Abstract
The transient receptor potential V1, or TRPV1, channel has a complex polymodal activation profile that integrates information from membrane potential changes, heat, and protons in addition to channel gating following ligand binding. TRPV1 is expressed along the peripheral pain pathway from the distal endings of nociceptor neurons to dorsal root ganglia; but has limited expression in the central nervous system and is detected in arteriolar smooth muscle cells and various epithelia. Several TRPV1 antagonist candidate drugs have been tested in clinical trials over the past 5 years with varying results. The reported side-effect profile of these oral drug formulations includes hyperthermia and impaired detection of painful heat. These adverse events have tentatively been linked to characteristic in vitro profiles of the candidate drugs, specifically the ability of these molecules to differentially block one or several opening modalities. Thus the selection of lead candidates that are selective for specific modalities could be key to the development of a successful TRPV1 antagonist drug. This minireview updates the details of TRPV1 activation modes, existing in vitro assays available for screening of novel molecules and the clinical and preclinical profiles of next-generation TRPV1 candidate drugs developed by pharmaceutical companies.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Sagar DR et al (2004) TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. Eur J Neurosci 20:175–184
Sexton A et al (2007) 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1. FASEB J 21:2695–2703
Ross RA (2004) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140: 790–801
Tewksbury JJ et al (2001) Seed dispersal. Directed deterrence by capsaicin in chilies. Nature 412:403–404
Szolcsányi J (2004) Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 38:377–384
Dray A (1992) Mechanism of action of capsaicin-like molecules on sensory neurons. Life Sci 51:1759–1765
Laird JM et al (2001) A new model of visceral pain and referred hyperalgesia in the mouse. Pain 92:335–342
Lin Q, Wu J, Willis WD (1999) Dorsal root reflexes and cutaneous neurogenic inflammation following intradermal injection of capsaicin in rats. J Neurophysiol 82:2602–2611
Mitchell K et al (2010) Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates. Mol Pain 6:94
Caterina MJ et al (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313
Helme RD, McKernan S (1985) Neurogenic flare responses following topical application of capsaicin in humans. Ann Neurol 18:505–509
Simone DA et al (1989) Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38:99–107
Petersen KL, Rowbotham MC (1999) A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport 10:1511–1516
Modir JG, Wallace MS (2010) Human experimental pain models 3: heat/capsaicin sensitization and intradermal capsaicin models. Methods Mol Biol 617:169–174
Aykanat V et al (2012) Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica. Br J Clin Pharmacol 73(1):37–45. doi:10.1111/1365-2125.2011.04059.x, “Accepted Article”
Klein RM et al (2008) Determinants of molecular specificity in phosphoinositide regulation. Phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) is the endogenous lipid regulating TRPV1. J Biol Chem 283:26208–26216
Lukacs V et al (2007) Dual regulation of TRPV1 by phosphoinositides. J Neurosci 27:7070–7080
Zhang X, Huang J, McNaughton PA (2005) NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J 24:4211–4223
Chuang HH et al (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962
Lin Q et al (2007) Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin. Mol Pain 3:30–45
Ferreira J, da Silva GL, Calixto JB (2004) Contribution of vanilloid receptors to the overt nociception induced by B2 kinin receptor activation in mice. Br J Pharmacol 141: 787–794
NCBI GeneBank: Human gene ID 7442. http://www.ncbi.nlm.nih.gov/gene?term=7442. Accessed Feb 2012
Caterina MJ et al (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824
Moiseenkova-Bell VY et al (2008) Structure of TRPV1 channel revealed by electron cryomicroscopy. Proc Natl Acad Sci USA 105: 7451–7455
Garcia-Martinez C et al (2000) Identification of an aspartic residue in the P-loop of the vanilloid receptor that modulates pore properties. J Biol Chem 275:32552–32558
Ferrer-Montiel A et al (2004) Molecular architecture of the vanilloid receptor Insights for drug design. Eur J Biochem 271:1820–1826
Jordt S-E, Tominaga M, Julius D (2000) Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA 97:8134–8139
Welch JM, Simon SA, Reinhart PH (2000) The activation of rat vanilloid receptor 1 bycaps aicin involves the pore domain and differs from the activation by either acid or heat. Proc Natl Acad Sci USA 25:13889–13894
Lishko PV et al (2007) The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity. Neuron 54:905–918
Schindl R et al (2008) The first ankyrin-like repeat is the minimum indispensable key structure for functional assembly of homo- and heteromeric TRPC4/TRPC5 channels. Cell Calcium 43:260–269
Rosenbaum T et al (2004) Ca2+/calmodulin modulates TRPV1 activation by capsaicin. J Gen Physiol 123:53–62
Valente P et al (2008) Identification of molecular determinants of channel gating in the transient receptor potential box of vanilloid receptor. FASEB J 22:3298–3309
Prescott E, Julius D (2003) A modular PIP2 site as a determinant of capsaicin receptor sensitivity. Science 300:1284–1288
Bhave G et al (2003) Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor potential vanilloid 1 (TRPV1). Proc Natl Acad Sci USA 100: 12480–12485
Mandadi S et al (2004) Activation of protein kinase C reverses capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels. Cell Calcium 35:471–478
Jun J et al (2004) Phosphorylation of vanilloid receptor 1 by Ca2+/calmodulin-dependent kinase II regulates its vanilloid binding. J Biol Chem 979:7048–7054
Lehto SG et al (2008) Antihyperalgesic effects of (R, E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)-acrylamide (AMG8562), a novel transient receptor potential vanilloid type 1 modulator that does not cause hyperthermia in rats. J Pharmacol Exp Ther 326:218–229
Pingle SC, Matta JA, Ahern GP (2007) Capsaicin receptor: TRPV1 a promiscuous TRP channel. Handb Exp Pharmacol 179:155–171
Vyklicky L et al (2003) Vanilloid receptor TRPV1 is not activated by vanilloids applied intracellularly. Neuroreport 14:1061–1065
Sutton KG et al (2005) Functional characterisation of the S512Y mutant vanilloid human TRPV1 receptor. Br J Pharmacol 146:702–711
Gavva NR et al (2004) Molecular determinants of vanilloid sensitivity in TRPV1. J Biol Chem 279:20283–20295
Chou MZ et al (2004) Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. Biochemistry 43:2501–2511
Aneiros E et al (2011) The biophysical and molecular basis of TRPV1 proton gating. EMBO J 30:994–1002
Voets T et al (2004) The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 430:748–754
Garcia-Sanz N et al (2007) A role of the transient receptor potential domain of vanilloid receptor I in channel gating. J Neurosci 27:11641–11650
Brauchi S et al (2006) A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels. J Neurosci 26:4835–4840
Vlachova V et al (2003) Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. J Neurosci 23:1340–1350
Grandl J et al (2010) Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain. Nat Neurosci 13:708–714
Lu G et al (2005) TRPV1b, a functional human vanilloid receptor splice variant. Mol Pharmacol 67:1119–1127
Vos MH et al (2006) TRPV1b overexpression negatively regulates TRPV1 responsiveness to capsaicin, heat and low pH in HEK293 cells. J Neurochem 99:1088–1102
Schumacher MA et al (2000) Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem 275: 2756–2762
Eilers H et al (2007) The rat vanilloid receptor splice variant VR.5′sv Blocks TRPV1 activation. Neuroreport 18:969–973
Sharif Naeini R et al (2006) An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 9:93–98
Tian W et al (2006) Regulation of TRPV1 by a novel renally expressed rat TRPV1 splice variant. Am J Physiol Renal Physiol 290:F117–F126
Lyall V et al (2004) The mammalian amiloride-insensitive non-specific salt taste receptor is a vanilloid receptor-1 variant. J Physiol 558:147–159
Glinsukon T et al (1980) Acute toxicity of capsaicin in several animal species. Toxicon 18:215–220
Jordt SE, Julius D (2002) Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell 108:421–430
Szallasi A, Blumberg PM (1993) [3H]resiniferatoxin binding by the vanilloid receptor: species-related differences, effects of temperature and sulfhydryl reagents. Naunyn Schmiedebergs Arch Pharmacol 347:84–91
Numazaki M et al (2003) Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc Natl Acad Sci USA 100:8002–8006
Jerman JC et al (2000) Characterization using FLIPR of rat vanilloid receptor (rVR1) pharmacology. Br J Pharmacol 130:916–922
Rami HK et al (2006) Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett 16: 3287–3291
Jung J et al (1999) Capsaicin binds to the intracellular domain of the capsaicin activated ion channel. J Neurosci 19:529–538
Gunthorpe MJ et al (2000) Voltage- and time-dependent properties of the recombinant rat vanilloid receptor (rVR1). J Physiol 525:747–759
Hellwig N et al (2004) TRPV1 acts as proton channel to induce acidification in nociceptive neurons. J Biol Chem 279:34553–34561
Meyers JR et al (2003) Lighting up the senses: FM1-43 loading of sensory cells through nonselective Ion channels. J Neurosci 23:4054–4065
Binshtok AM, Bean BP, Woolf CJ (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449:607–610
Chung M-K, Guler AD, Caterina MJ (2008) TRPV1 shows dynamic ionic selectivity during agonist stimulation. Nat Neurosci 11:555–564
Heat activation of TRPV1 on Nanion’s Patchliner®. Nanion’s application note. http://www.nanion.de. Accessed Sept 2011
Peters MF et al (2010) Comparing label-free biosensors for pharmacological screening with cell-based functional assays. Assay Drug Dev Technol 8:219–227
Liu J et al (2009) A label-free cell-based functional assay for identification and characterization of TRPV1 channel modulators [abstract]. 15th Annual meeting of the Society for Biomolecular Screening
Reubish D et al (2009) Functional assessment of temperature-gated ion-channel activity using a real-time PCR machine. Biotechniques 47(3):iii–ix
Aneiros E, Dabrowski M (2009) Novel temperature activation cell-based assay on thermo-TRP ion channels. J Biomol Screen 14:662–667
Papakosta M et al (2011) Chimeric approach reveals that differences in the TRPV1 pore domain determine species-specific sensitivity to block of heat activation. J Biol Chem 286(45):39663–39672. doi:10.1074/jbc.M111.273581
Szallasi A, Blumberg PM (1999) Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51:159–212
Gavva NR et al (2008) Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 136:202–210
Iida T et al (2005) Attenuated fever response in mice lacking TRPV1. Neurosci Lett 378:28–33
Toth DM et al (2010) Nociception, neurogenic inflammation and thermoregulation in TRPV1 knockdown transgenic mice. Cell Mol Life Sci 68:2589–25601
Rowbotham MC et al (2011) Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 152:1192–1200
Krarup AL et al (2011) Randomised clinical trial: the efficacy of transient receptor potential vanilloid 1 antagonist AZD1386 in human esophageal pain. Aliment Pharmacol Ther 33:113–1122
Abbott presentation at Society for Neuroscience Meeting in San Diego (2011)
Chizh BA et al (2007) The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor mediated activity and inflammatory hyperalgesia in humans. Pain 132:132–141
Crutchlow M (2009) Pharmacologic inhibition of TRPV1 impairs sensation of potentially injurious heat in healthy subjects. Am Soc Clin Pharmacol Ther (ASCPT)
Vidal-Mosquera M et al (2011) Triazine-based vanilloid 1 receptor open channel blockers:design, synthesis, evaluation, and SAR analysis. J Med Chem 54(21):7441–7452. doi:doi.org/10.1021/jm200981s
Surowy CS et al (2008) (R)-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)-urea (ABT-102) blocks polymodal activation of transient receptor potential vanilloid 1 receptors in vitro and heat-evoked firing of spinal dorsal horn neurons in vivo. J Pharmacol Exp Ther 326:879–888
Xia R et al (2011) TRPV1: a therapy target that attracts the pharmaceutical interests. Adv Exp Med Biol 704:637–665
Krarup AL et al (2011) Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment Pharmacol Ther 33:1113–1122
Daewoong Press release (2009) “Daewoong Pharmaceutical (CEO: Jong Wook Lee) has received approval from the KFDA (Korean Food and Drug Administration) to enter into clinical trials for a next generation neural pain killer: DWP05195”. http://www.daewoong.co.kr/www_pharm/english_new/aboutus/whatsnews_view.asp?idx=60652. Accessed Feb 2012
FierceBiotech Press cut (2008) Posted October 24, 2008. Further Clinical Trials in Osteoarthritis Pain Suspended for GRC 6211. http://www.fiercebiotech.com/press-releases/further-clinical-trials-osteoarthritis-pain-suspended-grc-6211. Accessed Feb 2012
Gunthorpe MJ et al (2007) Characterisation of SB-705498, a potent and selective TRPV1 antagonist which inhibits the capsaicin-, acid- and heat-mediated activation of the vanilloid receptor. J Pharmacol Exp Ther 321:1183–1192
Round P, Priestley A, Robinson J (2011) An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy human subjects. Br J Clin Pharmacol 72:921–931
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Radresa, O., Zicha, S., Brown, W., Laird, J.M.A. (2012). TRPV1 as a Polymodal Sensor: Potential to Discover TRPV1 Antagonists Selective for Specific Activating Modalities. In: Szallasi, A., Bíró, T. (eds) TRP Channels in Drug Discovery. Methods in Pharmacology and Toxicology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-077-9_11
Download citation
DOI: https://doi.org/10.1007/978-1-62703-077-9_11
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-076-2
Online ISBN: 978-1-62703-077-9
eBook Packages: Springer Protocols