Gene Symbol: TRPV1;
Other names: Vanilloid Receptor 1 (VR1), Capsaicin Receptor
1. General Information
Background and structure
Transient receptor potential vanilloid receptor 1 (TRPV1) is one of 6 members of the subfamily of vanilloid receptors that belongs to the family of transient receptor potential (TRP) channels. TRP channels are an intrinsic part of the mammalian sensory system responding to a broad range of stimuli such as temperature, touch, pain, osmolarity, pheromones, and taste (8). TRPV1, TRPV2, TRPV3 and TRPV4 are all involved in thermoactivation. These channels share a similar structure with 6 putative transmembrane domains, a loop structure between transmembrane regions 5 and 6 believed to be involved in pore formation, ankyrin repeats, and both the N- and C-termini located in the cytoplasm (8, 41).
TRPV1 plays an important role in nociception and was the first of the TRPV family channels to be cloned. TRPV1 was cloned using capsaicin, the pungent component of hot chili pepper, by screening an expression cDNA library of dorsal root ganglia (5). TRPV1 is a non-selective cation channel and can be activated by numerus stimuli such as vanilloids (capsaicin, resiniferatoxin), low pH, elevated temperature (10), endogenous lipoxygenases (leukotriene B4, 12- or 15-HPETE) (24), endogenous anandamide (40) and ethanol (43). In addition, ethanol can potentiate the effects of capsaicin, protons and heat. TRPV1 is broadly distributed. It is highly expressed in dorsal root ganglia, trigeminal ganglia, in small sensory C fibers and some Aδ fibers. It is also detectable in brain, spinal cord, bladder, kidney, liver, spleen, testis, lung and bowel (17).
The cation selective channel is probably made of a tetrameric quaternary structure (25). Modulation of the activity of TRPV1 is under the control of many intracellular signals that act on the N-terminal and C-terminal portions of the monomer including phosphorylation. Binding of pro-inflammatory agents such as prostaglandins to its receptor induces a cascade of events that lead to activation of cAMP-dependent protein kinase that in turn can phosphorylate TRPV1. Histamine can also activate TRPV1 through phosphorylation by protein kinase C (PKC). Activation of TRPV1 contributes to the release of substance P and CGRP from peripheral terminal of neurons (25).
TRPV1 is activated by a number of agonists (see Table 1) although clear identification of endogenous ligands has been elusive. Increased temperature is a well-established pathological activator of TRPV1 under certain conditions. Local acidification can activate TRPV1 and cause pain and inflammation. There is accumulating evidence for endogenous chemical mediators such as anandamide or leukotrienes in TRPV1 activation.
Intracellular Ca2+ is involved in the mechanism of sensitization of TRPV1. Increased intracellular Ca2+ results in activation of phospholypase C (PLC) (35) which hydrolyses the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into 1,4,5-trisphosphate (IP3) and diacylglycerol. In an opposing effect, depletion of PIP2 is responsible for desentization of TRPV1 (35).
Three alternatively spliced TRPV1 mRNAs have been characterized: VR.5’sv (38), TRPV1var (42) and TRPV1β (48). The TRPV1var variant expressed in the kidney encodes the first 248 amino-acids and comprises only one ankyrin domain (42). Another variant called VR.5’sv, expressed in DRG, brain and peripheral blood mononuclear cells is missing most of the N-terminal region and two ankyrin domains (38). Finally, the third alternatively spliced TRPV1 variant known as TRPV1β lacks amino-acids 399 to 408 (before the first transmembrane domain). Interestingly, all these variants can modulate the activity of the canonical TRPV1 protein as demonstrated by coexpression studies of TRPV1 with the variants (38, 42, 48).
The role of TRPV1 in pain sensation has been clearly demonstrated by the advent of TRPV1 knockout mice (4). Knockout mice exhibited impaired thermal sensitivity to pain triggered by heat or capsaicin.
TRPV1 has been implicated in neurogenic inflammation using pharmacological agonists and antagonists in animal models and by genetic approaches comparing severity of insults in wild type or TRPV1-/- (KO) mice. Neurogenic inflammation is characterized by edema, hyperalgesia, vasodilatation and inflammatory cell infiltration caused by nociceptor overstimulation at the site of injury. The role of TRPV1 in a variety of inflammatory diseases affecting multiple organs has been an active area of investigation.
In some models, activation of TRPV1 plays a central role in the inflammatory response. TRPV1 is expressed in C-fibers innervating the respiratory tract as well as in lung epithelial cells and has been implicated in bronchoconstriction, mucus secretion, cough, and airway irritation. TRPV1 appears to mediate inflammatory tracheal hyperreactivity to carbachol in sensitized mice (3) and cough after RTX and ethanol treatment (15) which either directly activate or lower the activation threshold for TRPV1.
TRPV1 is also involved in acute and chronic inflammation in a model of knee joint injury (26). However, low dose of the TRPV1 agonist RTX produced an analgesic effect and less edema in a knee joint inflammation model (29) possibly through receptor desensitization. TRPV1 is also present in the bladder and and is involved acute bladder inflammation (7). In addition, TRPV1 promotes inflammation in colitis in both rats (27) and mice (28).
Under certain circumstances, TRPV1 activation may confer protection against inflammation. Activation of TRPV1 by agonists (RTX or SA13353) reduced the severity of ishemia/reperfusion-induced renal injury in rats (45) and the severity of LPS-induced rheumatoid arthritis in mice (32). Similar observations were made in a murine model of experimental autoimmune encephalomyelitis (EAE). SA13353 or capsaicin inhibited the production of TNF-α and IL-1β (44). TRPV1 also had a protective effect against the onset of sepsis after endotoxin treatment (LPS) (9) and in rat model of sepsis by cecal ligation and puncture (12). As a member of the acid sensing system, TRPV1 participates in the homeostasis of gastric acid secretion through activation of the sensory nerves and release of CGRP (18-20).
Thus depending upon the cellular environment, TRPV1 may reduce the severity of inflammatory insults or accentuates its effects.
2. TRPV1 and the exocrine pancreas
Acute pancreatitis is associated with vasodilation, edema, neutrophil infiltration and acinar cell necrosis. Many of these features are manifestations of neurogenic inflammation and there is accumulating evidence that neural factors contribute to the pathogenesis of the disease (30). Using the TRPV1 agonist capsaicin to denervate neonatal rats, Nathan and al. demonstrated that TRPV1 mediated the neurogenic aspect of acute pancreatitis (34). Antagonists such as capsazepine (23) or desensitization of pancreatic primary sensory neurons with RTX (36) ameliorated the severity of caerulein-induced pancreatitis.
TRPV1 activation of primary sensory nerves causes the release of substance P during the inflammatory insult (33). Substance P is a 11 amino-acids peptide that stimulates plasma extravasation (14) and genetic deletion of its receptor (NK1-R) ameliorates caerulein induced acute pancreatitis (16). In the search for the endogenous ligands for TRPV1, Hwang and co-workers (24) demonstrated that products from lipoxygenases such as 12-S-HPETE, 15-S-HPETE and LTB4 could directly activate TRPV1 (24). Administration of LTB4 through the celiac artery produced pancreatitis-like inflammation (47). Moreover, blockade of TRPV1 with the TRPV1 antagonist capsazepine or inhibition of the 5-lipoxygenase- activating protein (FLAG) by preteatment with MK886 reduced the severity of the pancreatitis induced by LTB4 indicating that LTB4 was an endogenous ligand of TRPV1 and played a role in inducing acute pancreatitis (47).
TRPV1 and pain sensation during pancreatitis
Through retrograde labeling of pancreatic nerves and immunostaining with anti-TRPV1 antibody it has been possible to localize the pancreatic afferents expressing TRPV1 (13). Dorsal root ganglia (T9-T12) had the highest concentration of neurons expressing TRPV1 (65% of the neurons). Some TRPV1 expressing afferents were also detected in the nodose ganglia where 35% of the neurons expressed TRPV1 (13).
TRPV1 mediates pain in acute pancreatitis. Rats subjected to L-arginine-induced pancreatitis exhibited a 2.5 fold increase of c-fos expression in spinal neurons suggesting activation of nociceptive pathways and a 3 fold increase in spontaneous abdominal contractions (an indicator of nociceptive sensation). Administration of the TRPV1 antagonist capsazepine reduced both c-fos expression and abdominal contractions (49).
TRPV1 activity is potentiated by protease-activated receptor 2 (PAR-2) activation (11, 22). Both TRPV1 and PAR-2 are expressed in the same subset of primary afferent neurons (21) . In HEK293 cells co-expressing both TRPV1 and PAR-2, it was demonstrated that PAR-2 could potentiate the activity of TRPV1. Further, it has been demonstrated that PAR-2 activation by the selective agonist SL-NH2 could cause thermal hyperalgesia and mechanical allodynia at a dose that does not produce inflammation (46). Direct infusion of trypsin or PAR-2 agonist in the pancreatic duct of rats induced a nociceptive response as demonstrated by measurement of an electromyographic recording from the acromiotrapezius (21).
TRPV1 mediates hyperalgesia in a TNBS-induced chronic pancreatitis model in the rat (50). A decrease in the response frequency in the Von Frey filament (VFF) test was observed after administration of the TRPV1 antagonist SB-366791 to rats exhibiting chronic pancreatitis after treatment with TNBS. Interestingly, the level of TRPV1 expression and the number of DRG neurons expressing TRPV1 were increased in these rats. TRPV1’s effect on hyperalgesia in the TNBS-induced model is mediated by nerve growth factor (NGF) (51). Anti-NGF treatment to rats with chronic pancreatitis reduced their response to the VFF test. In addition, TRPV1 expression in DRG neurons was also reduced when rats with chronic pancreatitis were subjected to anti-NGF treatment.
Recently, Schwartz and co-authors (39) demonstrated a synergistic effect of TRPV1 and TRPA1 on both pancreatic pain and inflammation in caerulein-induced acute pancreatitis using specific antagonists for TRPV1 and TRPA1. These findings are in agreement with the observation that the cannabinoid agonist, WIN 55,212-2, known to activate TRPA1, attenuated capsaicin-evoked responses (2). Alternatively, TRPV1 can also modulate the TRPA1 response to nociceptive stimuli as exemplified by TRPV1’s prevention of mustard oil-induced TRPA1 internalization (1). The interactions between TRPV1 and TRPA1 also have been demonstrated in electrophysiological responses in CHO cells co-expressing TRPV1/TRPA1 and in trigeminal sensory neurons. Both cell types exhibited characteristics suggesting that TRPV1 modulates TRPA1 responses (37).
Finally, TRPV4, another channel of the TRP family that can be activated by changes in osmotic pressure (31), is also present in pancreatic sensory nerves and also contributes to nociceptive sensation in caerulein-induced acute pancreatitis (6).
In summary, TRPV1 expressed in primary sensory neurons is involved in neurogenic inflammation of the pancreas and in nociceptive sensation.
3. Tools available for the study of TRPV1
a. TRPV1 Antibodies
A large number of anti-TRPV1 antibodies are available commercially. Most are polyclonal antisera raised in rabbit, goat or even guinea pig, but some monoclonal antibodies are available. Antibodies have been used to identify TRPV1 in rat, human, mouse, chicken and/or zebrafish. Below, are listed some available antisera.
- Gp 14100 (Neuromics, Edina, CA). Used in immunohistochemistry (Baiou et al., J Comp Neurol. 2007; 503:334-337).
- Ab63083 (Abcam, Cambridge, MA). Used in immunohistochemistry (Nie et al., Am J Obstet Gynecol 2010; 202: 346. E1-8).
- ACC-030 (Alomone, Jerusalem, Israel). Used in immunohistochemistry, immunoelectronmicroscopy and western blot (Tominaga et al., Neuron 1998; 21: 531-543).
Affinity purified polyclonal antisera
- P-19 antibody (Santa Cruz Biotechnology, CA; catalog number: sc-12498). Used in Western blots (Vos et al., J Neurochem 2006; 99: 1088-102). Used in immunoprecipitation assay (Stanchev et al., Pain 2009; 143: 26-36).
- N-15 and C-15 antibodies (Santa Cruz Biotechnology, CA; catalog number sc-12500 and sc-12503 respectively). Used in Western blot and immunohistofluorescence (Faussone-Pellegrini et al., (Histochem Cell Biol. 2005; 124: 61-68).
- AB 5370 (EMD-Millipore Calbiochem, Billerica, MA). Used for Western blot, immunohistochemistry and immunoelectron microscopy: Tóth et al., (Brain Res Mol Brain Res. 2005; 135: 162-168).
- PC-420 (EMD-Millipore Calbiochem, Billerica, MA). Used in immunohistochemistry (Zhong et al., Dig Dis Sic. 2008; 53: 194-203).
- Y7101-ig (Abcam, Cambridge, MA). Used in immunochemistry (Peng et al., Am J Physiol Renal Physiol. 2008; 295: F1324-1335).
- H00007442-M01 (Novus Biologicals, Littleton, CO). Used in Western blot (El Karim et al., Pain 2011; 152: 2211-2223).
b. cDNA clones
There are three commercial suppliers of TRPV1 cDNA constructs: Genecopoeia (Rockville, MD); OriGene (Rockville, MD) and DNASU plasmid Repository (ASU-Biodesign Institute, Arizona State University, Arizona). These 3 companies offer human and mouse clones. Rat cDNAs are only offered by Genecopoeia and OriGene
c. Genetically modified mice
Mice with genetic deletion of TRPV1 are available from Jackson Laboratories (catalog number B6.129S4-Trpv1tm1Jul/J).
d. Agonists and antagonists
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2. Akopian AN, Ruparel NB, Patwardhan A, and Hargreaves KM. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci 28: 1064-1075, 2008. PMID 18234885
3. Buckley TL, and Nijkamp FP. Airways hyperreactivity and cellular accumulation in a delayed-type hypersensitivity reaction in the mouse. Modulation by capsaicin-sensitive nerves. Am J Respir Crit Care Med 149: 400-407, 1994. PMID 8306037
4. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, and Julius D. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288: 306-313, 2000. PMID 10764638
5. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, and Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389: 816-824, 1997. PMID 9349813
6. Ceppa E, Cattaruzza F, Lyo V, Amadesi S, Pelayo JC, Poole DP, Vaksman N, Liedtke W, Cohen DM, Grady EF, Bunnett NW, and Kirkwood KS. Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol 299: G556-571, 2010. PMID 20539005
7. Charrua A, Cruz CD, Cruz F, and Avelino A. Transient receptor potential vanilloid subfamily 1 is essential for the generation of noxious bladder input and bladder overactivity in cystitis. J Urol 177: 1537-1541, 2007. PMID 17382774
8. Clapham DE. TRP channels as cellular sensors. Nature 426: 517-524, 2003. PMID 14654832
9. Clark N, Keeble J, Fernandes ES, Starr A, Liang L, Sugden D, de Winter P, and Brain SD. The transient receptor potential vanilloid 1 (TRPV1) receptor protects against the onset of sepsis after endotoxin. Faseb J 21: 3747-3755, 2007. PMID 17601984
10. Cortright DN, and Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur J Biochem 271: 1814-1819, 2004. PMID 15128291
11. Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H, Tominaga M, and Noguchi K. Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci 24: 4293-4299, 2004. PMID 15128843
12. Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Gurbuz N, Bayraktar N, and Bayraktar M. Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 99: 1501-1507; table of contents, 2004. PMID 15502055
13. Fasanella KE, Christianson JA, Chanthaphavong RS, and Davis BM. Distribution and neurochemical identification of pancreatic afferents in the mouse. J Comp Neurol 509: 42-52, 2008. PMID 18418900
14. Figini M, Emanueli C, Grady EF, Kirkwood K, Payan DG, Ansel J, Gerard C, Geppetti P, and Bunnett N. Substance P and bradykinin stimulate plasma extravasation in the mouse gastrointestinal tract and pancreas. Am J Physiol 272: G785-793, 1997. PMID 9142909
15. Gatti R, Andre E, Barbara C, Dinh TQ, Fontana G, Fischer A, Geppetti P, and Trevisani M. Ethanol potentiates the TRPV1-mediated cough in the guinea pig. Pulm Pharmacol Ther 22: 33-36, 2009. PMID 19049892
16. Grady EF, Yoshimi SK, Maa J, Valeroso D, Vartanian RK, Rahim S, Kim EH, Gerard C, Gerard N, Bunnett NW, and Kirkwood KS. Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice. Br J Pharmacol 130: 505-512, 2000. PMID 10821777
17. Gunthorpe MJ, Benham CD, Randall A, and Davis JB. The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 23: 183-191, 2002. PMID 11931994
18. Holzer P. Efferent-like roles of afferent neurons in the gut: Blood flow regulation and tissue protection. Auton Neurosci 125: 70-75, 2006. PMID 16542883
19. Holzer P. Role of visceral afferent neurons in mucosal inflammation and defense. Curr Opin Pharmacol 7: 563-569, 2007. PMID 18029228
20. Holzer P. Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 292: G699-705, 2007. PMID 17122365
21. Hoogerwerf WA, Shenoy M, Winston JH, Xiao SY, He Z, and Pasricha PJ. Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain. Gastroenterology 127: 883-891, 2004. PMID 15362043
22. Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, and Pasricha PJ. The proteinase-activated receptor 2 is involved in nociception. J Neurosci 21: 9036-9042, 2001. PMID 11698614
23. Hutter MM, Wick EC, Day AL, Maa J, Zerega EC, Richmond AC, Jordan TH, Grady EF, Mulvihill SJ, Bunnett NW, and Kirkwood KS. Transient receptor potential vanilloid (TRPV-1) promotes neurogenic inflammation in the pancreas via activation of the neurokinin-1 receptor (NK-1R). Pancreas 30: 260-265, 2005. PMID 15782105
24. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, and Oh U. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A 97: 6155-6160, 2000. PMID 10823958
25. Jara-Oseguera A, Simon SA, and Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol 1: 255-269, 2008. PMID 20021438
26. Keeble J, Russell F, Curtis B, Starr A, Pinter E, and Brain SD. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum 52: 3248-3256, 2005. PMID 16200599
27. Kihara N, de la Fuente SG, Fujino K, Takahashi T, Pappas TN, and Mantyh CR. Vanilloid receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut 52: 713-719, 2003. PMID 12692058
28. Kimball ES, Wallace NH, Schneider CR, D’Andrea MR, and Hornby PJ. Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice. Neurogastroenterol Motil 16: 811-818, 2004. PMID 15601431
29. Kissin EY, Freitas CF, and Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg 101: 1433-1439, 2005. PMID 16244007
30. Liddle RA. The role of Transient Receptor Potential Vanilloid 1 (TRPV1) channels in pancreatitis. Biochim Biophys Acta 1772: 869-878, 2007. PMID 17428642
31. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, and Heller S. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103: 525-535, 2000. PMID 11081638
32. Murai M, Tsuji F, Nose M, Seki I, Oki K, Setoguchi C, Suhara H, Sasano M, and Aono H. SA13353 (1-[2-(1-Adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea) inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons mediated via transient receptor potential vanilloid 1 in vivo. Eur J Pharmacol 588: 309-315, 2008. PMID 18508045
33. Nathan JD, Patel AA, McVey DC, Thomas JE, Prpic V, Vigna SR, and Liddle RA. Capsaicin vanilloid receptor-1 mediates substance P release in experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 281: G1322-1328, 2001. PMID 11668042
34. Nathan JD, Peng RY, Wang Y, McVey DC, Vigna SR, and Liddle RA. Primary sensory neurons: a common final pathway for inflammation in experimental pancreatitis in rats. Am J Physiol Gastrointest Liver Physiol 283: G938-946, 2002. PMID 12223354
35. Rohacs T, Thyagarajan B, and Lukacs V. Phospholipase C mediated modulation of TRPV1 channels. Mol Neurobiol 37: 153-163, 2008. PMID 18528787
36. Romac JM, McCall SJ, Humphrey JE, Heo J, and Liddle RA. Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas 36: 394-401, 2008. PMID 18437086
37. Salas MM, Hargreaves KM, and Akopian AN. TRPA1-mediated responses in trigeminal sensory neurons: interaction between TRPA1 and TRPV1. Eur J Neurosci 29: 1568-1578, 2009. PMID 19419422
38. Schumacher MA, Moff I, Sudanagunta SP, and Levine JD. 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, 2000. PMID 10644739
39. Schwartz ES, Christianson JA, Chen X, La JH, Davis BM, Albers KM, and Gebhart GF. Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation. Gastroenterology 140: 1283-1291 e1281-1282, 2011. PMID 21185837
40. Smart D, Gunthorpe MJ, Jerman JC, Nasir S, Gray J, Muir AI, Chambers JK, Randall AD, and Davis JB. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 129: 227-230, 2000. PMID 10694225
41. Szallasi A, Cortright DN, Blum CA, and Eid SR. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6: 357-372, 2007. PMID 17464295
42. Tian W, Fu Y, Wang DH, and Cohen DM. Regulation of TRPV1 by a novel renally expressed rat TRPV1 splice variant. Am J Physiol Renal Physiol 290: F117-126, 2006. PMID 16091583
43. Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B, Amadesi S, Gray J, Jerman JC, Brough SJ, Owen D, Smith GD, Randall AD, Harrison S, Bianchi A, Davis JB, and Geppetti P. Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5: 546-551, 2002. PMID 11992116
44. Tsuji F, Murai M, Oki K, Seki I, Ueda K, Inoue H, Nagelkerken L, Sasano M, and Aono H. Transient receptor potential vanilloid 1 agonists as candidates for anti-inflammatory and immunomodulatory agents. Eur J Pharmacol 627: 332-339, 2010. PMID 19878665
45. Ueda K, Tsuji F, Hirata T, Ueda K, Murai M, Aono H, Takaoka M, and Matsumura Y. Preventive effect of SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 agonist, on ischemia/reperfusion-induced renal injury in rats. J Pharmacol Exp Ther 329: 202-209, 2009. PMID 19147859
46. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, and Wallace JL. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7: 821-826, 2001. PMID 11433347
47. Vigna SR, Shahid RA, Nathan JD, McVey DC, and Liddle RA. Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. Pancreas 40: 708-714, 2011. PMID 21602738
48. Wang C, Hu HZ, Colton CK, Wood JD, and Zhu MX. An alternative splicing product of the murine trpv1 gene dominant negatively modulates the activity of TRPV1 channels. J Biol Chem 279: 37423-37430, 2004. PMID 15234965
49. Wick EC, Hoge SG, Grahn SW, Kim E, Divino LA, Grady EF, Bunnett NW, and Kirkwood KS. Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 290: G959-969, 2006. PMID 16399878
50. Xu GY, Winston JH, Shenoy M, Yin H, Pendyala S, and Pasricha PJ. Transient receptor potential vanilloid 1 mediates hyperalgesia and is up-regulated in rats with chronic pancreatitis. Gastroenterology 133: 1282-1292, 2007. PMID 17698068
51. Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, Mehta K, and Pasricha PJ. Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology 141: 370-377, 2011. PMID 21473865