenstall, P. A. Direct activation of the ion channel TRPA1 by Ca2+. Nature Neurosci. 10, 277–279 (2007).
Sawada, Y., Hosokawa, H., Hori, A., Matsumura, K. & Kobayashi, S. Cold sensitivity of recombinant TRPA1 channels. Brain Res. 1160, 39–46 (2007).
Doerner, J. F., Gisselmann, G., Hatt, H. & Wetzel, C. H. Transient receptor potential channel A1 is directly gated by calcium ions. J. Biol. Chem. 282, 13180–13189 (2007).
Akopian, A. N., Ruparel, N. B., Jeske, N. A. & Hargreaves, K. M. TRPA1 desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization. J. Physiol. 583, 175–193 (2007).
Dhaka, A. et al. TRPM8 is required for cold sensation in mice. Neuron 54, 371–378 (2007).
Takashima, Y. et al. Diversity in the neural circuitry of cold sensing revealed by genetic axonal labeling of transient receptor potential melastatin 8 neurons. J. Neurosci. 27, 14147–14157 (2007).
Chung, M. K., Lee, H., Mizuno, A., Suzuki, M. & Caterina, M. J. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J. Biol. Chem. 279, 21569–21575 (2004).
Suzuki, M., Watanabe, Y., Oyama, Y., Mizuno, A., Kusano, E., Hirao, A., Ookawara S. Localization of mechanosensitive channel TRPV4 in mouse skin. Neurosci. Lett. 353, 189–192 (2003).
Chung, M. K., Lee, H. & Caterina, M. J. Warm temperatures activate TRPV4 in mouse 308 keratinocytes. J. Biol. Chem. 278, 32037–32046 (2003).
Hoffmann, T., Sauer, S. K., Horch, R. E. & Reeh, P. W. Sensory transduction in peripheral nerve axons elicits ectopic action potentials. J. Neurosci. 28, 6281–6284 (2008).
Hwang, S. J., Burette, A., Rustioni, A. & Valtschanoff, J. G. Vanilloid receptor VR1-positive primary afferents are glutamatergic and contact spinal neurons that co-express neurokinin receptor NK1 and glutamate receptors. J. Neurocytol. 33, 321–329 (2004).
Yang, K., Kumamoto, E., Furue, H. & Yoshimura, M. Capsaicin facilitates excitatory but not inhibitory synaptic transmission in substantia gelatinosa of the rat spinal cord. Neurosci. Lett. 255, 135–138 (1998).
Kosugi, M., Nakatsuka, T., Fujita, T., Kuroda, Y. & Kumamoto, E. Activation of TRPA1 channel facilitates excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. J. Neurosci. 27, 4443–4451 (2007).
Ferrini, F., Salio, C., Vergnano, A. M. & Merighi, A. Vanilloid receptor-1 (TRPV1)-dependent activation of inhibitory neurotransmission in spinal substantia gelatinosa neurons of mouse. Pain 129, 195–209 (2007).
Fischbach, T., Greffrath, W., Nawrath, H. & Treede, R. D. Effects of anandamide and noxious heat on intracellular calcium concentration in nociceptive DRG neurons of rats. J. Neurophysiol. 98, 929–938 (2007).
Wang, S. et al. Phospholipase C and protein kinase A mediate bradykinin sensitization of TRPA1: a molecular mechanism of inflammatory pain. Brain 131, 1241–1251 (2008).
Wang, H. et al. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J. Neurosci. 25, 7986–7992 (2005).
Gibson, H. E., Edwards, J. G., Page, R. S., Van Hook, M. J. & Kauer, J. A. TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron 57, 746–759 (2008).
Starowicz, K. et al. Tonic endovanilloid facilitation of glutamate release in brainstem descending antinociceptive pathways. J. Neurosci. 27, 13739–13749 (2007).
Ji, R. R., Samad, T. A., Jin, S. X., Schmoll, R. & Woolf, C. J. p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36, 57–68 (2002).
Zhang, X., Huang, J. & McNaughton, P. A. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005). Documentation of the changes in TRPV1 that contribute to peripheral sensitization.
Zhu, W. & Oxford, G. S. Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1. Mol. Cell Neurosci. 34, 689–700 (2007).
Mandadi, S. et al. Increased sensitivity of desensitized TRPV1 by PMA occurs through PKCɛ-mediated phosphorylation at S800. Pain 123, 106–116 (2006).
Lukacs, V. et al. Dual regulation of TRPV1 by phosphoinositides. J. Neurosci. 27, 7070–7080 (2007).
Kawamata, T. et al. Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced thermal hyperalgesia. Neuroscience 154, 1067–1076 (2008).
Facer, P. et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol. 7, 11 (2007).
Lauria, G. et al. Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies. J. Peripher. Nerv. Syst. 11, 262–271 (2006).
Culshaw, A. J. et al. Identification and biological characterization of 6-aryl-7-isopropylquinazolinones as novel TRPV1 antagonists that are effective in models of chronic pain. J. Med. Chem. 49, 471–474 (2006).
Dai, Y. et al. Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J. Clin. Invest. 117, 1979–1987 (2007).
Diogenes, A., Akopian, A. N. & Hargreaves, K. M. NGF up-regulates TRPA1: implications for orofacial pain. J. Dent. Res. 86, 550–555 (2007).
Obata, K. et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J. Clin. Invest. 115, 2393–2401 (2005).
Grant, A. D. et al. Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J. Physiol. 578, 715–733 (2007).
Alessandri-Haber, N. et al. Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 39, 497–511 (2003).
Xiao, R. et al. Calcium plays a central role in the sensitization of TRPV3 channel to repetitive stimulations. J. Biol. Chem. 283, 6162–6174 (2008).
Xu, H., Delling, M., Jun, J. C. & Clapham, D. E. Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nature Neurosci. 9, 628–635 (2006).
Liu, B. & Qin, F. Functional control of cold- and menthol-sensitive TRPM8 ion channels by phosphatidylinositol 4,5-bisphosphate. J. Neurosci. 25, 1674–1681 (2005).
Premkumar, L. S., Raisinghani, M., Pingle, S. C., Long, C. & Pimentel, F. Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation. J. Neurosci. 25, 11322–11329 (2005).
Rohacs, T., Lopes, C. M., Michailidis, I. & Logothetis, D. E. PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nature Neurosci. 8, 626–634 (2005).
Andersson, D. A., Nash, M. & Bevan, S. Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. J. Neurosci. 27, 3347–3355 (2007).
Vanden Abeele, F. et al. Ca2+-independent phospholipase A2-dependent gating of TRPM8 by lysophospholipids. J. Biol. Chem. 281, 40174–40182 (2006).
Barton, N. J. et al. Attenuation of experimental arthritis in TRPV1R knockout mice. Exp. Mol. Pathol. 81, 166–170 (2006).
Birder, L. A. et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nature Neurosci. 5, 856–860 (2002).
Iida, T., Shimizu, I., Nealen, M. L., Campbell, A. & Caterina, M. Attenuated fever response in mice lacking TRPV1. Neurosci. Lett. 378, 28–33 (2005).
Ciura, S. & Bourque, C. W. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperosmolality. J. Neurosci. 26, 9069–9075 (2006).
Marsch, R. et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J. Neurosci. 27, 832–839 (2007).
Razavi, R. et al. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes. Cell 127, 1123–1135 (2006).
Steiner, A. A. et al. Nonthermal activation of transient receptor potential vanilloid-1 channels in abdominal viscera tonically inhibits autonomic cold-defense effectors. J. Neurosci. 27, 7459–7468 (2007).
Gavva, N. R. et al. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation. J. Neurosci. 27, 3366–3374 (2007).
Szallasi, A., Cortright, D. N., Blum, C. A. & Eid, S. R. The vanilloid receptor TRPV1, 10 years from channel cloning to antagonist proof-of-concept. Nature Rev. Drug Discov. 6, 357–372 (2007).
Kanai, Y., Hara, T. & Imai, A. Participation of the spinal TRPV1 receptors in formalin-evoked pain transduction: a study using a selective TRPV1 antagonist, iodo-resiniferatoxin. J. Pharm. Pharmacol. 58, 489–493 (2006).
Lappin, S. C., Randall, A. D., Gunthorpe, M. J. & Morisset, V. TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation. Eur. J. Pharmacol. 540, 73–81 (2006).
Cui, M. et al. TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J. Neurosci. 26, 9385–9393 (2006). First evidence that TRP receptor antagonists may act on the central terminals of nociceptors to produce analgesia.
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).
Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006). Demonstration that TRPA1 is a receptor-operated channel and that this contributes to the detection of inflammation.
Petrus, M. et al. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain 3, 40 (2007).
Bessac, B. F. et al. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J. Clin. Invest. 118, 1899–1910 (2008). By virtue of its capacity to respond to oxidants and other irritants TRPA1 may have a major role in respiratory diseases.
Colburn, R. W. et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron 54, 379–386 (2007).
Bautista, D. M. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208 (2007).
Xing, H., Chen, M., Ling, J., Tan, W. & Gu, J. G. TRPM8 mechanism of cold allodynia after chronic nerve injury. J. Neurosci. 27, 13680–13690 (2007).
Proudfoot, C. J. et al. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16, 1591–1605 (2006).
Chung, M. K. & Caterina, M. J. TRP channel knockout mice lose their cool. Neuron 54, 345–347 (2007).
Dhaka, A., Earley, T. J., Watson, J. & Patapoutian, A. Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28, 566–575 (2008).
Alessandri-Haber, N., Dina, O. A., Joseph, E. K., Reichling, D. & Levine, J. D. A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J. Neurosci. 26, 3864–3874 (2006).
Chen, X., Alessandri-Haber, N. & Levine, J. D. Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4−/− mice. Mol. Pain 3, 31 (2007).
Lee, H., Iida, T., Mizuno, A., Suzuki, M. & Caterina, M. J. Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J. Neurosci. 25, 1304–1310 (2005).
Liedtke, W. & Friedman, J. M. Abnormal osmotic regulation in Trpv4−/− mice. Proc. Natl Acad. Sci. USA 100, 13698–13703 (2003).
Mizuno, A., Matsumoto, N., Imai, M. & Suzuki, M. Impaired osmotic sensation in mice lacking TRPV4. Am. J. Physiol. Cell Physiol. 285, C96–C101 (2003).
Shibasaki, K., Suzuki, M., Mizuno, A. & Tominaga, M. Effects of body temperature on neural activity in the hippocampus: regulation of resting membrane potentials by transient receptor potential vanilloid 4. J. Neurosci. 27, 1566–1575 (2007).
Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation with mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003).
Todaka, H., Taniguchi, J., Satoh, J., Mizuno, A. & Suzuki, M. Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays an essential role in thermal hyperalgesia. J. Biol. Chem. 279, 35133–35138 (2004).
Brierley, S. M. et al. Selective role for TRPV4 ion channels in visceral sensory pathways. Gastroenterology 134, 2059–2069 (2008).
Yin, J. et al. Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4. Circ. Res. 102, 966–974 (2008).
Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005).
Zimmermann, M. Pathobiology of neuropathic pain. Eur. J. Pharmacol. 429, 23–37 (2001).
Leinninger, G. M., Edwards, J. L., Lipshaw, M. J. & Feldman, E. L. Mechanisms of disease: mitochondria as new therapeutic targets in diabetic neuropathy. Nature Clin. Pract. Neurol. 2, 620–628 (2006).
Pop-Busui, R., Sima, A. & Stevens, M. Diabetic neuropathy and oxidative stress. Diabetes Metab. Res. Rev. 22, 257–273 (2006).
Zhang, L. & Barritt, G. J. TRPM8 in prostate cancer cells: a potential diagnostic and prognostic marker with a secretory function? Endocr. Relat. Cancer 13, 27–38 (2006).
Novakova-Tousova, K. et al. Functional changes in the vanilloid receptor subtype 1 channel during and after acute desensitization. Neuroscience 149, 144–154 (2007).
Mason, L., Moore, R. A., Derry, S., Edwards, J. E. & McQuay, H. J. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ 328, 991 (2004).
Amantini, C. et al. Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J. Neurochem. 102, 977–990 (2007).
Athanasiou, A. et al. Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochem. Biophys. Res. Commun. 364, 131–137 (2007).
Simpson, D. M., Brown, S. & Tobias, J. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 70, 2305–2313 (2008).
Nolano, M. et al. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 81, 135–145 (1999).
Karai, L. et al. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J. Clin. Invest. 113, 1344–1352 (2004).
Meyers, J. R. et al. Lighting up the senses: FM1–43 loading of sensory cells through nonselective ion channels. J. Neurosci. 23, 4054–4065 (2003).
Chung, M. K., Guler, A. D. & Caterina, M. J. TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nature Neurosci. 11, 555–564 (2008).
Binshtok, A. M., Bean, B. P. & Woolf, C. J. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610 (2007). Demonstrates the use of TRPV1 as a delivery system to target a normally ineffective cationic sodium channel into nociceptors.
Chizh, B. A. et al. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 132, 132–141 (2007). Preclinical proof-of-concept study in human volunteers of a TRPV1 antagonist.
Arendt-Nielsen, L., Curatolo, M. & Drewes, A. Human experimental pain models in drug development: translational pain research. Curr. Opin. Investig. Drugs 8, 41–53 (2007).
Ravert, H. T., Bencherif, B., Madar, I. & Frost, J. J. PET imaging of opioid receptors in pain: progress and new directions. Curr. Pharm. Des 10, 759–768 (2004).
Schweinhardt, P., Bountra, C. & Tracey, I. Pharmacological FMRI in the development of new analgesic compounds. NMR Biomed. 19, 702–711 (2006).
Rukwied, R. et al. Potentiation of nociceptive responses to low pH injections in humans by prostaglandin E2. J. Pain 8, 443–451 (2007).
Wang, D. H. The vanilloid receptor and hypertension. Acta Pharmacol. Sin. 26, 286–294 (2005).
Gavva, N. R. et al. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136, 202–210 (2008). TRPV1-antagonist-induced hyperthermia is a potential important side effect as revealed in this Phase II study.
Sharif-Naeini, R., Ciura, S. & Bourque, C. W. TRPV1 gene required for thermosensory transduction and anticipatory secretion from vasopressin neurons during hyperthermia. Neuron 58, 179–185 (2008).
Lehto, S. et al. Antihyperalgesic effects of AMG8562, a novel vanilloid receptor TRPV1 modulator that does not cause hyperthermia in rats. J. Pharmacol. Exp. Ther. 17 Apr 2008 (doi:10.1124/jpet.107.132233).
Zambrowicz, B. P. & Sands, A. T. Knockouts model the 100 best-selling drugs — will they model the next 100? Nature Rev. Drug Discov. 2, 38–51 (2003).
Hatcher, J. P. & Chessell, I. P. Transgenic models of pain: a brief review. Curr. Opin. Investig. Drugs 7, 647–652 (2006).
Seong, E., Saunders, T. L., Stewart, C. L. & Burmeister, M. To knockout in 129 or in C57BL/6: that is the question. Trends Genet. 20, 59–62 (2004).
Keskintepe, L., Norris, K., Pacholczyk, G., Dederscheck, S. M. & Eroglu, A. Derivation and comparison of C57BL/6 embryonic stem cells to a widely used 129 embryonic stem cell line. Transgenic Res. 16, 751–758 (2007).
Zhu, W. Xu, P., Cuascut, F. X., Hall, A. K. & Oxford, G. S. Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid 1. J. Neurosci. 27, 13770–13780 (2007).
Wang, X., Miyares, R. L. & Ahern, G. P. Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J. Physiol. 564, 541–547 (2005).
Pogatzki-Zahn, E. M., Shimizu, I., Caterina, M. & Raja, S. N. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain 115, 296–307 (2005).
Keeble, J. et al. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum. 52, 3248–3256 (2005).
Bolcskei, K. et al. Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice. Pain 117, 368–376 (2005).
Jin, X. & Gereau, R. W.t. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J. Neurosci. 26, 246–255 (2006).
Pabbidi, R. M. et al. Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity. Mol. Pain 4, 9 (2008).
Wang, Z. Y., Wang, P., Merriam, F. V. & Bjorling, D. E. Lack of TRPV1 inhibits cystitis-induced increased mechanical sensitivity in mice. Pain 139, 158–167 (2008).
Alessandri-Haber, N., Dina, O. A., Joseph, E. K. & Reichling, D. B. & Levine, J. D. Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J. Neurosci. 28, 1046–1057 (2008).
Alessandri-Haber, N., Joseph, E., Dina, O. A., Liedtke, W. & Levine, J. D. TRPV4 mediates pain-related behavior induced by mild hypertonic stimuli in the presence of inflammatory mediator. Pain 118, 70–79 (2005).
Matta, J. A. et al. General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc. Natl Acad. Sci. USA 105, 8784–8789 (2008).
Escalera, J., von Hehn, C. A., Bessac, B. F., Sivula, M. & Jordt, S. E. TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J. Biol. Chem. 283, 24136–24144 (2008).
Cruz-Orengo, L. et al. Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Mol. Pain 4, 30 (2008).
Andersson, D. A., Gentry, C., Moss, S. & Bevan, S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J. Neurosci. 28, 2485–2494 (2008).
Materazzi, S. et al. Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc. Natl Acad. Sci. USA 105, 12045–12050 (2008).
Moore, R. A., Derry, S. & McQuay, H. J. Topical agents in the treatment of rheumatic pain. Rheum. Dis. Clin. North Am. 34, 415–432 (2008).
Cruz, F. & Dinis, P. Resiniferatoxin and botulinum toxin type A for treatment of lower urinary tract symptoms. Neurourol. Urodyn. 26, 920–927 (2007).
Watson, C. P. et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin. Ther. 15, 510–526 (1993).
A.P. has received research support from the Genomics Institute of the Novartis Foundation. S.T. is a full-time employee of GlaxoSmithKline. C.J.W. has been a scientific advisor, consultant or received research support from Solace Pharmaceuticals, Hydra Biosciences, Pfizer, GlaxoSmithKline and Abbott.
IUPHAR Receptor Database
Glenmark GRC15133 and GRC 17173
A high-threshold primary sensory neuron that detects or responds to noxious stimuli.
- Inflammatory pain
Pain associated with tissue injury and inflammation characterized by reduced threshold and increased responsiveness.
- Neuropathic pain
Pain associated with a lesion to the nervous system.
- Michael addition reaction
Nucleophilic addition to an alpha or beta unsaturated carbonyl group.
- Click reaction
Copper(I)-catalysed azide-alkyne cycloaddition reaction that can be used for in vivo labelling of molecules.
Endogenous agonists of cannabinoid receptors in animals.
An endogenous ligand of the TRPV1 receptor.
- Peripheral sensitization
Reduction in the threshold for activation of the peripheral terminal of nociceptors produced by inflammatory mediators.
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Patapoutian, A., Tate, S. & Woolf, C. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 8, 55–68 (2009). https://doi.org/10.1038/nrd2757
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