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1

Capsaicin Receptor: TRPV1 A Promiscuous TRP Channel  

Microsoft Academic Search

TRPV1, the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent\\u000a ingredient in hot chili peppers. The receptor has a diverse tissue distribution, with high expression in sensory neurons.\\u000a TRPV1 is a nonselective cation channel with significant permeability to calcium, protons, and large polyvalent cations. It\\u000a is the most polymodal TRP channel,

S. C. Pingle; J. A. Matta; G. P. Ahern

2

Capsaicin receptor TRPV1 in urothelium of neurogenic human bladders and effect of intravesical resiniferatoxin  

Microsoft Academic Search

ObjectivesTo study TRPV1 immunoreactivity in the urothelium of patients with neurogenic detrusor overactivity (NDO) before and after treatment with resiniferatoxin (RTX) and controls. Functional capsaicin TRPV1 receptors have been demonstrated in urothelial cells of rodent urinary bladder, and TRPV1-knockout mice exhibit diminished nitric oxide and stretch-evoked adenosine triphosphate release from urothelial cells. In patients with NDO, TRPV1 suburothelial nerve density

Apostolos Apostolidis; Ciaran M. Brady; Yiangos Yiangou; John Davis; Clare J. Fowler; Praveen Anand

2005-01-01

3

Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists  

PubMed Central

The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of ‘synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine–chlorine) and the regiochemistry (C-5, C-6) of the halogenation.The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay.All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives.Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC50=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist.In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists.

Appendino, Giovanni; Harrison, Selena; De Petrocellis, Luciano; Daddario, Nives; Bianchi, Federica; Schiano Moriello, Aniello; Trevisani, Marcello; Benvenuti, Francesca; Geppetti, Pierangelo; Di Marzo, Vincenzo

2003-01-01

4

Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1)  

PubMed Central

Protein kinase C (PKC) modulates the function of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). This modulation manifests as increased current when the channel is activated by capsaicin. In addition, studies have suggested that phosphorylation by PKC might directly gate the channel, because PKC-activating phorbol esters induce TRPV1 currents in the absence of applied ligands. To test whether PKC both modulates and gates the TRPV1 function by direct phosphorylation, we used direct sequencing to determine the major sites of PKC phosphorylation on TRPV1 intracellular domains. We then tested the ability of the PKC-activating phorbol 12-myristate 13-acetate (PMA) to potentiate capsaicin-induced currents and to directly gate TRPV1. We found that mutation of S800 to alanine significantly reduced the PMA-induced enhancement of capsaicin-evoked currents and the direct activation of TRPV1 by PMA. Mutation of S502 to alanine reduced PMA enhancement of capsaicin-evoked currents, but had no effect on direct activation of TRPV1 by PMA. Conversely, mutation of T704 to alanine had no effect on PMA enhancement of capsaicin-evoked currents but dramatically reduced direct activation of TRPV1 by PMA. These results, combined with pharmacological studies showing that inactive phorbol esters also weakly activate TRPV1, suggest that PKC-mediated phosphorylation modulates TRPV1 but does not directly gate the channel. Rather, currents induced by phorbol esters result from the combination of a weak direct ligand-like activation of TRPV1 and the phosphorylation-induced enhancement of the TRPV1 function. Furthermore, modulation of the TRPV1 function by PKC appears to involve distinct phosphorylation sites depending on the mechanism of channel activation.

Bhave, Gautam; Hu, Hui-Juan; Glauner, Kathi S.; Zhu, Weiguo; Wang, Haibin; Brasier, D. J.; Oxford, Gerry S.; Gereau, Robert W.

2003-01-01

5

From The Cover: Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1)  

Microsoft Academic Search

Protein kinase C (PKC) modulates the function of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). This modulation manifests as increased current when the channel is activated by capsaicin. In addition, studies have suggested that phosphorylation by PKC might directly gate the channel, because PKC-activating phorbol esters induce TRPV1 currents in the absence of applied ligands. To test whether

Gautam Bhave; Hui-Juan Hu; Kathi S. Glauner; Weiguo Zhu; Haibin Wang; D. J. Brasier; Gerry S. Oxford; Robert W. Gereau IV

2003-01-01

6

The effects of Sympathetic Outflow on Upregulation of Vanilloid Receptors TRPV1 in Primary Afferent Neurons Evoked by Intradermal Capsaicin  

PubMed Central

The vanilloid receptor TRPV1 is a key nociceptive molecule located in primary afferent nociceptive neurons in dorsal root ganglia (DRG) for initiating neurogenic inflammation and pain. Our recent study demonstrates that up-regulation of TRPV1 receptors by intradermal injection of capsaicin is modulated by activation of the protein kinase C (PKC) cascade. Neurogenic inflammation and pain resulting from capsaicin injection are sympathetically dependent, responding to norepinephrine, adenosine 5?-triphosphate (ATP) and/or neuropeptide Y released from sympathetic efferents. In a rat model of acute neurogenic inflammatory pain produced by capsaicin injection, we used immunofluorescence and Western blots combined with pharmacology and surgical sympathectomies to analyze whether the capsaicin-evoked up-regulation of TRPV1 in DRG neurons is affected by sympathetic outflow by way of activating the PKC cascade. Sympathetic denervation reduced significantly the capsaicin-evoked expressions of TRPV1, calcitonin gene-related peptide and/or phosphorylated PKC and their co-expression. These reductions could be restored by exogenous pretreatment with an analog of ATP, ?,?-methylene ATP. Inhibition of PKC with chelerythrine chloride prevented the ATP effect. Consistent results were obtained from experiments in which capsaicin-evoked changes in cutaneous inflammation (vasodilation and edema) were examined after sympathetic denervation, and the effects of the above pharmacological manipulations were evaluated. Our findings suggest that the capsaicin-evoked up-regulation of TRPV1 receptors in DRG neurons is modulated sympathetically by the action of ATP released from sympathetic efferents to activate the PKC cascade. Thus, this study proposes a potential new mechanism of sympathetic modulation of neurogenic inflammation.

Xu, Xijin; Wang, Peng; Zou, Xiaoju; Li, Dingge; Fang, Li; Gong, Kerui; Lin, Qing

2010-01-01

7

Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief.  

PubMed

Anesiva Inc is developing Adlea (ALRGX-4975) - an injectable preparation of capsaicin, a TRPV1 (transient receptor potential vanilloid subfamily 1) receptor agonist - for the potential management of pain associated with osteoarthritis, tendonitiand postsurgical conditions, as well as for neuropathic pain occurring secondary to nerve injury. Adlea functions by desensitizing those neurons that conduct a long-lasting, throbbing form of pain. In phase II clinical trials, a single injection of Adlea significantly reduced pain levels in patients following total knee arthroplasty (TKA) or bunionectomy, and reduced pain in patients with osteoarthritis (OA) or Morton's neuroma. Phase II trials are ongoing to test Adlea in patients who are undergoing total hip arthroplasty or arthroscopic shoulder surgery and in patients with knee OA. Phase III clinical trials for the compound have been slated to begin in 2008 in patients following TKA or bunionectomy. Adlea appears to exhibit promise as a new medication in the treatment of conditions of chronic neuropathic pain. PMID:18240098

Remadevi, Radhika; Szallisi, Arpad

2008-02-01

8

The TRPV1 receptor and nociception  

Microsoft Academic Search

The capsaicin receptor TRPV1 is an emerging target for the treatment of pain with a unique expression profile in peripheral nociceptors and the ability to show polymodal activation, TRPV1 is an important integrator of responses to inflammatory mediators. Sensitization of TRPV1 during chronic pain is believed to contribute to the transduction of noxious signaling for normally innocuous stimuli and consequently

David C. Immke; Narender R. Gavva

2006-01-01

9

Calcium-sensing receptor in rat vagal bronchopulmonary sensory neurons regulates the function of the capsaicin receptor TRPV1.  

PubMed

Extracellular calcium-sensing receptor (CaSR) has been known to play a critical role in the maintainance of systemic Ca(2+) homeostasis. Recent studies have shown that CaSR is also expressed in many tissues that are not directly related to plasma Ca(2+) regulation, such as the central and peripheral nervous system, where the function of this receptor remains to be defined. In this study, we aimed to investigate the expression of CaSR and its potential interaction with transient receptor potential vanilloid receptor type 1 (TRPV1) in rat vagal bronchopulmonary sensory neurons. Our immunohistochemical experiments demonstrated the expression of CaSR in these sensory neurons as well as in trachea and lung parenchyma. Results from our whole-cell patch-clamp recordings in isolated neurons showed that strong activation of CaSR with high concentrations of its agonists, including spermine, NPS R-568 and Ca(2+), inhibited the capsaicin-evoked whole-cell inward current. Blockade of CaSR with its antagonists NPS 2390 and NPS 2143 significantly enhanced the capsaicin-evoked TRPV1 current. These data suggest that CaSR is likely to be involved in the integration of primary bronchopulmonary sensory inputs in physiological and/or pathophysiological conditions. PMID:23913765

Gu, Qihai; Vysotskaya, Zhanna V; Moss, Charles R; Kagira, Martin K; Gilbert, Carolyn A

2013-08-02

10

Calcium-Dependent and Independent Mechanisms of Capsaicin Receptor (TRPV1)-Mediated Cytokine Production and Cell Death in Human Bronchial Epithelial Cells  

PubMed Central

Activation of the capsaicin receptor (VR1 or TRPV1) in bronchial epithelial cells by capsaicinoids and other vanilloids promotes pro-inflammatory cytokine production and cell death. The purpose of this study was to investigate the role of TRPV1-mediated calcium flux from extracellular sources as an initiator of these responses and to define additional cellular pathways that control cell death. TRPV1 antagonists and reduction of calcium concentrations in treatment solutions attenuated calcium flux, induction of interleukin-6 and 8 gene expression, and IL-6 secretion by cells treated with capsaicin or resiniferatoxin. Most TRPV1 antagonists also attenuated cell death, but the relative potency and extent of protection did not directly correlate with inhibition of total calcium flux. Treatment solutions with reduced calcium content or chelators had no effect on cytotoxicity. Inhibitors of arachidonic acid metabolism and cyclo-oxygenases also prevented cell death indicating that TRPV1 agonists disrupted basal arachidonic acid metabolism and altered cyclo-oxygenase function via a TRPV1-dependent mechanism in order to produce toxicity. These data confirm previous results demonstrating calcium flux through TRPV1 acts as a trigger for cytokine production by vanilloids, and provides new mechanistic insights on mechanisms of cell death produced by TRPV1 agonists in respiratory epithelial cells.

Reilly, Christopher A.; Johansen, Mark E.; Lanza, Diane L.; Lee, Jeewoo; Lim, Ju-Ok; Yost, Garold S.

2008-01-01

11

Activation of protein kinase C reverses capsaicin-induced calcium-dependent desensitization of TRPV1 ion channels  

Microsoft Academic Search

Ca2+ selective ion channels of vanilloid receptor subtype-1 (TRPV1) in capsaicin-sensitive dorsal root ganglion (DRG) neurons and TRPV1 transfected Chinese hamster ovarian (CHO) cells are desensitized following calcium-dependent tachyphylaxis induced by successive applications of 100nM capsaicin. Tachyphylaxis of TRPV1 to 100nM capsaicin stimuli was not observed in the absence of extracellular calcium. Capsaicin sensitivity of desensitized TRPV1 ion channels recovered

Sravan Mandadi; Mitsuko Numazaki; Makoto Tominaga; Manjunatha B Bhat; Patricia J Armati; Basil D Roufogalis

2004-01-01

12

Burning mouth syndrome as a trigeminal small fibre neuropathy: Increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score  

Microsoft Academic Search

Burning mouth syndrome (BMS) is often an idiopathic chronic and intractable pain condition, affecting 1.5–5.5% of middle-aged and elderly women. We have studied the heat and capsaicin receptor TRPV1, and its regulator nerve growth factor (NGF), in BMS. Patients with BMS (n=10) and controls (n=10) were assessed for baseline and post-topical capsaicin pain scores, and their tongue biopsies immunostained for

Z. Yilmaz; T. Renton; Y. Yiangou; J. Zakrzewska; I. P. Chessell; C. Bountra; P. Anand

2007-01-01

13

Capsaicin-Induced Changes in LTP in the Lateral Amygdala Are Mediated by TRPV1  

Microsoft Academic Search

The transient receptor potential vanilloid type 1 (TRPV1) channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA). Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was

Carsten Zschenderlein; Christine Gebhardt; Oliver von Bohlen Und Halbach; Christoph Kulisch; Doris Albrecht; Mark L. Baccei

2011-01-01

14

Tachykinin (NK1, NK2 and NK3) receptor, transient receptor potential vanilloid 1 (TRPV1) and early transcription factor, cFOS, mRNA expression in rat tissues following systemic capsaicin treatment.  

PubMed

Capsaicin, the pungent component of chilli pepper, stimulates TRPV1-expressing cells which are followed by desensitisation to subsequent exposure to capsaicin and other TRPV1 activators. At high systemic doses (>125mg/kg), capsaicin produces long-term changes in both tachykinin receptor and TRPV1 expression and function in rats. However, whether desensitising (low) doses of capsaicin (~50mg/kg) affect tachykinin receptor and TRPV1 gene expression in the short term has yet to be investigated. The aim of the present study was to compare tachykinin receptor (NK1, NK2 and NK3) and TRPV1 mRNA expression 24h after administration of capsaicin (50mg/kgs.c.). Tachykinin receptor and TRPV1 mRNA were detected in all tissues studied with expression levels differing by up to 2500-fold between tissues. The highest expression of TRPV1 and NK1 mRNA was observed in the salivary gland, whereas NK2 mRNA expression was highest in the urinary bladder and NK3 mRNA expression in the frontal cortex. In the cervical spinal cord of rats treated with capsaicin, NK1 and NK3 mRNA expression were reduced by 56% and 80%, respectively (P<0.05), whereas NK2 and TRPV1 mRNA expression were increased 2.2- and 1.4-fold, respectively (P<0.05). NK1 and NK2 mRNA expression were decreased (P<0.05) in the urinary bladder and gastric fundus, respectively, following capsaicin treatment. There was a marked 100-fold increase in cFOS mRNA expression and 100-fold decrease in NK2 mRNA expression in the whole blood of capsaicin-treated rats. In conclusion, these studies show that tachykinin receptor and TRPV1 mRNA expression undergo significant changes within 24h of systemic low-dose capsaicin administration. PMID:23499799

Kunde, Dale A; Crawford, Amanda; Geraghty, Dominic P

2013-03-13

15

Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain  

PubMed Central

Background Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. Methods Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies from each patient were examined using immunohistological methods with specific antibodies to the capsaicin receptor TRPV1, related vanilloid thermoreceptors TRPV3 and TRPV4, and nerve growth factor (NGF). Results TRPV1-positive intra-epidermal nerve fibres were significantly increased in patients with breast pain and tenderness (TRPV1 fibres / mm epidermis, median [range] – no pain group, n = 8, 0.69 [0–1.27]; pain group, n = 10, 2.15 [0.77–4.38]; p = 0.0009). Nerve Growth Factor, which up-regulates TRPV1 and induces nerve sprouting, was present basal keratinocytes: some breast pain specimens also showed NGF staining in supra-basal keratinocytes. TRPV4-immunoreactive fibres were present in sub-epidermis but not significantly changed in painful breast tissue. Both TRPV3 and TRPV4 were significantly increased in keratinocytes in breast pain tissues; TRPV3, median [range] – no pain group, n = 6, 0.75 [0–2]; pain group, n = 11, 2 [1-3], p = 0.008; TRPV4, median [range] – no pain group, n = 6, [0–1]; pain group, n = 11, 1 [0.5–2], p = 0.014). Conclusion Increased TRPV1 intra-epidermal nerve fibres could represent collateral sprouts, or re-innervation following nerve stretch and damage by polymodal nociceptors. Selective TRPV1-blockers may provide new therapy in breast pain. The role of TRPV3 and TRPV4 changes in keratinocytes deserve further study.

Gopinath, Preethi; Wan, Elaine; Holdcroft, Anita; Facer, Paul; Davis, John B; Smith, Graham D; Bountra, Chas; Anand, Praveen

2005-01-01

16

Acid and stretch, but not capsaicin, are effective stimuli for ATP release in the porcine bladder mucosa: Are ASIC and TRPV1 receptors involved?  

PubMed

Stretch-evoked ATP release from the bladder mucosa is a key event in signaling bladder fullness. Our aim was to examine whether acid and capsaicin can also release ATP and to determine the receptors involved, using agonists and antagonists at TRPV1 and acid-sensing ion channels (ASICs). Strips of porcine bladder mucosa were exposed to acid, capsaicin or stretch. Strip tension was monitored. Bath fluid was collected for ATP measurement. Gene expression of ASICs and TRPV1 in porcine bladders was quantified using quantitative real-time PCR (qRT-PCR). Stretch stimulus (150% of original length) repeatedly and significantly increased ATP release to approximately 45 times basal release. Acid (pH 6.5, 6.0, 5.6) contracted mucosal strips and also increased ATP release up to 30-fold, without evidence of desensitization. Amiloride (0.3 ?M) reduced the acid-evoked ATP release by approximately 70%, while capsazepine (10 ?M) reduced acid-evoked ATP release at pH 6.0 and pH 5.6 (by 68% and 61%, respectively). Capsaicin (0.1-10 ?M) was ineffective in causing ATP release, and also failed to contract porcine mucosal or detrusor strips. Gene expression for ASIC1, ASIC2, ASIC3 and TRPV1 was seen in the lateral wall, dome, trigone and neck of both detrusor and mucosa. In conclusion, stretch and acid induce ATP release in the porcine bladder mucosa, but capsaicin is ineffective. The pig bladder is a well-known model for the human bladder, however these data suggest that it should be used with caution, particularly for TRPV1 related studies. PMID:22421400

Sadananda, Prajni; Kao, Felicity C L; Liu, Lu; Mansfield, Kylie J; Burcher, Elizabeth

2012-03-07

17

Moving towards supraspinal TRPV1 receptors for chronic pain relief  

Microsoft Academic Search

Transient receptor potential vanilloid type 1 (TRPV1) receptor is a non selective ligand-gated cation channel activated by capsaicin, heat, protons and endogenous lipids termed endovanilloids. As well as peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is also expressed in spinal and supraspinal structures such as those belonging to the endogenous antinociceptive descending pathway which is a circuitry

Enza Palazzo; Livio Luongo; Vito de Novellis; Liberato Berrino; Francesco Rossi; Sabatino Maione

2010-01-01

18

The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology  

Microsoft Academic Search

The cloning of the vanilloid receptor 1 opened a floodgate for discoveries regarding the function of this complex molecule. It has been found that, in addition to heat, protons and vanilloids, this receptor also responds to various endogenous ligands. Furthermore, it has been also emerged that, through associations with other molecules, the vanilloid receptor 1 plays an important role in

István Nagy; Péter Sántha; Gábor Jancsó; László Urbán

2004-01-01

19

TRPV1 activation and induction of nociceptive response by a non-pungent capsaicin-like compound, capsiate  

Microsoft Academic Search

Capsiate is a capsaicin-like ingredient of a non-pungent cultivar of red pepper, CH-19 sweet. To elucidate the mechanisms underlying the non-pungency of capsiate, we investigated whether capsiate activates the cloned capsaicin receptor, TRPV1 (VR1). In patch-clamp experiments, capsiate was found to activate TRPV1 expressed transiently in HEK293 cells with a similar potency as capsaicin. Capsiate induced nociceptive responses in mice

T. Iida; T. Moriyama; K. Kobata; A. Morita; N. Murayama; S. Hashizume; T. Fushiki; S. Yazawa; T. Watanabe; M. Tominaga

2003-01-01

20

The cannabinomimetic arachidonyl-2-chloroethylamide (ACEA) acts on capsaicin-sensitive TRPV1 receptors but not cannabinoid receptors in rat joints  

PubMed Central

The vasoactive effects of the synthetic cannabinoid (CB) arachidonyl-2-chloroethylamide (ACEA) was tested in the knee joints of urethane-anaesthetised rats. Experiments were also performed to determine whether these vasomotor responses could be blocked by the selective CB1 receptor antagonists AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (10?9 mol) and AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) (10?8 mol), as well as the selective CB2 receptor antagonist AM630 (6-iodo-2-methyl-1-[2-4(morpholinyl)ethyl]-[1H-indol-3-yl](4-methoxyphenyl)methanone) (10?8 mol). Peripheral application of ACEA (10?14–10?9 mol) onto the exposed surface of the knee joint capsule caused a dose-dependent increase in synovial blood flow. The dilator action of the CB occurred within 1 min after drug administration and rapidly returned to control levels shortly thereafter. The maximal vasodilator effect of ACEA corresponded to a 30% increase in articular perfusion compared to control levels. The hyperaemic action of ACEA was not significantly altered by coadministration of AM251, AM281 or AM630 (P>0.05; two-way ANOVA). The transient receptor potential channel vanilloid receptor 1 (TRPV1) antagonist capsazepine (10?6 mol) significantly reduced the vasodilator effect of ACEA on joint blood vessels (P=0.002). Furthermore, destruction of unmyelinated and thinly myelinated joint sensory nerves by capsaicin (8-methyl-N-vanillyl-6-nonenamide) treatment also attenuated ACEA responses (P<0.0005). These data clearly demonstrate a vasodilator effect of the cannabinomimetic ACEA on knee joint perfusion. Rather than a classic CB receptor pathway, ACEA exerts its vasomotor influence by acting via TRPV1 receptors located on the terminal branches of capsaicin-sensitive afferent nerves innervating the joint.

Baker, Chris L; McDougall, Jason J

2004-01-01

21

Capsaicin-induced vasoconstriction in the mouse knee joint: A study using TRPV1 knockout mice  

Microsoft Academic Search

Capsaicin is the pungent component of chilli peppers that concomitantly activates and desensitizes C-fibre and A? sensory nerve fibres. Stimulation causes an acute neurogenic response including vasodilation, plasma extravasation and hypersensitivity. However, in the present study we have shown that capsaicin produces a dose-dependent vasoconstrictor effect in the mouse knee joint via Transient Receptor Potential Vanilloid 1 (TRPV1) receptor activation.

Julie Elizabeth Keeble; Susan Diana Brain

2006-01-01

22

Ca 2 ? \\/Calmodulin Modulates TRPV1 Activation by Capsaicin  

Microsoft Academic Search

cells, Ca 2 ? \\/calmodulin decreased the capsaicin-activated current. This inhibition was not mimicked by Mg 2 ? , re- flected a decrease in open probability, and was slowly reversible. Furthermore, increasing the calmodulin concen- tration in our patches by coexpression of wild-type calmodulin with TRPV1 produced inhibition by Ca 2 ? alone. In contrast, patches excised from cells coexpressing

Tamara Rosenbaum; Ariela Gordon-Shaag; Mika Munari; Sharona E. Gordon

23

A proinflammatory chemokine, CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1  

Microsoft Academic Search

Pain, a critical component of host defense, is one hallmark of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was cotransfected into human embryonic kidney (HEK)293 cells together with transient receptor potential vanilloid 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. In these cells, capsaicin

Ning Zhang; Saadet Inan; Alan Cowan; Ronghua Sun; Ji Ming Wang; Thomas J. Rogers; Michael Caterina; Joost J. Oppenheim

2005-01-01

24

Proton activation does not alter antagonist interaction with the capsaicin-binding pocket of TRPV1.  

PubMed

Vanilloid receptor 1 (TRPV1) is activated by chemical ligands (e.g., capsaicin and protons) and heat. In this study, we show that (2E)-3-[2-piperidin-1-yl-6-(trifluoromethyl)pyridin-3-yl]-N-quinolin-7-ylacrylamide (AMG6880), 5-chloro-6-[(3R)-3-methyl-4-[6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzimidazol-2-yl]piperazin-1-yl]pyridin-3-yl)methanol (AMG7472), and N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC) are potent antagonists of rat TRPV1 activation by either capsaicin or protons (pH 5) (defined here as group A antagonists), whereas (2E)-3-(6-tert-butyl-2-methylpyridin-3-yl)-N-(1H-indol-6-yl)acrylamide (AMG0610), capsazepine, and (2E)-3-(4-chlorophenyl)-N-(3-methoxyphenyl)acrylamide (SB-366791) are antagonists of capsaicin, but not proton, activation (defined here as group B antagonists). By using capsaicin-sensitive and insensitive rabbit TRPV1 channels, we show that antagonists require the same critical molecular determinants located in the transmembrane domain 3/4 region to block both capsaicin and proton activation, suggesting the presence of a single binding pocket. To determine whether the differential pharmacology is a result of proton activation-induced conformational changes in the capsaicin-binding pocket that alter group B antagonist affinities, we have developed a functional antagonist competition assay. We hypothesized that if group B antagonists bind at the same or an overlapping binding pocket of TRPV1 as group A antagonists, and proton activation does not alter the binding pocket, then group B antagonists should compete with and prevent group A antagonism of TRPV1 activation by protons. Indeed, we found that each of the group B antagonists competed with and prevented BCTC, AMG6880 or AMG7472 antagonism of rat TRPV1 activation by protons with pA2 values similar to those for blocking capsaicin, indicating that proton activation does not alter the conformation of the TRPV1 capsaicin-binding pocket. In conclusion, group A antagonists seem to lock the channel conformation in the closed state, blocking both capsaicin and proton activation. PMID:16135784

Gavva, Narender R; Tamir, Rami; Klionsky, Lana; Norman, Mark H; Louis, Jean-Claude; Wild, Kenneth D; Treanor, James J S

2005-08-31

25

Novel methodology to identify TRPV1 antagonists independent of capsaicin activation.  

PubMed

TRPV1 was originally characterized as an integrator of various noxious stimuli such as capsaicin, heat, and protons. TRPV1-null mice exhibit a deficiency in sensing noxious heat stimuli, suggesting that TRPV1 is one of the main heat sensors on nociceptive primary afferent neurons and a candidate target for heat hypersensitivity in chronic pain. Several different potent and selective TRPV1 antagonists have been developed by more than 50 companies since the characterization of the receptor in 1997. A consequence of this competitive interest is the crowding of patentable chemical space, because very similar in vitro screening assays are used. To circumvent this issue and to expand our understanding of TRPV1 biology, we sought to take advantage of recent advancements in automated patch-clamp technology to design a novel screening cascade. This SAR-driving assay identified novel modulators that blocked the depolarization-induced activation of outwardly-rectifying TRPV1 currents independent of agonist stimulation, and we correlated the pharmacology to three other innovative assays for higher-throughput screening. Ultimately, we have identified a screening paradigm that would have good predictive value for future TRPV1 drug discovery projects and novel chemical space with a higher probability of gaining intellectual property coverage. PMID:23264449

Zicha, Stephen; Radresa, Olivier; Laplante, Patricia; Morton, Michael; Jones, Karen; Main, Martin; Trivedi, Shephali; Julien, Ron P; Griffin, Andrew; Labrecque, Jean; Ahmad, Sultan; Brown, William

2012-12-20

26

Capsaicin induces NKCC1 internalization and inhibits chloride secretion in colonic epithelial cells independently of TRPV1.  

PubMed

Colonic chloride secretion is regulated via the neurohormonal and immune systems. Exogenous chemicals (e.g., butyrate, propionate) can affect chloride secretion. Capsaicin, the pungent ingredient of the chili peppers, exerts various effects on gastrointestinal function. Capsaicin is known to activate the transient receptor potential vanilloid type 1 (TRPV1), expressed in the mesenteric nervous system. Recent studies have also demonstrated its presence in epithelial cells but its role remains uncertain. Because capsaicin has been reported to inhibit colonic chloride secretion, we tested whether this effect of capsaicin could occur by direct action on epithelial cells. In mouse colon and model T84 human colonic epithelial cells, we found that capsaicin inhibited forskolin-dependent short-circuit current (FSK-I(sc)). Using PCR and Western blot, we demonstrated the presence of TRPV1 in colonic epithelial cells. In T84 cells, TRPV1 localized at the basolateral membrane and in vesicular compartments. In permeabilized monolayers, capsaicin activated apical chloride conductance, had no effect on basolateral potassium conductance, but induced NKCC1 internalization demonstrated by immunocytochemistry and basolateral surface biotinylation. AMG-9810, a potent inhibitor of TRPV1, did not prevent the inhibition of the FSK-I(sc) by capsaicin. Neither resiniferatoxin nor N-oleoyldopamine, two selective agonists of TRPV1, blocked the FSK-I(sc). Conversely capsaicin, resiniferatoxin, and N-oleoyldopamine raised intracellular calcium ([Ca(2+)](i)) in T84 cells and AMG-9810 blocked the rise in [Ca(2+)](i) induced by capsaicin and resiniferatoxin suggesting the presence of a functional TRPV1 channel. We conclude that capsaicin inhibits chloride secretion in part by causing NKCC1 internalization, but by a mechanism that appears to be independent of TRPV1. PMID:23139219

Bouyer, Patrice G; Tang, Xu; Weber, Christopher R; Shen, Le; Turner, Jerrold R; Matthews, Jeffrey B

2012-11-08

27

A novel function of capsaicin-sensitive TRPV1 channels: Involvement in cell migration  

Microsoft Academic Search

Cell migration relies on a tight temporal and spatial regulation of the intracellular Ca2+ concentration ([Ca2+]i). [Ca2+]i in turn depends on Ca2+ influx via channels in the plasma membrane whose molecular nature is still largely unknown for migrating cells. A mechanosensitive component of the Ca2+ influx pathway was suggested. We show here that the capsaicin-sensitive transient receptor potential channel TRPV1,

J. Waning; J. Vriens; G. Owsianik; L. Stüwe; S. Mally; A. Fabian; C. Frippiat; B. Nilius; A. Schwab

2007-01-01

28

Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.  

PubMed

The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate. PMID:22412190

Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir; Wang, KeWei; Zheng, Jie

2012-03-12

29

Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations  

PubMed Central

The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate.

Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir

2012-01-01

30

TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications  

Microsoft Academic Search

The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by capsaicin, heat, protons and endogenous ligands such as anandamide. It is largely expressed in the urinary tract of mammals. Structures in which the receptor expression is firmly established include sensory fibers and urothelial cells, although the presence of TRPV1 in other cell types has been reported.

António Avelino; Francisco Cruz

2006-01-01

31

Expression and distribution of vanilloid receptor 1 (TRPV1) in the adult rat brain  

Microsoft Academic Search

The vanilloid receptor (TRPV1 or VR1) is a molecular integrator of various painful stimuli, including capsaicin, acid, and high temperature. It can also be activated by endogenous ligands, like the cannabinoid 1 receptor (CB1) agonist anandamide. TRPV1 is well characterized at the terminals of sensory nerves involved in the pain pathway. There is also evidence that TRPV1 is expressed in

Attila Tóth; Judit Boczán; Noémi Kedei; Erzsébet Lizanecz; Zsolt Bagi; Zoltán Papp; István Édes; László Csiba; Peter M. Blumberg

2005-01-01

32

The pharmacological challenge to tame the transient receptor potential vanilloid-1 (TRPV1) nocisensor  

PubMed Central

The transient receptor potential vanilloid-1 (TRPV1) cation channel is a receptor that is activated by heat (>42?°C), acidosis (pH<6) and a variety of chemicals among which capsaicin is the best known. With these properties, TRPV1 has emerged as a polymodal nocisensor of nociceptive afferent neurones, although some non-neuronal cells and neurones in the brain also express TRPV1. The activity of TRPV1 is controlled by a multitude of regulatory mechanisms that either cause sensitization or desensitization of the channel. As many proalgesic pathways converge on TRPV1 and this nocisensor is upregulated and sensitized by inflammation and injury, TRPV1 is thought to be a central transducer of hyperalgesia and a prime target for the pharmacological control of pain. As a consequence, TRPV1 agonists causing defunctionalization of sensory neurones and a large number of TRPV1 blockers have been developed, some of which are in clinical trials. A major drawback of many TRPV1 antagonists is their potential to cause hyperthermia, and their long-term use may carry further risks because TRPV1 has important physiological functions in the peripheral and central nervous system. The challenge, therefore, is to pharmacologically differentiate between the physiological and pathological implications of TRPV1. There are several possibilities to focus therapy specifically on those TRPV1 channels that contribute to disease processes. These approaches include (i) site-specific TRPV1 antagonists, (ii) modality-specific TRPV1 antagonists, (iii) uncompetitive TRPV1 (open channel) blockers, (iv) drugs interfering with TRPV1 sensitization, (v) drugs interfering with intracellular trafficking of TRPV1 and (vi) TRPV1 agonists for local administration.

Holzer, P

2008-01-01

33

Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks  

Microsoft Academic Search

The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence,

Gilbert Y. Wong; Narender R. Gavva

2009-01-01

34

Functional study on TRPV1-mediated signalling in the mouse small intestine: involvement of tachykinin receptors.  

PubMed

Afferent nerves in the gut not only signal to the central nervous system but also provide a local efferent-like effect. This effect can modulate intestinal motility and secretion and is postulated to involve the transient receptor potential of the vanilloid type 1 (TRPV1). By using selective TRPV1 agonist and antagonists, we studied the efferent-like effect of afferent nerves in the isolated mouse jejunum. Mouse jejunal muscle strips were mounted in organ baths for isometric tension recordings. Jejunal strips contracted to the TRPV1 agonist capsaicin. Contractions to capsaicin showed rapid tachyphylaxis and were insensitive to tetrodotoxin, hexamethonium, atropine or L-nitroarginine. Capsaicin did not affect contractions to electrical stimulation of enteric motor nerves and carbachol. Tachykinin NK1, NK2 and NK3 receptor blockade by RP67580, nepadutant plus SR-142801 reduced contractions to capsaicin to a similar degree as contractions to substance P. The effect of the TRPV1 antagonists capsazepine, SB-366791, iodo-resiniferatoxin (iodo-RTX) and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC) was studied. Capsazepine inhibited contractions not only to capsaicin but also those to carbachol. SB-366791 reduced contractions both to capsaicin and carbachol. Iodo-RTX partially inhibited the contractions to capsaicin without affecting contractions to carbachol. BCTC concentration-dependently inhibited and at the highest concentration used, abolished the contractions to capsaicin without affecting those to carbachol. From these results, we conclude that activation of TRPV1 in the mouse intestine induces a contraction that is mediated by tachykinins most likely released from afferent nerves. The TRPV1-mediated contraction does not involve activation of intrinsic enteric motor nerves. Of the TRPV1 antagonists tested, BCTC combined strong TRPV1 antagonism with TRPV1 selectivity. PMID:18194153

de Man, J G; Boeckx, S; Anguille, S; de Winter, B Y; de Schepper, H U; Herman, A G; Pelckmans, P A

2008-01-13

35

Altered expression of TRPV1 and sensitivity to capsaicin in pulmonary myelinated afferents following chronic airway inflammation in the rat  

PubMed Central

Vagal pulmonary myelinated afferents are normally not activated by capsaicin, a selective agonist of transient receptor potential vanilloid type 1 (TRPV1) receptors. This study was carried out to investigate whether the expression of TRPV1 in these afferents is altered when chronic airway inflammation is induced by ovalbumin (Ova) sensitization. Two groups of Brown–Norway rats (sensitized and control) were exposed to aerosolized Ova and vehicle, respectively, 3 days per week for 3 weeks. After the C-fibre conduction in both vagus nerves was blocked, right-atrial injection of capsaicin elicited augmented breaths in sensitized rats breathing spontaneously, but not in control rats, indicating a stimulation of rapidly adapting receptors (RARs) by capsaicin. Single-unit fibre activities of RARs and slow adapting receptors (SARs), identified by their firing behaviour and adaptation indexes in response to lung inflation, were recorded in anaesthetized, vagotomized and artificially ventilated rats. Capsaicin injection evoked either negligible or no response in both RARs and SARs of control rats. However, in striking contrast, the same dose of capsaicin evoked an immediate stimulatory effect on these myelinated afferents in sensitized rats. Furthermore, the immunohistochemistry experiments showed that there was a significant increase in the proportion of TRPV1-expressing pulmonary neurones in nodose ganglia of sensitized rats; this increase in TRPV1 expression was found mainly in neurofilament-positive (myelinated) neurones. In conclusion, allergen-induced airway inflammation clearly elevated capsaicin sensitivity in myelinated pulmonary afferents, which probably resulted from an increased expression of TRPV1 in these sensory nerves.

Zhang, Guangfan; Lin, Ruei-Lung; Wiggers, Michelle; Snow, Diane M; Lee, Lu-Yuan

2008-01-01

36

Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-\\/- mice  

Microsoft Academic Search

The vanilloid receptor TRPV1 (formerly VR1) has been implicated in the activation of nociceptive sensory nerves by capsaicin, noxious heat, protons, bradykinin, cannabinoids such as anandamide, and certain metabolites of arachidonic acid. Using TRPV1 knockout mouse (TRPV1-\\/-) we address the question of whether TRPV1 is obligatory for action potential discharge in vagal C-fibre terminals evoked by capsaicin, anandamide, acid and

M. Kollarik; B. J. Undem

2003-01-01

37

Ph?1? toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels.  

PubMed

Ph?1? toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Ph?1? when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Ph?1? on Ca(2+) transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Ph?1? reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ?-conotoxin MVIIA (a selective N-type Ca(2+) channel blocker) was effective only when administered intrathecally. Ph?1?, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca(2+) transients in DRG neurons. The simultaneous administration of Ph?1? and SB366791 inhibited the capsaicin-induced Ca(2+) transients that were additive suggesting that they act through different targets. Moreover, Ph?1? did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Ph?1? may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors. PMID:23597507

Castro-Junior, Celio J; Milano, Julie; Souza, Alessandra H; Silva, Juliana F; Rigo, Flávia K; Dalmolin, Geruza; Cordeiro, Marta N; Richardson, Michael; Barros, Alexandre G A; Gomez, Renato S; Silva, Marco A R; Kushmerick, Christopher; Ferreira, Juliano; Gomez, Marcus V

2013-04-15

38

Modulation of human TRPV1 receptor activity by extracellular protons and host cell expression system  

Microsoft Academic Search

The transient receptor potential vanilloid 1 (TRPV1) receptor is a ligand-gated cation channel that can be activated by capsaicin, heat, protons and cytosolic lipids. We compared activation of recombinant human TRPV1 receptors stably expressed in human 293 cells, derived from kidney embryonic cells, and in human 1321N1 cells, derived from brain astrocytes. Cellular influx of calcium was measured in response

Bruce R. Bianchi; Chih-Hung Lee; Michael F. Jarvis; Rachid El Kouhen; Robert B. Moreland; Connie R. Faltynek; Pamela S. Puttfarcken

2006-01-01

39

Investigation of the role of TRPV1 receptors in acute and chronic nociceptive processes using gene-deficient mice  

Microsoft Academic Search

Capsaicin-sensitive, TRPV1 (transient receptor potential vanilloid 1) receptor-expressing primary sensory neurons exert local and systemic efferent effects besides the classical afferent function. The TRPV1 receptor is considered a molecular integrator of various physico-chemical noxious stimuli. In the present study its role was analysed in acute nociceptive tests and chronic neuropathy models by comparison of wild-type (WT) and TRPV1 knockout (KO)

Kata Bölcskei; Zsuzsanna Helyes; Árpád Szabó; Katalin Sándor; Krisztián Elekes; József Németh; Róbert Almási; Erika Pintér; Gábor Peth?; János Szolcsányi

2005-01-01

40

Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice  

PubMed Central

The vanilloid receptor TRPV1 (formerly VR1) has been implicated in the activation of nociceptive sensory nerves by capsaicin, noxious heat, protons, bradykinin, cannabinoids such as anandamide, and certain metabolites of arachidonic acid. Using TRPV1 knockout mouse (TRPV1?/?) we address the question of whether TRPV1 is obligatory for action potential discharge in vagal C-fibre terminals evoked by capsaicin, anandamide, acid and bradykinin. The response of a defined subtype of the vagal afferent bronchopulmonary C-fibres (conduction velocity < 0.7 ms?1) to the putative TRPV1 activators was studied in vitro in the mouse isolated/perfused lung–nerve preparation. Capsaicin (1 ?m) evoked action potential discharge of ?90% (28/31) of C-fibres in the TRPV1+/+ mice, but failed to activate bronchopulmonary C-fibres in TRPV1?/? animals (n = 10). Anandamide (3–100 ?m) induced concentration-dependent activation of capsaicin-sensitive TRPV1+/+ C-fibres with a threshold of 3–10 ?m, but failed to evoke substantive discharge in TRPV1?/? C-fibres. In the TRPV1+/+ mice, the B2 receptor-mediated activation by bradykinin (1 ?m) was restricted to the capsaicin-sensitive C-fibres. Bradykinin was effective in evoking B2 receptor-mediated action potential discharge in TRPV1?/? C-fibres, but the response was significantly (P < 0.05) less persistent than in TRPV1+/+ C-fibres. Exposing the tissue to acid (pH = 5) excited both TRPV1+/+ and TRPV1?/? C-fibres. We conclude that TRPV1 is obligatory for vagal C-fibre activation by capsaicin and anandamide. By contrast, whereas TRPV1 may have a modulatory role in bradykinin and acid-induced activation of bronchopulmonary C-fibres, it is not required for action potential discharge evoked by these stimuli.

Kollarik, M; Undem, B J

2004-01-01

41

TRPV1 properties in thoracic dorsal root ganglia neurons are modulated by intraperitoneal capsaicin administration in the late phase of type-1 autoimmune diabetes.  

PubMed

Pharmacological therapies in type 1 diabetes for efficient control of glycemia and changes in pain alterations due to diabetic neuropathy are a continuous challenge. Transient receptor potential vanilloid type 1 (TRPV1) from dorsal root ganglia (DRG) neurons is one of the main pharmacological targets in diabetes, and its ligand capsaicin can be a promising compound for blood-glucose control. Our goal is to elucidate the effect of intraperitoneal (i.p.) capsaicin administration in type 1 diabetic mice against TRPV1 receptors from pancreatic DRG primary afferent neurons. A TCR(+/-)/Ins-HA(+/-) diabetic mice (dTg) was used, and patch-clamp and immunofluorescence microscopy measurements have been performed on thoracic T(9)-T(12) DRG neurons. Capsaicin (800 ?g/kg, i.p. three successive days) administration in the late-phase diabetes reduces blood-glucose levels, partly reverses the TRPV1 current density and recovery time constant, without any effect on TRPV1 expression general pattern, in dTg mice. A TRPV1 hypoalgesia profile was observed in late-phase diabetes, which was partly reversed to normoalgesic profile upon capsaicin i.p. administration. According to the soma dimensions of the thoracic DRG neurons, a detailed analysis of the TRPV1 expression upon capsaicin i.p. treatment was done, and the proportion of large A-fiber neurons expressing TRPV1 increased in dTg capsaicin-treated mice. In conclusion, the benefits of low-dose capsaicin intraperitoneal treatment in late-phase type-1 diabetes should be further exploited. PMID:23111447

Radu, Beatrice Mihaela; Iancu, Adina Daniela; Dumitrescu, Diana Ionela; Flonta, Maria Luisa; Radu, Mihai

2012-10-31

42

Moving towards supraspinal TRPV1 receptors for chronic pain relief  

PubMed Central

Transient receptor potential vanilloid type 1 (TRPV1) receptor is a non selective ligand-gated cation channel activated by capsaicin, heat, protons and endogenous lipids termed endovanilloids. As well as peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is also expressed in spinal and supraspinal structures such as those belonging to the endogenous antinociceptive descending pathway which is a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes periaqueductal grey (PAG) and rostral ventromedial medulla (RVM) whose activation leads to analgesia. Such an effect is associated with a glutamate increase and the activation of OFF and inhibition of ON cell population in the rostral ventromedial medulla (RVM). Activation of the antinociceptive descending pathway via TPRV1 receptor stimulation in the PAG may be a novel strategy for producing analgesia in chronic pain. This review will summarize the more recent insights into the role of TRPV1 receptor within the antinociceptive descending pathway and its possible exploitation as a target for new pain-killer agents in chronic pain conditions, with particular emphasis on the most untreatable pain state: neuropathic pain.

2010-01-01

43

The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons  

Microsoft Academic Search

We have studied the effect of key neurotrophic factors (NTFs) on morphology, levels of the vanilloid receptor-1 (TRPV1) and responses to capsaicin in adult human sensory neurons in vitro. Avulsed dorsal root ganglia (DRG, n=5) were cultured with or without a combination of nerve growth factor (NGF), glial cell (line)-derived growth factor (GDNF) and neurotrophin3 (NT3) for 5 days. In

U. Anand; W. R. Otto; M. A. Casula; N. C. Day; J. B. Davis; C. Bountra; R. Birch; P. Anand

2006-01-01

44

?-Arrestin-2 Desensitizes the Transient Receptor Potential Vanilloid 1 (TRPV1) Channel*  

PubMed Central

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel activated by multiple stimuli and is implicated in a variety of pain disorders. Dynamic sensitization of TRPV1 activity by A-kinase anchoring protein 150 demonstrates a critical role for scaffolding proteins in nociception, yet few studies have investigated scaffolding proteins capable of mediating receptor desensitization. In this study, we identify ?-arrestin-2 as a scaffolding protein that regulates TRPV1 receptor activity. We report ?-arrestin-2 association with TRPV1 in multiple cell models. Moreover, siRNA-mediated knockdown of ?-arrestin-2 in primary cultures resulted in a significant increase in both initial and repeated responses to capsaicin. Electrophysiological analysis further revealed significant deficits in TRPV1 desensitization in primary cultures from ?-arrestin-2 knock-out mice compared with wild type. In addition, we found that ?-arrestin-2 scaffolding of phosphodiesterase PDE4D5 to the plasma membrane was required for TRPV1 desensitization. Importantly, inhibition of PDE4D5 activity reversed ?-arrestin-2 desensitization of TRPV1. Together, these results identify a new endogenous scaffolding mechanism that regulates TRPV1 ligand binding and activation.

Por, Elaine D.; Bierbower, Sonya M.; Berg, Kelly A.; Gomez, Ruben; Akopian, Armen N.; Wetsel, William C.; Jeske, Nathaniel A.

2012-01-01

45

Effects of the novel TRPV1 receptor antagonist SB366791 in vitro and in vivo in the rat  

Microsoft Academic Search

The TRPV1 capsaicin receptor is a non-selective cation channel localized in the cell membrane of a subset of primary sensory neurons and functions as an integrator molecule in nociceptive\\/inflammatory processes. The present paper characterizes the effects of SB366791, a novel TRPV1 antagonist, on capsaicin-evoked responses both in vitro and in vivo using rat models. SB366791 (100 and 500nM) significantly inhibited

Angelika Varga; József Németh; Árpád Szabó; Jason J. McDougall; Chunfen Zhang; Krisztián Elekes; Erika Pintér; János Szolcsányi; Zsuzsanna Helyes

2005-01-01

46

Lipids as regulators of the activity of transient receptor potential type V1 (TRPV1) channels  

Microsoft Academic Search

After 7 years from its cloning, the transient receptor potential vanilloid type-1 (TRPV1) channel remains the sole membrane receptor mediating the pharmacological effects of the hot chilli pepper pungent component, capsaicin, and of the Euphorbia toxin, resiniferatoxin. Yet, this ion channel represents one of the most complex examples of how the activity of a protein can be regulated. Among the

Luciano De Petrocellis; Vincenzo Di Marzo

2005-01-01

47

Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.  

PubMed

The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

Wong, Gilbert Y; Gavva, Narender R

2008-12-25

48

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity  

PubMed Central

Retinoids are structurally related derivatives of vitamin A and are required for normal vision as well as cell proliferation and differentiation. Clinically, retinoids are effective in treating many skin disorders and cancers. Application of retinoids evokes substantial irritating side effects, including pain and inflammation; however, the precise mechanisms accounting for the sensory hypersensitivity are not understood. Here we show that both naturally occurring and synthetic retinoids activate recombinant or native transient receptor potential channel vanilloid subtype 1 (TRPV1), an irritant receptor for capsaicin, the pungent ingredient of chili peppers. In vivo, retinoids produced pain-related behaviors that were either eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1 function. These findings identify TRPV1 as an ionotropic receptor for retinoids and provide cellular and molecular insights into retinoid-evoked hypersensitivity. These findings also suggest that selective TRPV1 antagonists are potential therapeutic drugs for treating retinoid-induced sensory hypersensitivity.

Yin, Shijin; Luo, Jialie; Qian, Aihua; Du, Junhui; Yang, Qing; Zhou, Shentai; Yu, Weihua; Du, Guangwei; Clark, Richard B.; Walters, Edgar T.; Carlton, Susan M.; Hu, Hongzhen

2013-01-01

49

Differential effects of TRPV1 receptor ligands against nicotine-induced depression-like behaviors  

PubMed Central

Background The contributions of brain cannabinoid (CB) receptors, typically CB1 (CB type 1) receptors, to the behavioral effects of nicotine (NC) have been reported to involve brain transient receptor potential vanilloid 1 (TRPV1) receptors, and the activation of candidate endogenous TRPV1 ligands is expected to be therapeutically effective. In the present study, the effects of TRPV1 ligands with or without affinity for CB1 receptors were examined on NC-induced depression-like behavioral alterations in a mouse model in order to elucidate the "antidepressant-like" contributions of TRPV1 receptors against the NC-induced "depression" observed in various types of tobacco abuse. Results Repeated subcutaneous NC treatments (NC group: 0.3 mg/kg, 4 days), like repeated immobilization stress (IM) (IM group: 10 min, 4 days), caused depression-like behavioral alterations in both the forced swimming (reduced swimming behaviors) and the tail suspension (increased immobility times) tests, at the 2 h time point after the last treatment. In both NC and IM groups, the TRPV1 agonists capsaicin (CP) and olvanil (OL) administered intraperitoneally provided significant antidepressant-like attenuation against these behavioral alterations, whereas the TRPV1 antagonist capsazepine (CZ) did not attenuate any depression-like behaviors. Furthermore, the endogenous TRPV1-agonistic CB1 agonists anandamide (AEA) and N-arachidonyldopamine (NADA) did not have any antidepressant-like effects. Nevertheless, a synthetic "hybrid" agonist of CB1 and TRPV1 receptors, arvanil (AR), caused significant antidepressant-like effects. The antidepressant-like effects of CP and OL were antagonized by the TRPV1 antagonist CZ. However, the antidepressant-like effects of AR were not antagonized by either CZ or the CB1 antagonist AM 251 (AM). Conclusions The antidepressant-like effects of TRPV1 agonists shown in the present study suggest a characteristic involvement of TRPV1 receptors in NC-induced depression-like behaviors, similar to those caused by IM. The strong antidepressant-like effects of the potent TRPV1 plus CB1 agonist AR, which has been reported to cause part of its TRPV1-mimetic and cannabimimetic effects presumably via non-TRPV1 or non-CB1 mechanisms support a contribution from other sites of action which may play a therapeutically important role in the treatment of NC abuse.

2011-01-01

50

Functional Recovery from Desensitization of Vanilloid Receptor TRPV1 Requires Resynthesis of Phosphatidylinositol 4,5-Bisphosphate  

Microsoft Academic Search

Capsaicin and other naturally occurring pungent molecules have long been used as topical analgesics to treat a variety of chronic pain conditions. The analgesic effects of these compounds involve long-term desensitization of nociceptors after strong stimulation. To elucidate the underlying mechanisms, we studied the recovery from desensitization of the vanilloid receptor TRPV1.We showed that prolonged applications of capsaicin led to

Beiying Liu; Chunguang Zhang; Feng Qin

2005-01-01

51

Role of TRPV1 receptors in descending modulation of pain  

Microsoft Academic Search

Transient receptor potential vanilloid type 1 (TRPV1) receptor is a ligand-gated non-selective cation channel activated by heat (>43°C), low pH and endogenous lipid molecules such as anandamide, N-arachidonoyl-dopamine, N-acyl-dopamines and products of lipoxygenases (12- and 15-(S)-HPETE) termed endovanilloids. Apart from peripheral primary afferent neurons and dorsal root ganglia, TRPV1 receptor is expressed throughout the brain. Recent evidence shows that TRPV1

Enza Palazzo; Francesco Rossi; Sabatino Maione

2008-01-01

52

Induction of TRPV1 desensitization by a biased receptor agonist.  

PubMed

Selective suppression of hyperactive sensory neurons is an attractive strategy for managing pathological pain. Blocking Na(+) channels to eliminate action potentials and desensitizing transduction channels can both reduce sensory neuron excitability. The novel synthetic vanilloid ligand cap-ET preserves agonist activation of intracellular Ca(2+) signals and large organic cation transport but loses effective electric current induction. Cap-ET can therefore be used to deliver the membrane impermeable Na(+) channel blocker QX-314 to substantially inhibit voltage-activated Na(+) currents. We explored, besides facilitating entry of organic cationic therapeutics, whether cap-ET can also produce receptor desensitization similar to the natural agonist capsaicin. Using the YO-PRO-1 based fluorescent dye uptake assay, we found that cap-ET effectively triggered Ca(2+) dependent desensitization of TRPV1 when the receptor was pre-sensitized with the surrogate oxidative chemical phenylarsine oxide (PAO), suggesting an alternative use of permanently charged cationic capsaicinoids in differential neuronal silencing. PMID:21829089

Wang, Elaine E; Li, Hui; Wang, Shu; Chuang, Alexander Y; Chuang, Huai-hu

2011-11-01

53

Attenuated fever response in mice lacking TRPV1  

Microsoft Academic Search

TRPV1, the capsaicin receptor, is expressed not only in nociceptive neurons, but also in other locations, including the hypothalamus. Studies involving systemic or intrahypothalamic capsaicin administration have suggested a role for TRPV1 in body temperature control. To explore this possibility, we examined thermoregulatory responses in TRPV1?\\/? mice. These mutant animals exhibited no obvious changes in circadian body temperature fluctuation, tolerance

Tohko Iida; Isao Shimizu; Michele L. Nealen; Ashley Campbell; Michael Caterina

2005-01-01

54

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  

Microsoft Academic Search

BACKGROUND: Transient receptor potential (TRP) receptors expressed by primary sensory neurons mediate thermosensitivity, and may play a role in sensory pathophysiology. We previously reported that human dorsal root ganglion (DRG) sensory neurons co-expressed TRPV1 and TRPV3, and that these were increased in injured human DRG. Related receptors TRPV4, activated by warmth and eicosanoids, and TRPM8, activated by cool and menthol,

Paul Facer; Maria A Casula; Graham D Smith; Christopher D Benham; Iain P Chessell; Chas Bountra; Marco Sinisi; Rolfe Birch; Praveen Anand

2007-01-01

55

COOL (TRPM8) AND HOT (TRPV1) RECEPTORS IN THE BLADDER AND MALE GENITAL TRACT  

Microsoft Academic Search

Purpose:Overactive bladder symptoms due to various etiologies have been successfully treated with capsaicin by desensitization of the temperature sensitive vanilloid receptor TRPV1. Recently another temperature sensitive receptor, TRPM8, activated by menthol and cool temperatures (8C to 28C) was described that may be the proposed cool receptor, at least in part mediating the bladder response in the diagnostic ice water test.

ROBERT J. STEIN; SOLEDAD SANTOS; JIRO NAGATOMI; YUKIO HAYASHI; BRANDON S. MINNERY; MACRINA XAVIER; ANKUR S. PATEL; JOEL B. NELSON; WILLIAM J. FUTRELL; NAOKI YOSHIMURA; MICHAEL B. CHANCELLOR; FERNANDO DE MIGUEL

2004-01-01

56

Expression and functionality of TRPV1 receptor in human MCF-7 and canine CF.41 cells.  

PubMed

As canine mammary tumours (CMT) and human breast cancer share clinical and prognostic features, the former have been proposed as a model to study carcinogenesis and improved therapeutic treatment in human breast cancer. In recent years, it has been shown that transient receptor potential vanilloid 1 (TRPV1) is expressed in different neoplastic tissues and its activation has been associated with regulation of cancer growth and progression. The aim of the present research was to demonstrate the presence of TRPV1 in human and canine mammary cancer cells, MCF-7 and CF.41, respectively, and to study the role of TRPV1 in regulating cell proliferation. The images obtained by Western blot showed a signal at 100 kDa corresponding to the molecular weight of TRPV1 receptor. All tested TRPV1 agonists and antagonists caused a significant decrease (P?capsaicin and capsazepine induced a significant increase (P?TRPV1 activation in MCF-7 and CF.41 cells. PMID:23510405

Vercelli, C; Barbero, R; Cuniberti, B; Odore, R; Re, G

2013-03-19

57

Identification and characterisation of SB366791, a potent and selective vanilloid receptor (VR1\\/TRPV1) antagonist  

Microsoft Academic Search

Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by

M. J. Gunthorpe; H. K. Rami; J. C. Jerman; D. Smart; C. H. Gill; E. M. Soffin; S. Luis Hannan; S. C. Lappin; J. Egerton; G. D. Smith; A. Worby; L. Howett; D. Owen; S. Nasir; C. H. Davies; M. Thompson; P. A. Wyman; A. D. Randall; J. B. Davis

2004-01-01

58

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol  

PubMed Central

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol.

Blednov, Y.A.; Harris, R.A.

2009-01-01

59

TRPV1-mediated calcium signal couples with cannabinoid receptors and sodium-calcium exchangers in rat odontoblasts.  

PubMed

Odontoblasts are involved in the transduction of stimuli applied to exposed dentin. Although expression of thermo/mechano/osmo-sensitive transient receptor potential (TRP) channels has been demonstrated, the properties of TRP vanilloid 1 (TRPV1)-mediated signaling remain to be clarified. We investigated physiological and pharmacological properties of TRPV1 and its functional coupling with cannabinoid (CB) receptors and Na(+)-Ca(2+) exchangers (NCXs) in odontoblasts. Anandamide (AEA), capsaicin (CAP), resiniferatoxin (RF) or low-pH evoked Ca(2+) influx. This influx was inhibited by capsazepine (CPZ). Delay in time-to-activation of TRPV1 channels was observed between application of AEA or CAP and increase in [Ca(2+)](i). In the absence of extracellular Ca(2+), however, an immediate increase in [Ca(2+)](i) was observed on administration of extracellular Ca(2+), followed by activation of TRPV1 channels. Intracellular application of CAP elicited inward current via opening of TRPV1 channels faster than extracellular application. With extracellular RF application, no time delay was observed in either increase in [Ca(2+)](i) or inward current, indicating that agonist binding sites are located on both extra- and intracellular domains. KB-R7943, an NCX inhibitor, yielded an increase in the decay time constant during TRPV1-mediated Ca(2+) entry. Increase in [Ca(2+)](i) by CB receptor agonist, 2-arachidonylglycerol, was inhibited by CB1 receptor antagonist or CPZ, as well as by adenylyl cyclase inhibitor. These results showed that TRPV1-mediated Ca(2+) entry functionally couples with CB1 receptor activation via cAMP signaling. Increased [Ca(2+)](i) by TRPV1 activation was extruded by NCXs. Taken together, this suggests that cAMP-mediated CB1-TRPV1 crosstalk and TRPV1-NCX coupling play an important role in driving cellular functions following transduction of external stimuli to odontoblasts. PMID:22656960

Tsumura, Maki; Sobhan, Ubaidus; Muramatsu, Takashi; Sato, Masaki; Ichikawa, Hideki; Sahara, Yoshinori; Tazaki, Masakazu; Shibukawa, Yoshiyuki

2012-05-30

60

TRPV1 receptors modulate retinal development.  

PubMed

We investigated the possible participation of TRPV1 channels in retinal apoptosis and overall development. Retinas from newborn, male albino rats were treated in vitro with capsazepine, a TRPV1 antagonist. The expression of cell cycle markers was not changed after TRPV1 blockade, whereas capsazepine reduced the number of apoptotic cells throughout the retina,increased ERK1/2 and p38 phosphorylation and slightly reduced JNK phosphorylation. The expression of BAD, Bcl-2, as well as integral and cleaved capsase-3 were similar in all experimental conditions. Newborn rats were kept for 2 months after receiving high doses of capsazepine. In their retinas, calbindin and parvalbumin protein levels were upregulated, but only the number of amacrine-like, parvalbumin-positive cells was increased. The numbers of calretinin, calbindin, ChAT, vimentin, PKC-alpha and GABA-positive cells were similar in both conditions. Protein expression of synapsin Ib was also increased in the retinas of capsazepine-treated rats. Calretinin, vimentin, GFAP, synapsin Ia, synaptophysin and light neurofilament protein levels were not changed when compared to control values. Our results indicate that TRPV1 channels play a role in the control of the early apoptosis that occur during retinal development, which might be dependent on MAPK signaling. Moreover, it seems that TRPV1 function might be important for neuronal and synaptic maturation in the retina. PMID:21414401

Leonelli, Mauro; Martins, Daniel O; Britto, Luiz R G

2011-03-23

61

A Modular PIP2 Binding Site as a Determinant of Capsaicin Receptor Sensitivity  

Microsoft Academic Search

The capsaicin receptor (TRPV1), a heat-activated ion channel of the pain pathway, is sensitized by phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis after phospholipase C activation. We identify a site within the C-terminal domain of TRPV1 that is required for PIP2-mediated inhibition of channel gating. Mutations that weaken PIP2-TRPV1 interaction reduce thresholds for chemical or thermal stimuli, whereas TRPV1 channels in which this region

Elizabeth D. Prescott; David Julius

2003-01-01

62

Lipids as regulators of the activity of transient receptor potential type V1 (TRPV1) channels.  

PubMed

After 7 years from its cloning, the transient receptor potential vanilloid type-1 (TRPV1) channel remains the sole membrane receptor mediating the pharmacological effects of the hot chilli pepper pungent component, capsaicin, and of the Euphorbia toxin, resiniferatoxin. Yet, this ion channel represents one of the most complex examples of how the activity of a protein can be regulated. Among the several chemicophysical stimuli that can modulate TRPV1 permeability to cations, endogenous lipids appear to play a major role, either as allosteric effectors or as direct agonists, or both. Furthermore, the capability of some mediators, such as the endocannabinoid anandamide, or the eicosanoid precursors 12- and 5-hydroperoxy-eicosatetraenoic acids, to activate TRPV1 receptors provides a striking example of the "site-dependent" and "metabolic" functional plasticity, respectively, typical of bioactive lipids. In this article, the multi-faceted and most recently discovered aspects of TRPV1 regulation are reviewed, with particular emphasis on the interaction between these membrane channels and some lipid molecules. PMID:15936040

De Petrocellis, Luciano; Di Marzo, Vincenzo

2005-08-19

63

Functional plasticity of central TRPV1 receptors in brainstem dorsal vagal complex circuits of streptozotocin-treated hyperglycemic mice.  

PubMed

Emerging data indicate that central neurons participate in diabetic processes by modulating autonomic output from neurons in the dorsal motor nucleus of the vagus (DMV). We tested the hypothesis that synaptic modulation by transient receptor potential vanilloid type 1 (TRPV1) receptors is reduced in the DMV in slices from a murine model of type 1 diabetes. The TRPV1 agonist capsaicin robustly enhanced glutamate release onto DMV neurons by acting at preterminal receptors in slices from intact mice, but failed to do so in slices from diabetic mice. TRPV1 receptor protein expression in the vagal complex was unaltered. Brief insulin preapplication restored TRPV1-dependent modulation of glutamate release in a PKC- and PI3K-dependent manner. The restorative effect of insulin was prevented by brefeldin A, suggesting that insulin induced TRPV1 receptor trafficking to the terminal membrane. Central vagal circuits critical to the autonomic regulation of metabolism undergo insulin-dependent synaptic plasticity involving TRPV1 receptor modulation in diabetic mice after several days of chronic hyperglycemia. PMID:21957263

Zsombok, Andrea; Bhaskaran, Muthu D; Gao, Hong; Derbenev, Andrei V; Smith, Bret N

2011-09-28

64

Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization  

PubMed Central

The pharmacological desensitization of receptors is a fundamental mechanism for regulating the activity of neuronal systems. The TRPA1 channel plays a key role in the processing of noxious information and can undergo functional desensitization by unknown mechanisms. Here we show that TRPA1 is desensitized by homologous (mustard oil; a TRPA1 agonist) and heterologous (capsaicin; a TRPV1 agonist) agonists via Ca2+-independent and Ca2+-dependent pathways, respectively, in sensory neurons. The pharmacological desensitization of TRPA1 by capsaicin and mustard oil is not influenced by activation of protein phosphatase 2B. However, it is regulated by phosphatidylinositol-4,5-bisphosphate depletion after capsaicin, but not mustard oil, application. Using a biosensor, we establish that capsaicin, unlike mustard oil, consistently activates phospholipase C in sensory neurons. We next demonstrate that TRPA1 desensitization is regulated by TRPV1, and it appears that mustard oil-induced TRPA1 internalization is prevented by coexpression with TRPV1 in a heterologous expression system and in sensory neurons. In conclusion, we propose novel mechanisms whereby TRPA1 activity undergoes pharmacological desensitization through multiple cellular pathways that are agonist dependent and modulated by TRPV1.

Akopian, Armen N; Ruparel, Nikita B; Jeske, Nathaniel A; Hargreaves, Kenneth M

2007-01-01

65

Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1  

Microsoft Academic Search

In the urinary bladder, the capsaicin-gated ion channel TRPV1 is expressed both within afferent nerve terminals and within the epithelial cells that line the bladder lumen. To determine the significance of this expression pattern, we analyzed bladder function in mice lacking TRPV1. Compared with wild-type littermates, trpv1?\\/? mice had a higher frequency of low-amplitude, non-voiding bladder contractions. This alteration was

Y. Nakamura; S. Kiss; M. L. Nealen; S. Barrick; A. J. Kanai; E. Wang; G. Ruiz; W. C. de Groat; G. Apodaca; S. Watkins; M. J. Caterina; L. A. Birder

2002-01-01

66

GROUP III METABOTROPIC GLUTAMATE RECEPTORS AND TRPV1 CO-LOCALIZE AND INTERACT ON NOCICEPTORS  

PubMed Central

Several lines of evidence indicate group III metabotropic glutamate receptors (mGluRs) have systemic anti-hyperalgesic effects. We hypothesized this could occur through modulation of TRPV1 receptors on nociceptors. To address this question we performed anatomical studies to determine if group III mGluRs were expressed on cutaneous axons and if they co-localized with TRPV1. Immunostaining at the electron microscopic level demonstrated that 22% of unmyelinated axons labeled for mGluR8. Immunostaining at the light microscopic level in lumbar dorsal root ganglia (DRG) demonstrated that 80% and 28% of neurons labeled for mGluR8 or TRPV1, respectively. Of those neurons labeled for mGluR8, 25% labeled for TRPV1; of those labeled for TRPV1, 71% labeled for mGluR8. In behavior studies intraplantar injection of the group III mGluR agonist, L-AP-4 (0.1 1.0, 10.0 µM) had no effect on paw withdrawal latency (PWL) to heat in naďve rats but administration of 10 µM L-AP-4 prior to 0.05% capsaicin (CAP), significantly attenuated CAP-induced lifting/licking and reduced flinching behavior. The L-AP-4 effect was specific since administration of a group III antagonist UBP1112 (100 µM) blocked the L-AP-4 effect on CAP, resulting in behaviors similar to CAP alone. Intraplantar injection of UBP1112 alone did not result in nociceptive behaviors, indicating group III mGluRs are not tonically active. Finally, the anti-hyperalgesic effect of group III in this paradigm was local and not systemic since intraplantar administration of L-AP-4 in one hind paw did not attenuate nociceptive behaviors following CAP injection in the contralateral hind paw. Adenyl cyclase/cAMP/PKA may be the second messenger pathway linking these two receptor families because intraplantar injection of forskolin (FSK, 10 µM) reduced PWL to heat and L-AP-4 reversed this FSK effect. Taken together, these results suggest group III mGluRs can negatively modulate TRPV1 through inhibition of AC and downstream intracellular activity, blocking TRPV1-induced activation of nociceptors.

Govea, R. M.; Zhou, S.; Carlton, S. M.

2012-01-01

67

Intact Microtubules Preserve Transient Receptor Potential Vanilloid 1 (TRPV1) Functionality through Receptor Binding*  

PubMed Central

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is a protein currently under scrutiny as a pharmacological target for pain management therapies. Recently, the role of TRPV1-microtubule interaction in transducing nociception stimuli to cells by cytoskeletal rearrangement was proposed. In this work, we investigate TRPV1-microtubule interaction in living cells under the resting or activated state of TRPV1, as well as in presence of structurally intact or depolymerized cytoskeletal microtubules. We combined a toolbox of high resolution/high sensitivity fluorescence imaging techniques (such as FRET, correlation spectroscopy, and fluorescence anisotropy) to monitor TRPV1 aggregation status, membrane mobility, and interaction with microtubules. We found that TRPV1 is a dimeric membrane protein characterized by two populations with different diffusion properties in basal condition. After stimulation with resiniferatoxin, TRPV1 dimers tetramerize. The tetramers and the slower population of TRPV1 dimers bind dynamically to intact microtubules but not to tubulin dimers. Upon microtubule disassembly, the interaction with TRPV1 is lost thereby inducing receptor self-aggregation with partial loss of functionality. Intact microtubules play an essential role in maintaining TRPV1 functionality toward activation stimuli. This previously undisclosed property mirrors the recently reported role of TRPV1 in modulating microtubule assembly/disassembly and suggests the participation of these two players in a feedback cycle linking nociception and cytoskeletal remodeling.

Storti, Barbara; Bizzarri, Ranieri; Cardarelli, Francesco; Beltram, Fabio

2012-01-01

68

Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis.  

PubMed

In the human colon, vanilloid receptor TRPV1 is overexpressed both in afferent nerve terminals and in epithelial cells during inflammation. In the past years, pharmacological experiments using TRPV1 agonists and antagonists revealed that TRPV1 receptors may play proinflammatory and protective roles in the gastrointestinal tract. Here, we applied a genetic approach to define the role of TRPV1 and analyzed the effects of dinitrobenzene sulfonic acid (DNBS)-induced colitis in TRPV1-deficient (TRPV1-/-) mice. Intrarectal infusion of DNBS induced increased inflammation in TRPV1-/- mice compared to wild-type littermates (TRPV1+/+) as evaluated by macroscopic scoring and myeloperoxidase assays. This finding indicates that TRPV1 receptors are required for the protection within sensory pathways that regulate the response following the initiation of colonic inflammation. Electrophysiological recordings from circular smooth-muscle cells, performed 8 and 24 h after DNBS treatment, revealed strong spontaneous oscillatory action potentials in TRPV1-/- but not in TRPV1+/+ colons, indicating an early TRPV1-mediated control of inflammation-induced irritation of smooth-muscle activities. These unexpected results suggest that TRPV1 receptors mediate endogenous protection against experimentally induced colonic inflammation. PMID:16389550

Massa, F; Sibaev, A; Marsicano, G; Blaudzun, H; Storr, M; Lutz, B

2005-12-31

69

Receptor changes in brain tissue of rats treated as neonates with capsaicin  

Microsoft Academic Search

Capsaicin, the hot chemical in chillies, administered to neonatal rats, causes destruction of polymodal nociceptive primary afferent neurons by acting on TRPV1 receptors causing intrinsic somatosensory deprivation. Although the effects of neonatal capsaicin treatment in the periphery have been extensively investigated, less is known about the brain networks to which the capsaicin sensory neurons are relayed. In the present study

Katerina Zavitsanou; Victoria S. Dalton; Hongqin Wang; Penny Newson; Loris A. Chahl

2010-01-01

70

The effects of the TRPV1 antagonist SB705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans  

Microsoft Academic Search

TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB-705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a

Boris A. Chizh; Mary B. O’Donnell; Antonella Napolitano; Jie Wang; Allison C. Brooke; Mike C. Aylott; Jonathan N. Bullman; Emily J. Gray; Robert Y. Lai; Pauline M. Williams; Jonathan M. Appleby

2007-01-01

71

Vanilloid receptor (TRPV1)-deficient mice show increased susceptibility to dinitrobenzene sulfonic acid induced colitis  

Microsoft Academic Search

In the human colon, vanilloid receptor TRPV1 is overexpressed both in afferent nerve terminals and in epithelial cells during\\u000a inflammation. In the past years, pharmacological experiments using TRPV1 agonists and antagonists revealed that TRPV1 receptors\\u000a may play proinflammatory and protective roles in the gastrointestinal tract. Here, we applied a genetic approach to define\\u000a the role of TRPV1 and analyzed the

F. Massa; A. Sibaev; G. Marsicano; H. Blaudzun; M. Storr; B. Lutz

2006-01-01

72

Structure and function of TRPV1  

Microsoft Academic Search

Capsaicin, the main ingredient in hot chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), is predicted to have six transmembrane (TM) domains and a short, pore-forming hydrophobic stretch between the fifth and sixth TM domains,

Makoto Tominaga; Tomoko Tominaga

2005-01-01

73

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans  

Microsoft Academic Search

The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent

Narender R. Gavva; James J. S. Treanor; Andras Garami; Liang Fang; Sekhar Surapaneni; Anna Akrami; Francisco Alvarez; Annette Bak; Mary Darling; Anu Gore; Graham R. Jang; James P. Kesslak; Liyun Ni; Mark H. Norman; Gabrielle Palluconi; Mark J. Rose; Margaret Salfi; Edward Tan; Andrej A. Romanovsky; Christopher Banfield; Gudarz Davar

2008-01-01

74

Effect of surgical and chemical sensory denervation on non-neural expression of the transient receptor potential vanilloid 1 (TRPV1) receptors in the rat.  

PubMed

Pretreatment with the ultrapotent capsaicin analog resiniferatoxin (RTX) has been applied as a selective pharmacological tool in inflammation and pain studies to desensitize transient receptor potential vanilloid 1 (TRPV1) receptor-expressing sensory nerve endings. The discovery of TRPV1 receptor on non-neural cells challenges systemic RTX desensitization as a method acting exclusively on a population of sensory neurons, but not on non-neural cells. Systemic RTX desensitization was used for chemical denervation and transection of the sciatic and saphenous nerves for surgical denervation in rats. Quantitative real-time PCR and immunohistochemistry were applied to investigate the presence and alterations of the TRPV1 receptor mRNA and protein following chemical and surgical denervation. We provided the first evidence for non-neural TRPV1 immunopositivity and mRNA expression in the rat dorsal paw and plantar skin as well as the oral mucosa. Neither chemical nor surgical denervation influenced the level of TRPV1 receptor mRNA and protein expression in non-neural cells of either skin regions or mucosa. Therefore, RTX and consequently capsaicin remain to be considered as selective neurotoxins for a population of primary afferent neurons. PMID:22528458

Kun, József; Helyes, Zsuzsanna; Perkecz, Anikó; Bán, Ágnes; Polgár, Beáta; Szolcsányi, János; Pintér, Erika

2012-04-19

75

TRPV1 activation improves exercise endurance and energy metabolism through PGC-1? upregulation in mice  

PubMed Central

Impaired aerobic exercise capacity and skeletal muscle dysfunction are associated with cardiometabolic diseases. Acute administration of capsaicin enhances exercise endurance in rodents, but the long-term effect of dietary capsaicin is unknown. The capsaicin receptor, the transient receptor potential vanilloid 1 (TRPV1) cation channel has been detected in skeletal muscle, the role of which remains unclear. Here we report the function of TRPV1 in cultured C2C12 myocytes and the effect of TRPV1 activation by dietary capsaicin on energy metabolism and exercise endurance of skeletal muscles in mice. In vitro, capsaicin increased cytosolic free calcium and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) expression in C2C12 myotubes through activating TRPV1. In vivo, PGC-1? in skeletal muscle was upregulated by capsaicin-induced TRPV1 activation or genetic overexpression of TRPV1 in mice. TRPV1 activation increased the expression of genes involved in fatty acid oxidation and mitochondrial respiration, promoted mitochondrial biogenesis, increased oxidative fibers, enhanced exercise endurance and prevented high-fat diet-induced metabolic disorders. Importantly, these effects of capsaicin were absent in TRPV1-deficient mice. We conclude that TRPV1 activation by dietary capsaicin improves energy metabolism and exercise endurance by upregulating PGC-1? in skeletal muscles. The present results indicate a novel therapeutic strategy for managing metabolic diseases and improving exercise endurance.

Luo, Zhidan; Ma, Liqun; Zhao, Zhigang; He, Hongbo; Yang, Dachun; Feng, Xiaoli; Ma, Shuangtao; Chen, Xiaoping; Zhu, Tianqi; Cao, Tingbing; Liu, Daoyan; Nilius, Bernd; Huang, Yu; Yan, Zhencheng; Zhu, Zhiming

2012-01-01

76

TRPV1 antagonist can suppress the atopic dermatitis-like symptoms by accelerating skin barrier recovery  

Microsoft Academic Search

BackgroundTransient receptor potential vanilloid type 1 (TRPV1) is a cation channel activated by diverse obnoxious stimuli like capsaicin, low pH or heat. Recently, it was revealed that TRPV1 might be deeply associated with skin permeability barrier function, suggesting that modulation of TRPV1 might be beneficial for the skin disorders with barrier damages.

Jun-Won Yun; Jung A. Seo; Yeon Su Jeong; II-Hong Bae; Won-Hee Jang; Jihae Lee; Sun-Young Kim; Song-Seok Shin; Byoung-Young Woo; Ki-Wha Lee; Kyung-Min Lim; Young-Ho Park

2011-01-01

77

Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-? and estrogen receptor-? knockout mice.  

PubMed

In women, pain symptoms and nociceptive thresholds vary with the reproductive cycle, suggesting the role of estrogen receptors (ERs) in modulating nociception. Our previous data strongly suggest an interaction between ERs and ATP-induced purinergic (P2X3) as well as ERs and capsaicin-induced vanilloid (TRPV1) receptors at the level of dorsal root ganglion (DRG) neurons. In this study, we investigated the expression of P2X3 and TRPV1 receptors by western blotting and immunohistochemistry in lumbosacral DRGs from wild type, ER?, and ER? knockout mice. We found a significant decrease for both P2X3 and TRPV1 in ER?KO and ER?KO. This phenomenon was visualized in L1, L2, L4, and L6 levels for P2X3 receptors and in L1, L2, and S2 levels for TRPV1 receptors. This tan interaction between P2X3/TRPV1 and ERs expression in sensory neurons may represent a novel mechanism that can explain the sex differences in nociception observed in clinical practice. The DRG is an important site of visceral afferent convergence and cross-sensitization and a potential target for designing new anti-nociceptive therapies. PMID:22581043

Cho, Taehoon; Chaban, Victor V

2012-06-20

78

Thimerosal decreases TRPV1 activity by oxidation of extracellular sulfhydryl residues  

Microsoft Academic Search

TRPV1, a receptor for capsaicin, plays a key role in mediating thermal and inflammatory pain. Because the modulation of ion channels by the cellular redox state is a significant determinant of channel function, we investigated the effects of sulfhydryl modification on the activity of TRPV1. Thimerosal, which oxidizes sulfhydryls, blocked the capsaicin-activated inward current (Icap) in cultured sensory neurons, in

Yunju Jin; Dong Kwan Kim; Lee-Yong Khil; Uhtaek Oh; Jun Kim; Jiyeon Kwak

2004-01-01

79

TRPV1 shows dynamic ionic selectivity during agonist stimulation  

Microsoft Academic Search

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is gated by noxious heat, capsaicin and other diverse stimuli. It is a nonselective cation channel that prefers Ca2+ over Na+. These permeability characteristics, as in most channels, are widely presumed to be static. On the contrary, we found that activation of native or recombinant rat TRPV1 leads to

Man-Kyo Chung; Ali D Güler; Michael J Caterina

2008-01-01

80

The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept  

Microsoft Academic Search

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I\\/II clinical trials for the indications of chronic inflammatory pain and migraine.

Daniel N. Cortright; Charles A. Blum; Samer R. Eid; Arpad Szallasi

2007-01-01

81

Analgesic Compound from Sea Anemone Heteractis crispa Is the First Polypeptide Inhibitor of Vanilloid Receptor 1 (TRPV1)*  

PubMed Central

Venomous animals from distinct phyla such as spiders, scorpions, snakes, cone snails, or sea anemones produce small toxic proteins interacting with a variety of cell targets. Their bites often cause pain. One of the ways of pain generation is the activation of TRPV1 channels. Screening of 30 different venoms from spiders and sea anemones for modulation of TRPV1 activity revealed inhibitors in tropical sea anemone Heteractis crispa venom. Several separation steps resulted in isolation of an inhibiting compound. This is a 56-residue-long polypeptide named APHC1 that has a Bos taurus trypsin inhibitor (BPTI)/Kunitz-type fold, mostly represented by serine protease inhibitors and ion channel blockers. APHC1 acted as a partial antagonist of capsaicin-induced currents (32 ± 9% inhibition) with half-maximal effective concentration (EC50) 54 ± 4 nm. In vivo, a 0.1 mg/kg dose of APHC1 significantly prolonged tail-flick latency and reduced capsaicin-induced acute pain. Therefore, our results can make an important contribution to the research into molecular mechanisms of TRPV1 modulation and help to solve the problem of overactivity of this receptor during a number of pathological processes in the organism.

Andreev, Yaroslav A.; Kozlov, Sergey A.; Koshelev, Sergey G.; Ivanova, Ekaterina A.; Monastyrnaya, Margarita M.; Kozlovskaya, Emma P.; Grishin, Eugene V.

2008-01-01

82

Structural determinant of TRPV1 desensitization interacts with calmodulin  

Microsoft Academic Search

The capsaicin receptor, TRPV1 (VR1), is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. Extracellular Ca2+-dependent desensitization of TRPV1 observed in patch-clamp experiments when using both heterologous expression systems and native sensory ganglia is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy. Here, we

Mitsuko Numazaki; Tomoko Tominaga; Kumiko Takeuchi; Namie Murayama; Hidenori Toyooka; Makoto Tominaga

2003-01-01

83

Caged capsaicins: New tools for the examination of TRPV1 channels in somatosensory neurons.  

PubMed

The vanilloid capsaicin, N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide, is the pungent ingredient of chili peppers and is used in pain research as an activating ligand of heat-sensitive transduction channels in nociceptive neurons. Here we describe the synthesis and application of two capsaicin derivatives modified at the hydroxy function of the vanillyl motif: alpha-carboxy-4,5-dimethoxy-2-nitrobenzyl-caged (CDMNB-caged) capsaicin and {7-[bis(carboxymethyl)amino]coumarin-4-yl}methoxycarbonyl-caged (BCMACMOC-caged) capsaicin. These compounds show dramatically reduced pungency, but release active capsaicin upon irradiation with UV light. CDMNB-caged capsaicin can be used to perform concentration-jump experiments, while BCMACMOC-caged capsaicin is membrane-impermeant and can be applied selectively to the intracellular or extracellular sides of a plasma membrane. Both compounds can serve as valuable research tools in pain physiology. PMID:17154194

Gilbert, Daniel; Funk, Katharina; Dekowski, Brigitte; Lechler, Ralf; Keller, Sandro; Möhrlen, Frank; Frings, Stephan; Hagen, Volker

2007-01-01

84

Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin  

Microsoft Academic Search

BACKGROUND: Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the

Manuela Simonetti; Alessandra Fabbro; Marianna D'Arco; Marina Zweyer; Andrea Nistri; Rashid Giniatullin; Elsa Fabbretti

2006-01-01

85

TRPV1 Antagonists Elevate Cell Surface Populations of Receptor Protein and Exacerbate TRPV1-Mediated Toxicities in Human Lung Epithelial Cells  

PubMed Central

TRPV1 mediates cell death and pro-inflammatory cytokine production in lung epithelial cells exposed to prototypical receptor agonists. This study shows that NHBE, BEAS-2B and TRPV1 over-expressing BEAS-2B cells pre-treated with various TRPV1 antagonists become sensitized to the prototypical TRPV1 agonist, nonivamide, via a mechanism that involves translocation of existing receptor from the endoplasmic reticulum to the plasma membrane. As such, typical cellular responses to agonist treatment, as measured by calcium flux, inflammatory cytokine gene induction, and cytotoxicity were exacerbated. These data were in contrast to the results obtained when TRPV1 antagonists were co-administered with nonivamide; conditions which inhibited TRPV1-mediated effects. The antagonists LJO-328, SC0030, and capsazepine increased the cytotoxicity of nonivamide by ~20-fold and agonist-induced calcium flux by ~6-fold. Inflammatory-cytokine gene induction by nonivamide was also increased significantly by pre-treatment with the antagonists. The enhanced responses were inhibited by the co-administration of antagonists with nonivamide, confirming that increases in sensitivity were attributable to increased TRPV1-associated activity. Sensitization was attenuated by brefeldin A (a golgi transport inhibitor), but not cycloheximide (a protein synthesis inhibitor), or actinomycin D (a transcription inhibitor). Sensitized cells exhibited increased calcium flux from extracellular calcium sources, while unsensitized cells exhibited calcium flux originating primarily from intracellular stores. These results demonstrate the presence of a novel mechanism for regulating the sub-cellular distribution of TRPV1 and subsequent control of cellular sensitivity to TRPV1 agonists.

Johansen, Mark E.; Reilly, Christopher A.; Yost, Garold S.

2008-01-01

86

Integrative Binding Sites within Intracellular Termini of TRPV1 Receptor  

PubMed Central

TRPV1 is a nonselective cation channel that integrates wide range of painful stimuli. It has been shown that its activity could be modulated by intracellular ligands PIP2 or calmodulin (CaM). The detailed localization and description of PIP2 interaction sites remain unclear. Here, we used synthesized peptides and purified fusion proteins of intracellular regions of TRPV1 expressed in E.coli in combination with fluorescence anisotropy and surface plasmon resonance measurements to characterize the PIP2 binding to TRPV1. We characterized one PIP2 binding site in TRPV1 N-terminal region, residues F189-V221, and two independent PIP2 binding sites in C–terminus: residues K688-K718 and L777-S820. Moreover we show that two regions, namely F189-V221 and L777-S820, overlap with previously localized CaM binding sites. For all the interactions the equilibrium dissociation constants were estimated. As the structural data regarding C-terminus of TRPV1 are lacking, restraint-based molecular modeling combined with ligand docking was performed providing us with structural insight to the TRPV1/PIP2 binding. Our experimental results are in excellent agreement with our in silico predictions.

Grycova, Lenka; Holendova, Blanka; Bumba, Ladislav; Bily, Jan; Jirku, Michaela; Lansky, Zdenek; Teisinger, Jan

2012-01-01

87

Epidermal Growth Factor Receptor Transactivation by the Cannabinoid Receptor (CB1) and Transient Receptor Potential Vanilloid 1 (TRPV1) Induces Differential Responses in Corneal Epithelial Cells.  

National Technical Information Service (NTIS)

Corneal epithelial injury induces release of endogenous metabolites that are cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1) agonists. We determined the functional contributions by CB1 and TRPV1 activation to eliciting re...

F. Zhang H. Yang J. E. Capo-Aponte Z. Pan Z. Wang

2010-01-01

88

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice  

Microsoft Academic Search

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1?\\/? mice, TRPV1?\\/? mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory

A. Sibaev; F. Massa; B. Yüce; G. Marsicano; H. A. Lehr; B. Lutz; B. Göke; H. D. Allescher; M. Storr

2006-01-01

89

Thermally active TRPV1 tonically drives central spontaneous glutamate release  

PubMed Central

Central synapses spontaneously release neurotransmitter at low rates. In brainstem, cranial visceral afferent terminals in caudal solitary tract nucleus (NTS) display pronounced activity-dependent asynchronous release of glutamate and this extra release depends on TRPV1 receptors (TRPV1+). Asynchronous release is absent for afferents lacking TRPV1 (TRPV1-) and resting EPSC frequency was greater in TRPV1+. Here, we studied this basal activity difference by assessing thermal sensitivity of spontaneous and miniature synaptic events in TRPV1+ and TRPV1- second order NTS neurons. The spontaneous EPSC rate decreased when temperature was decreased, increased steeply between 30 and 42°C only in TRPV1+ neurons and was calcium-dependent. TRPV1-specific antagonist SB366791, but not TTX, strongly attenuated thermal responses. Temperature changes failed to alter EPSC frequency in TRPV1- neurons. EPSC amplitudes and decay kinetics changed little with temperature. IPSCs in these second order NTS neurons were unaltered by temperature. Such results suggest that activated presynaptic TRPV1+ receptors trigger continuous, resting release of glutamate vesicles at physiological temperatures only in capsaicin-responsive terminals. In mechanically isolated individual neurons harvested from medial NTS, increases in temperature increased the rate of glutamate release only in TRPV1+ neurons whereas IPSC rates were unaffected. Cadmium failed to block thermal increases in glutamate release suggesting that calcium entry through TRPV1 channels may trigger glutamate release independent of voltage activated calcium channels. Together our findings indicate a new form of afferent signaling in which TRPV1 channels within central terminals of peripheral afferents tonically generate glutamate release in NTS at 37°C in the absence of afferent action potentials.

Shoudai, Kiyomitsu; Peters, James H.; McDougall, Stuart J.; Fawley, Jessica A.; Andresen, Michael C.

2010-01-01

90

Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition  

PubMed Central

BACKGROUND AND PURPOSE Capsaicin, an agonist of transient receptor potential vanilloid 1 (TRPV1) channels, is pro-nociceptive in the periphery but is anti-nociceptive when administered into the ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Here, we investigated how activation of TRPV1 channels in the vlPAG leads to anti-nociception. EXPERIMENTAL APPROACH We examined synaptic transmission and neuronal activity using whole-cell recordings in vlPAG slices in vitro and hot-plate nociceptive responses in rats after drug microinjection into the vlPAG in vivo. KEY RESULTS Capsaicin (1–10 µM) depressed evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in vlPAG slices presynaptically, while increasing miniature excitatory PSC frequency. Capsaicin-induced eIPSC depression was antagonized by cannabinoid CB1 and metabotropic glutamate (mGlu5) receptor antagonists, and prevented by inhibiting diacylglycerol lipase (DAGL), which converts DAG into 2-arachidonoylglycerol (2-AG), an endocannabinoid. Capsaicin induced membrane depolarization in 2/3 neurons recorded but, overall, increased neuronal firings by increasing evoked postsynaptic potentials. Intra-vlPAG capsaicin reduced hot-plate responses in rats, effects blocked by CB1 and mGlu receptor antagonists. Effects of capsaicin were antagonized by SB 366791, a TRPV1 channel antagonist. CONCLUSIONS AND IMPLICATIONS Capsaicin activated TRPV1s on glutamatergic terminals to release glutamate which activated postsynaptic mGlu5 receptors, yielding 2-AG from DAG by DAGL hydrolysis. 2-AG induces retrograde inhibition (disinhibition) of GABA release via presynaptic CB1 receptors. This disinhibition in the vlPAG leads to anti-nociception by activating the descending pain inhibitory pathway. This is a novel TRPV1 channel-mediated anti-nociceptive mechanism in the brain and a new interaction between vanilloid and endocannabinoid systems.

Liao, H-T; Lee, H-J; Ho, Y-C; Chiou, L-C

2011-01-01

91

Paradoxic effects of propofol on visceral pain induced by various TRPV1 agonists.  

PubMed

Intraperitoneal injection of propofol inhibits subsequent acetic acid-induced writhing response in mice. Propofol increases the sensitivity of dorsal root ganglion neurons to capsaicin through transient receptor potential ankyrin subtype-1 (TRPA1) and protein kinase C? (PKC?)-mediated phosphorylation of transient receptor potential vanilloid subtype-1 (TRPV1). Intraperitoneal co-injection of propofol may increase visceral nociception induced by TRPV1 agonists via sensitization of TRPV1. Therefore, we investigated the effects of intraperitoneal co-injection of propofol on nociception induced by acetic acid and capsaicin. The number of writhing movements induced by acetic acid or nociception time by capsaicin with or without propofol were counted. Neonatal capsaicin-treated mice were also used to demonstrate the role of TRPV1 in the effects of propofol on nociception, induced by TRPV1 agonists. Co-injection of propofol resulted in a pronociceptive effect on the writhing response induced by acetic acid, while the same dose of propofol ameliorated the response to capsaicin. The writhing response to intraperitoneal acetic acid was sharply inhibited following neonatal treatment with capsaicin. Co-injection with propofol reduced the number of writhing movements induced by acetic acid in neonatal capsaicin-treated mice. These results suggest that propofol binds to TRPV1 at the capsaicin-binding pocket. PMID:23596498

Ji, Wenjin; Cui, Can; Zhang, Zhiwei; Liang, Jiexian

2013-02-05

92

TRPV1 activation prevents high-salt diet-induced nocturnal hypertension in mice  

Microsoft Academic Search

High dietary salt-caused hypertension is associated with increasing reactive oxygen species generation and reduced nitric\\u000a oxide (NO) bioavailability. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, is proposed\\u000a to be involved in Dahl salt-sensitive hypertension, as determined in acute or short-term experiments. However, it remains\\u000a unknown whether activation of TRPV1 by dietary capsaicin could prevent the

Xinzhong Hao; Jing Chen; Zhidan Luo; Hongbo He; Hao Yu; Liqun Ma; Shuangtao Ma; Tianqi Zhu; Daoyan Liu; Zhiming Zhu

2011-01-01

93

Cold suppresses agonist-induced activation of TRPV1.  

PubMed

Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID:21666106

Chung, M-K; Wang, S

2011-06-10

94

Fas-associated factor 1 is a negative regulator in capsaicin induced cancer cell apoptosis  

Microsoft Academic Search

Vanilloid receptor1 (VR1\\/TRPV1) is expressed on peripheral nerves and involved in sensing of temperature and pain. Recent reports have demonstrated that tumor cells express TRPV1 and that capsaicin (CP), a ligand for TRPV1, induces apoptosis in cancer cells. The mechanism underlying CP-induced tumor cell apoptosis remains unclear. Here, we investigated the role of TRPV1 in tumor apoptosis using TRPV1-expressing cancer

Amiya K. Ghosh; Sreyashi Basu

2010-01-01

95

TRPV1 Activation in Primary Cortical Neurons Induces Calcium-Dependent Programmed Cell Death  

PubMed Central

Transient receptor potential cation channel, subfamily V, member 1 (TRPV1, also known as vanilloid receptor 1) is a receptor that detects capsaicin, a pungent component of chili peppers, and noxious heat. Although its function in the primary nociceptor as a pain receptor is well established, whether TRPV1 is expressed in the brain is still under debate. In this study, the responses of primary cortical neurons were investigated. Here, we report that 1) capsaicin induces caspase-3-dependent programmed cell death, which coincides with increased production of nitric oxide and peroxynitrite ; that 2) the prolonged capsaicin treatment induces a steady increase in the degree of capase-3 activation, which is prevented by the removal of capsaicin; 3) and that blocking calcium entry and calcium-mediated signaling prevents capsaicin-induced cell death. These results indicate that cortical neurons express TRPV1 whose prolonged activation causes cell death.

Song, Juhyun; Lee, Jun Hong; Lee, Sung Ho; Park, Kyung Ah

2013-01-01

96

Forced swim-induced musculoskeletal hyperalgesia is mediated by CRF2 receptors but not by TRPV1 receptors.  

PubMed

The exacerbation of musculoskeletal pain by stress in humans is modeled by the musculoskeletal hyperalgesia in rodents following a forced swim. We hypothesized that stress-sensitive corticotropin releasing factor (CRF) receptors and transient receptor vanilloid 1 (TRPV1) receptors are responsible for the swim stress-induced musculoskeletal hyperalgesia. We confirmed that a cold swim (26 °C) caused a transient, morphine-sensitive decrease in grip force responses reflecting musculoskeletal hyperalgesia in mice. Pretreatment with the CRF2 receptor antagonist astressin 2B, but not the CRF1 receptor antagonist NBI-35965, attenuated this hyperalgesia. Desensitizing the TRPV1 receptor centrally or peripherally using desensitizing doses of resiniferatoxin (RTX) failed to prevent the musculoskeletal hyperalgesia produced by cold swim. SB-366791, a TRPV1 antagonist, also failed to influence swim-induced hyperalgesia. Together these data indicate that swim stress-induced musculoskeletal hyperalgesia is mediated, in part, by CRF2 receptors but is independent of the TRPV1 receptor. PMID:23624287

Abdelhamid, Ramy E; Kovacs, Katalin J; Pasley, Jeffrey D; Nunez, Myra G; Larson, Alice A

2013-04-25

97

Structure Activity Relationships of 1,4-Dihydropyridines That Act as Enhancers of the Vanilloid Receptor 1 (TRPV1)  

PubMed Central

Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel "enhancers" of TRPV1 activity by examining changes in capsaicin-induced elevations in 45Ca2+-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on 45Ca2+-uptake by typically 2 – 3 fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca2+, as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion.

Roh, Eun Joo; Keller, Jason M.; Olah, Zoltan; Iadarola, Michael J.; Jacobson, Kenneth A.

2008-01-01

98

GABAA receptor modulation by piperine and a non-TRPV1 activating derivative?  

PubMed Central

The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABAA) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioural effects were investigated. GABAA receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (IGABA) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behaviour, thermoregulation and seizure threshold were analysed in mice. Piperine acted with similar potency on all GABAA receptor subtypes (EC50 range: 42.8 ± 7.6 ?M (?2?2)–59.6 ± 12.3 ?M (?3?2)). IGABA modulation by piperine did not require the presence of a ?2S-subunit, suggesting a binding site involving only ? and ? subunits. IGABA activation was slightly more efficacious on receptors formed from ?2/3 subunits (maximal IGABA stimulation through ?1?3 receptors: 332 ± 64% and ?1?2: 271 ± 36% vs. ?1?1: 171 ± 22%, p < 0.05) and ?3-subunits (?3?2: 375 ± 51% vs. ?5?2:136 ± 22%, p < 0.05). Replacing the piperidine ring by a N,N-diisobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABAA receptor modulation. SCT-66 displayed greater efficacy on GABAA receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABAA receptor modulators.

Khom, Sophia; Strommer, Barbara; Schoffmann, Angela; Hintersteiner, Juliane; Baburin, Igor; Erker, Thomas; Schwarz, Thomas; Schwarzer, Christoph; Zaugg, Janine; Hamburger, Matthias; Hering, Steffen

2013-01-01

99

Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin  

PubMed Central

Background Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated. Results Rat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization), while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist ?, ?-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491) and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors. Conclusion Comparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception-transducing receptors of trigeminal neurons. Culturing did not prevent differential receptor upregulation by algogenic substances like NGF or serotonin, indicating that chronic application led to distinct plastic changes in the molecular mechanisms mediating pain on trigeminal nociceptors.

Simonetti, Manuela; Fabbro, Alessandra; D'Arco, Marianna; Zweyer, Marina; Nistri, Andrea; Giniatullin, Rashid; Fabbretti, Elsa

2006-01-01

100

TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons  

SciTech Connect

Transient receptor potential vanilloid 1 (TRPV1) functions as a polymodal nociceptor and is activated by several vanilloids, including capsaicin, protons and heat. Although TRPV1 channels are widely distributed in the brain, their roles remain unclear. Here, we investigated the roles of TRPV1 in cytotoxic processes using TRPV1-expressing cultured rat cortical neurons. Capsaicin induced severe neuronal death with apoptotic features, which was completely inhibited by the TRPV1 antagonist capsazepine and was dependent on extracellular Ca{sup 2+} influx. Interestingly, nifedipine, a specific L-type Ca{sup 2+} channel blocker, attenuated capsaicin cytotoxicity, even when applied 2-4 h after the capsaicin. ERK inhibitor PD98059 and several antioxidants, but not the JNK and p38 inhibitors, attenuated capsaicin cytotoxicity. Together, these data indicate that TRPV1 activation triggers apoptotic cell death of rat cortical cultures via L-type Ca{sup 2+} channel opening, Ca{sup 2+} influx, ERK phosphorylation, and reactive oxygen species production.

Shirakawa, Hisashi; Yamaoka, Tomoko; Sanpei, Kazuaki; Sasaoka, Hirotoshi; Nakagawa, Takayuki [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan); Kaneko, Shuji [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501 (Japan)], E-mail: skaneko@pharm.kyoto-u.ac.jp

2008-12-26

101

cAMP-Dependent Protein Kinase Regulates Desensitization of the Capsaicin Receptor (VR1) by Direct Phosphorylation  

Microsoft Academic Search

The capsaicin receptor, VR1 (also known as TRPV1), is a ligand-gated ion channel expressed on nociceptive sensory neurons that responds to noxious thermal and chemical stimuli. Capsaicin responses in sensory neurons exhibit robust potentiation by cAMP-dependent protein kinase (PKA). In this study, we demonstrate that PKA reduces VR1 desensitization and directly phosphorylates VR1. In vitro phosphorylation, phosphopeptide mapping, and protein

Gautam Bhave; Weiguo Zhu; Haibin Wang; D. J Brasier; Gerry S Oxford; Robert W Gereau IV

2002-01-01

102

NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels  

PubMed Central

Nociceptors, or pain-sensitive receptors, are unique among sensory receptors in that their sensitivity is increased by noxious stimulation. This process, called sensitization or hyperalgesia, is mediated by a variety of proinflammatory factors, including bradykinin, ATP and NGF, which cause sensitization to noxious heat stimuli by enhancing the membrane current carried by the heat- and capsaicin-gated ion channel, TRPV1. Several different mechanisms for sensitization of TRPV1 have been proposed. Here we show that NGF, acting on the TrkA receptor, activates a signalling pathway in which PI3 kinase plays a crucial early role, with Src kinase as the downstream element which binds to and phosphorylates TRPV1. Phosphorylation of TRPV1 at a single tyrosine residue, Y200, followed by insertion of TRPV1 channels into the surface membrane, explains most of the rapid sensitizing actions of NGF.

Zhang, Xuming; Huang, Jiehong; McNaughton, Peter A

2005-01-01

103

CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice.  

PubMed

CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1(-/-) mice, TRPV1(-/-) mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1(+/+) and CB1(-/-) mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1(-/-) and TRPV1(-/-) mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1(-/-) mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1(+/+) mice pointing toward missing protective mechanisms in the CB1(-/-) mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability. PMID:16501934

Sibaev, A; Massa, F; Yüce, B; Marsicano, G; Lehr, H A; Lutz, B; Göke, B; Allescher, H D; Storr, M

2006-02-25

104

The Chimeric Approach Reveals That Differences in the TRPV1 Pore Domain Determine Species-specific Sensitivity to Block of Heat Activation*  

PubMed Central

The capsaicin-, heat-, and proton-activated ion channel TRPV1, a member of the transient receptor potential cation channel family is a polymodal nociceptor. For almost a decade, TRPV1 has been explored by the pharmaceutical industry as a potential target for example for pain conditions. Antagonists which block TRPV1 activation by capsaicin, heat, and protons were developed by a number of pharmaceutical companies. The unexpected finding of hyperthermia as an on-target side effect in clinical studies using polymodal TRPV1 antagonists has prompted companies to search for ways to circumvent hyperthermia, for example by the development of modality-selective antagonists. The significant lack of consistency of the pharmacology of many TRPV1 antagonists across different species has been a further obstacle. JYL-1421 for example was shown to block capsaicin and heat responses in human and monkey TRPV1 while it was largely ineffective in blocking heat responses in rat TRPV1. These findings suggested structural dissimilarities between different TRPV1 species relevant for small compound antagonism for example of heat activation. Using a chimeric approach (human and rat TRPV1) in combination with a novel FLIPR-based heat activation assay and patch-clamp electrophysiology we have identified the pore region as being strongly linked to the observed species differences. We demonstrate that by exchanging the pore domains JYL-1421, which is modality-selective in rat can be made modality-selective in human TRPV1 and vice-versa.

Papakosta, Marianthi; Dalle, Carine; Haythornthwaite, Alison; Cao, Lishuang; Stevens, Edward B.; Burgess, Gillian; Russell, Rachel; Cox, Peter J.; Phillips, Stephen C.; Grimm, Christian

2011-01-01

105

Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle.  

PubMed

The NMDA and TRPV1 receptors that are expressed in sensory neurons have been independently demonstrated to play important roles in peripheral pain mechanisms. In the present study, we investigated whether the 2 receptor-channel systems form a functional complex that provides the basis for the development of mechanical hyperalgesia. In the masseter muscle, direct application of NMDA induced a time-dependent increase in mechanical sensitivity, which was significantly blocked when the muscle was pretreated with a specific TRPV1 antagonist, AMG9810. The NR1 subunit of the NMDA receptor and TRPV1 were coexpressed in 32% of masseter afferents in trigeminal ganglia (TG). Furthermore, NR1 and NR2B formed protein-protein complexes with TRPV1 in TG as demonstrated by coimmunoprecipitation experiments. Calcium imaging analyses further corroborated that NMDA and TRPV1 receptors functionally interact. In TG culture, application of NMDA resulted in phosphorylation of serine, but not threonine or tyrosine, residues of TRPV1 in a time course similar to that of the development of NMDA-induced mechanical hyperalgesia. The NMDA-induced phosphorylation was significantly attenuated by CaMKII and PKC inhibitors, but not by a PKA inhibitor. Consistent with the biochemical data, the NMDA-induced mechanical hyperalgesia was also effectively blocked when the muscle was pretreated with a CaMKII or PKC inhibitor. Thus, NMDA receptors and TRPV1 functionally interact via CaMKII and PKC signaling cascades and contribute to mechanical hyperalgesia. These data offer novel mechanisms by which 2 ligand-gated channels in sensory neurons interact and reinforce the notion that TRPV1 functions as a signal integrator under pathological conditions. PMID:22609428

Lee, Jongseok; Saloman, Jami L; Weiland, Gustave; Auh, Q-Schick; Chung, Man-Kyo; Ro, Jin Y

2012-05-19

106

Functional interactions between NMDA receptors and TRPV1 in trigeminal sensory neurons mediate mechanical hyperalgesia in the rat masseter muscle  

PubMed Central

NMDA and TRPV1 receptors that are expressed in sensory neurons have been independently demonstrated to play important roles in peripheral pain mechanisms. In the present study, we investigated whether the two receptor-channel systems form a functional complex that provides the basis for the development of mechanical hyperalgesia. In the masseter muscle, direct application of NMDA induced a time dependent increase in mechanical sensitivity, which was significantly blocked when the muscle was pretreated with a specific TRPV1 antagonist, AMG9810. The NR1 subunit of the NMDA receptor and TRPV1 were co-expressed in 32% of masseter afferents in trigeminal ganglia (TG). Furthermore, NR1 and NR2B formed protein-protein complexes with TRPV1 in TG as demonstrated by co-immunoprecipitation experiments. Calcium imaging analyses further corroborated that NMDA and TRPV1 receptors functionally interact. In TG culture, application of NMDA resulted in phosphorylation of serine, but not threonine or tyrosine, residues of TRPV1 in a time course similar to that of the development of NMDA-induced mechanical hyperalgesia. The NMDA-induced phosphorylation was significantly attenuated by CaMKII and PKC inhibitors, but not by a PKA inhibitor. Consistent with the biochemical data, the NMDA-induced mechanical hyperalgesia was also effectively blocked when the muscle was pretreated with a CaMKII or PKC inhibitor. Thus, NMDA receptors and TRPV1 functionally interact via CaMKII and PKC signaling cascades and contribute to mechanical hyperalgesia. These data offer novel mechanisms by which two ligand-gated channels in sensory neurons interact and reinforce the notion that TRPV1 functions as a “signal integrator” under pathological conditions.

Lee, Jongseok; Saloman, Jami L.; Weiland, Gustave; Auh, Q-Schick; Chung, Man-Kyo; Ro, Jin Y.

2012-01-01

107

Activation of TRPV1 prevents OxLDL-induced lipid accumulation and TNF-?-induced inflammation in macrophages: role of liver X receptor ?.  

PubMed

The transient receptor potential vanilloid type 1 (TRPV1) is crucial in the pathogenesis of atherosclerosis; yet its role and underlying mechanism in the formation of macrophage foam cells remain unclear. Here, we show increased TRPV1 expression in the area of foamy macrophages in atherosclerotic aortas of apolipoprotein E-deficient mice. Exposure of mouse bone-marrow-derived macrophages to oxidized low-density lipoprotein (oxLDL) upregulated the expression of TRPV1. In addition, oxLDL activated TRPV1 and elicited calcium (Ca(2+)) influx, which were abrogated by the pharmacological TRPV1 antagonist capsazepine. Furthermore, oxLDL-induced lipid accumulation in macrophages was ameliorated by TRPV1 agonists but exacerbated by TRPV1 antagonist. Treatment with TRPV1 agonists did not affect the internalization of oxLDL but promoted cholesterol efflux by upregulating the efflux ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Moreover, the upregulation of ABC transporters was mainly through liver X receptor ?-(LXR?-) dependent regulation of transcription. Moreover, the TNF-?-induced inflammatory response was alleviated by TRPV1 agonists but aggravated by the TRPV1 antagonist and LXR ? siRNA in macrophages. Our data suggest that LXR ? plays a pivotal role in TRPV1-activation-conferred protection against oxLDL-induced lipid accumulation and TNF-?-induced inflammation in macrophages. PMID:23878415

Zhao, Jin-Feng; Ching, Li-Chieh; Kou, Yu Ru; Lin, Shing-Jong; Wei, Jeng; Shyue, Song-Kun; Lee, Tzong-Shyuan

2013-06-26

108

Interactions between CB1 receptors and TRPV1 channels mediated by 12-HPETE are cytotoxic to mesencephalic dopaminergic neurons  

PubMed Central

Background and purposes: We recently proposed the existence of neurotoxic interactions between the cannabinoid type 1 (CB1) receptor and transient receptor potential vanilloid 1 (TRPV1) channels in rat mesencephalic cultures. This study seeks evidence for the mediator(s) and mechanisms underlying the neurotoxic interactions between CB1 receptors and TRPV1 in vitro and in vivo. Experimental approach: The mediator(s) and mechanism(s) for the interactions between CB1 receptors and TRPV1 were evaluated by cell viability assays, immunocytochemistry, Fura-2 calcium imaging, mitochondrial morphology assay, ELISA and Western blot assay in vitro in neuron-enriched mesencephalic cultures. Injections into the substantia nigra and subsequent cell counts were also used to confirm these interactions in vivo. Key results: The neurotoxic interactions were mediated by 12(S)-hydroperoxyeicosatetraenoic acid (12(S)-HPETE), an endogenous TRPV1 agonist. CB1 receptor agonists (HU210 and WIN55,212-2) increased the level of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a downstream metabolite of 12(S)-HPETE, which stimulates TRPV1-mediated death of mesencephalic neurons, both in vitro and in vivo. The neurotoxicity was mediated by increased intracellular Ca2+ concentration ([Ca2+]i) through TRPV1, consequently leading to mitochondrial damage and was attenuated by baicalein, a 12-lipoxygenase inhibitor. Conclusion and implications: Activation of CB1 receptors in rat mesencephalic neurons was associated with biosynthesis of 12(S)-HPETE, which in turn stimulated TRPV1 activity, leading to increased [Ca2+]i, mitochondrial damage and neuronal death.

Kim, S R; Bok, E; Chung, Y C; Chung, E S; Jin, B K

2008-01-01

109

Transient Receptor Potential Vanilloid-1 (TRPV1) Is a Mediator of Lung Toxicity for Coal Fly Ash Particulate Material  

PubMed Central

Environmental particulate matter (PM) pollutants adversely affect human health, but the molecular basis is poorly understood. The ion channel transient receptor potential vanilloid-1 (TRPV1) has been implicated as a sensor for environmental PM and a mediator of adverse events in the respiratory tract. The objectives of this study were to determine whether TRPV1 can distinguish chemically and physically unique PM that represents important sources of air pollution; to elucidate the molecular basis of TRPV1 activation by PM; and to ascertain the contributions of TRPV1 to human lung cell and mouse lung tissue responses exposed to an insoluble PM agonist, coal fly ash (CFA1). The major findings of this study are that TRPV1 is activated by some, but not all of the prototype PM materials evaluated, with rank-ordered responses of CFA1 > diesel exhaust PM > crystalline silica; TRP melastatin-8 is also robustly activated by CFA1, whereas other TRP channels expressed by airway sensory neurons and lung epithelial cells that may also be activated by CFA1, including TRPs ankyrin 1 (A1), canonical 4? (C4?), M2, V2, V3, and V4, were either slightly (TRPA1) or not activated by CFA1; activation of TRPV1 by CFA1 occurs via cell surface interactions between the solid components of CFA1 and specific amino acid residues of TRPV1 that are localized in the putative pore-loop region; and activation of TRPV1 by CFA1 is not exclusive in mouse lungs but represents a pathway by which CFA1 affects the expression of selected genes in lung epithelial cells and airway tissue.

Deering-Rice, Cassandra E.; Johansen, Mark E.; Roberts, Jessica K.; Thomas, Karen C.; Romero, Erin G.; Lee, Jeewoo; Yost, Garold S.; Veranth, John M.

2012-01-01

110

AKAP150 mediates TRPV1 sensitivity to phosphatidylinositol-4, 5-bisphosphate  

PubMed Central

A-kinase anchoring protein 150 (AKAP150) is a scaffolding protein that controls protein kinase A- and C-mediated phosphorylation of the transient receptor potential family V type 1 (TRPV1), dictating receptor response to nociceptive stimuli. The phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) anchors AKAP150 to the plasma membrane in naďve conditions, and also affects TRPV1 activity. In the present study, we sought to determine whether the effects of PIP2 on TRPV1 are mediated through AKAP150. In trigeminal neurons and CHO cells, the manipulation of cellular PIP2 led to significant changes in the association of AKAP150 and TRPV1. Following PIP2 degradation, increased TRPV1:AKAP150 co-immunoprecipitation was observed, resulting in increased receptor response to capsaicin treatment. Phospholipase C activation in neurons isolated from AKAP150?/? animals indicated that PIP2 -mediated inhibition of TRPV1 in the whole cell environment requires expression of the scaffolding protein. Furthermore, the addition of PIP2 to neurons isolated from AKAP150 wild-type mice reduced PKA-sensitization of TRPV1 compared to isolated neurons from AKAP150?/? mice. These findings suggest that PIP2 degradation increases AKAP150 association with TRPV1 in the whole cell environment, leading to sensitization of the receptor to nociceptive stimuli.

Jeske, Nathaniel A.; Por, Elaine D.; Belugin, Sergei; Chaudhury, Sraboni; Berg, Kelly A.; Akopian, Armen N.; Henry, Michael A.; Gomez, Ruben

2011-01-01

111

A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde  

Microsoft Academic Search

The discovery of transient receptor potential (TRP) receptors has advanced understanding of temperature sensation, and pre-clinical studies have identified TRP as major novel analgesic targets in inflammatory and neuropathic pain states. We systematically investigated the sensory effects and interactions of TRP agonists capsaicin (TRPV1), menthol (TRPM8) and cinnamaldehyde (TRPA1) applied topically to the skin in 14 healthy human participants. Capsaicin

K. Roberts; R. Shenoy; P. Anand

2011-01-01

112

Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones  

PubMed Central

Protease-activated receptors (PAR1-4) are activated by proteases released by cell damage or blood clotting, and are known to be involved in promoting pain and hyperalgesia. Previous studies have shown that PAR2 receptors enhance activation of TRPV1 but the role of other PARs is less clear. In this paper we investigate the expression and function of the PAR1, 3 and 4 thrombin-activated receptors in sensory neurones. Immunocytochemistry and in situ hybridization show that PAR1 and PAR4 are expressed in 10 - 15% of neurons, distributed across all size classes. Thrombin or a specific PAR1 or PAR4 activating peptide (PAR1/4-AP) caused functional effects characteristic of activation of the PLC?/PKC pathway: intracellular calcium release, sensitisation of TRPV1, and translocation of the epsilon isoform of PKC (PKC?) to the neuronal cell membrane. Sensitisation of TRPV1 was significantly reduced by PKC inhibitors. Neurons responding to thrombin or PAR1-AP were either small nociceptive neurones of the peptidergic subclass, or larger neurones which expressed markers for myelinated fibres. Sequential application of PAR1-AP and PAR4-AP showed that PAR4 is expressed in a subset of the PAR1-expressing neurons. Calcium responses to PAR2-AP were by contrast seen in a distinct population of small IB4+ nociceptive neurones. PAR3 appears to be non-functional in sensory neurones. In a skin-nerve preparation the release of the neuropeptide CGRP by heat was potentiated by PAR1-AP. Culture with nerve growth factor (NGF) increased the proportion of thrombin-responsive neurons in the IB4- population, while glial-derived neurotropic factor (GDNF) and neurturin upregulated the proportion of thrombin-responsive neurons in the IB4+ population. We conclude that PAR1 and PAR4 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity.

2010-01-01

113

Complex regulation of TRPV1 and related thermo-TRPs: implications for therapeutic intervention.  

PubMed

The capsaicin receptor TRPV1 (Transient Receptor Potential, Vanilloid family member 1), the founding member of the heat-sensitive TRP ("thermo-TRP") channel family, plays a pivotal role in pain transduction. There is mounting evidence that TRPV1 regulation is complex and is manifest at many levels, from gene expression through post-translational modification and formation of receptor heteromers to subcellular compartmentalization and association with regulatory proteins. These mechanisms are believed to be involved both in disease-related changes in TRPV1 expression, and the long-lasting refractory state, referred to as "desensitization", that follows TRPV1 agonist treatment. The signaling cascades that regulate TRPV1 and related thermo-TRP channels are only beginning to be understood. Here we review our current knowledge in this rapidly changing field. We propose that the complex regulation of TRPV1 may be exploited for therapeutic purposes, with the ultimate goal being the development of novel, innovative agents that target TRPV1 in diseased, but not healthy, tissues. Such compounds are expected to be devoid of the side-effects (e.g. hyperthermia and impaired noxious heat sensation) that plague the clinical use of existing TRPV1 antagonists. PMID:21290313

Planells-Cases, Rosa; Valente, Pierluigi; Ferrer-Montiel, Antonio; Qin, Feng; Szallasi, Arpad

2011-01-01

114

Role of TRPV1 receptors on panic-like behaviors mediated by the dorsolateral periaqueductal gray in rats.  

PubMed

The transient receptors potential vanilloid type 1 channels (TRPV1) are expressed in several brain regions related to defensive behaviors, including the dorsolateral periaqueductal gray (dlPAG). The endocannabinoid anandamide, in addition to its agonist activity at cannabinoid type 1 (CB1), is also proposed as an endogenous agonist of these receptors, through which it could facilitate anxiety-like responses. The aim of this work was to test the hypothesis that TRPV1 in the dlPAG of rats would mediate panic-like responses in two models, namely the escape responses induced by chemical stimulation of this structure or by exposure to the elevated T-Maze (ETM). Antagonism of TRPV1 with capsazepine injected into the dlPAG reduced the defense response induced by local NMDA-injection, suggesting an anti-aversive effect. In the ETM, capsazepine inhibited escape response, suggesting a panicolytic-like effect. Interestingly, this effect was prevented by a CB1 antagonist (AM251). The present study showed that antagonism of TRPV1 in the dlPAG induces panicolytic-like effects, which can be prevented by a CB1 antagonist. Therefore, these antiaversive effects of TRPV1 blockade may ultimately occur due to a predominant action of anandamide through CB1 receptors. PMID:23474373

Almeida-Santos, A F; Moreira, F A; Guimarăes, F S; Aguiar, D C

2013-03-05

115

Endocannabinoid-binding CB1 and TRPV1 receptors as modulators of sperm capacitation  

PubMed Central

Mammalian spermatozoa reach the ability to fertilize only after they complete a complex series of physical-chemical modification, the capacitation. Recently, the endocannabinoid-binding type-1cannabinoid receptor (CB1) and transient receptor potential vanilloid 1 (TRPV1) channel have been proposed to play a key role in the control of capacitation. In particular CB1, acting via a Gi protein/cAMP/PKA pathway, maintains low cAMP levels in early stages of post ejaculatory life of male gametes. By this way it promotes the maintenance of membrane stability, thus avoiding the premature fusion of plasma membrane (PM) and outer acrosome membrane (OAM), which is mandatory for the exocytosis of acrosome content. TRPV1, on the contrary, becomes active during the latest stages of capacitation, and allows the rapid increase in intracellular calcium concentration that leads to the removal of the F-actin network interposed between PM and OAM, leading to their fusion and, ultimately, to the acrosome reaction.

Palestini, Paola; Chiarini, Marco; Maccarrone, Mauro; Mattioli, Mauro; Barboni, Barbara

2012-01-01

116

Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel.  

PubMed

Transient receptor potential (TRP) vanilloid 1 (TRPV1) is a molecular pain receptor belonging to the TRP superfamily of nonselective cation channels. As a polymodal receptor, TRPV1 responds to heat and a wide range of chemical stimuli. The influx of calcium after channel activation serves as a negative feedback mechanism leading to TRPV1 desensitization. The cellular calcium sensor calmodulin (CaM) likely participates in the desensitization of TRPV1. Two CaM-binding sites are identified in TRPV1: the N-terminal ankyrin repeat domain (ARD) and a short distal C-terminal (CT) segment. Here, we present the crystal structure of calcium-bound CaM (Ca(2+)-CaM) in complex with the TRPV1-CT segment, determined to 1.95-Ĺ resolution. The two lobes of Ca(2+)-CaM wrap around a helical TRPV1-CT segment in an antiparallel orientation, and two hydrophobic anchors, W787 and L796, contact the C-lobe and N-lobe of Ca(2+)-CaM, respectively. This structure is similar to canonical Ca(2+)-CaM-peptide complexes, although TRPV1 contains no classical CaM recognition sequence motif. Using structural and mutational studies, we established the TRPV1 C terminus as a high affinity Ca(2+)-CaM-binding site in both the isolated TRPV1 C terminus and in full-length TRPV1. Although a ternary complex of CaM, TRPV1-ARD, and TRPV1-CT had previously been postulated, we found no biochemical evidence of such a complex. In electrophysiology studies, mutation of the Ca(2+)-CaM-binding site on TRPV1-ARD abolished desensitization in response to repeated application of capsaicin, whereas mutation of the Ca(2+)-CaM-binding site in TRPV1-CT led to a more subtle phenotype of slowed and reduced TRPV1 desensitization. In summary, our results show that the TRPV1-ARD is an important mediator of TRPV1 desensitization, whereas TRPV1-CT has higher affinity for CaM and is likely involved in separate regulatory mechanisms. PMID:23109716

Lau, Sze-Yi; Procko, Erik; Gaudet, Rachelle

2012-11-01

117

Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism.  

PubMed

Agastache mexicana is a plant that has long been used in large demands in Mexican folk medicine to treat anxiety, insomnia and pain, among others affections. Chromatographic technique was used to identify ursolic acid (UA), 130.7mg/g and 20.3mg/g, as an antinociceptive active compound identified in ethyl acetate and methanol extracts of A. mexicana aerial parts, respectively. Temporal course curves of the antinociceptive response demonstrated a dose-dependent and significant activity of UA (1 to 100mg/kg, i.p.) with an ED50=2mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100mg/kg, i.p.), a non-steroidal anti-inflammatory drug, with an ED50=11.56mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium-flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor. Finally, an ED50=44mg/kg was calculated in the neurogenic and inflammatory nociception induced in the formalin test in rats. The antinociceptive response of UA in the formalin test was not modified in presence of naloxone, flumazenil or l-arginine. Nevertheless, it was reverted in presence of 1-H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, an inhibitor of soluble guanylyl cyclase) and increased in presence of N(G)-l-nitro-arginine methyl ester (l-NAME, inhibitor of nitric oxide synthase), theophylline (inhibitor of phosphodiesterase) and WAY100635 (an antagonist of 5-HT1A receptors). Current results provide evidence that the antinociceptive response of A. mexicana depends in part on the presence of UA. Moreover, this triterpene may exerts its antinociceptive effect mediated by the presence of cGMP and an additive synergism with 5HT1A receptors, but also an antagonistic activity towards TRPV1 receptors may be involved. PMID:23932918

Verano, Jazmín; González-Trujano, Ma Eva; Déciga-Campos, Myrna; Ventura-Martínez, Rosa; Pellicer, Francisco

2013-08-07

118

TRPV1 and the gut: from a tasty receptor for a painful vanilloid to a key player in hyperalgesia  

Microsoft Academic Search

Capsaicin, the pungent ingredient in red pepper, has been used since ancient times as a spice, despite the burning sensation associated with its intake. More than 50 years ago, Nikolaus Jancsó discovered that capsaicin can selectively stimulate nociceptive primary afferent neurons. The ensuing research established that the neuropharmacological properties of capsaicin are due to its activation of the transient receptor

Peter Holzer

2004-01-01

119

Comparison of the effects of pelargonic acid vanillylamide and capsaicin on human vanilloid receptors.  

PubMed

Pelargonic acid vanillylamide is like capsaicin a natural capsaicinoid from chili peppers and commonly used in food additives to create a hot sensation, even in self-defense pepper sprays and as an alternative to capsaicin in medical products for topical treatment of pain. Although the chemical structures of both compounds are similar, preclinical data suggest that capsaicin is the more potent compound. We therefore performed voltage-clamp recordings using cells transfected with the human vanilloid receptor TRPV1 in order to assess the responses of pelargonic acid vanillylamide and capsaicin at the receptor level. We provide evidence that at the molecular target TRPV1, the concentration-response curves, kinetics of current activation, as well as inhibition by the competitive antagonist capsazepine were not significantly different between the two capsaicinoids. We suggest that the different effects of the two capsaicinoids observed in previous studies may rather be due to different physicochemical or pharmacokinetic properties than to different pharmacological profiles at the receptor level. PMID:22961689

Weiser, Thomas; Roufogalis, Basil; Chrubasik, Sigrun

2012-09-07

120

Receptor Activity and Conformational Analysis of 5'-Halogenated Resiniferatoxin Analogues as TRPV1 Ligands  

PubMed Central

A series of 5’-halogenated resiniferatoxin analogues have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with Ki(ant) = 2.81 nM, which was thus 4.5-fold more potent than 5’-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene.

Lim, Kwang Su; Kang, Dong Wook; Kim, Yong Soo; Kim, Myeong Seop; Park, Seul-Gi; Choi, Sun; Pearce, Larry V.; Blumberg, Peter M.; Lee, Jeewoo

2012-01-01

121

Receptor changes in brain tissue of rats treated as neonates with capsaicin.  

PubMed

Capsaicin, the hot chemical in chillies, administered to neonatal rats, causes destruction of polymodal nociceptive primary afferent neurons by acting on TRPV1 receptors causing intrinsic somatosensory deprivation. Although the effects of neonatal capsaicin treatment in the periphery have been extensively investigated, less is known about the brain networks to which the capsaicin sensory neurons are relayed. In the present study the effect of neonatal capsaicin treatment on brain receptors that have been shown to interact with TRPV1 was examined. Wistar rats were treated on neonatal day 2 with capsaicin and at 15-16 weeks of age, brains were processed to measure levels of muscarinic M(1)/M(2) and M(2)/M(4), serotonin 5HT(2A), cannabinoid CB(1), dopamine D(1), D(2) receptors and dopamine transporter. Overall increases in levels of muscarinic M(1)/M(4) (F=8.219, df=1, p=0.005), muscarinic M(2)/M(4) (F=99.759, df=1, p<0.0001), serotonin 5HT(2A) (F=28.892, df=1, p<0.0001), dopamine D(1) (F=8.726, df=1, p=0.008) and cannabinoid CB(1) (F=25.084, df=1, p<0.0001) receptors were found in the brains of capsaicin-treated rats, although significant regional changes occurred only in muscarinic M(2)/M(4) and serotonin 5HT(2A) receptors. The results of the present study suggest that neonatal intrinsic somatosensory deprivation may have a significant impact on substrates at the central nervous system that manifest as changes in central cholinergic, monaminergic and cannabinoid systems in the adult animal. PMID:20123014

Zavitsanou, Katerina; Dalton, Victoria S; Wang, Hongqin; Newson, Penny; Chahl, Loris A

2010-02-01

122

Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats.  

PubMed

A possible mechanism of oesophageal hypersensitivity is the acid-induced activation of transient receptor potential vanilloid receptor 1 (TRPV1) in the primary sensory neurons. We investigated TRPV1 expression and its colocalization with substance P (SP) and isolectin B4 (IB4)-positive cells in the thoracic dorsal root ganglia (DRGs) and nodose ganglia (NGs) of rats with reflux-induced oesophagitis (RO). RO was developed by fundus ligation and partial obstruction of the pylorus of Sprague-Dawley rats. Four groups of rats were used; fundus ligated acute (RO 48 h), chronic 7 days (RO 7D), RO 7D + omeprazole (7D + Omz, 40 mg kg(-1), i.p.) and sham-operated controls. Immunohistochemical analysis of TRPV1, SP and IB4 expression were carried out in spinal cord (SC), DRGs and NGs. RO rats exhibited significant inflammation and increase in TRPV1-ir and SP-ir expressions in the SC, DRGs and NGs. The maximum colocalization of TRPV1 and SP was observed in RO 7D rats, but Omz prevented inflammation and over expression of TRPV1 and SP. TRPV1-ir significantly increased in IB4-positive cells in DRGs and SC, but not in the NGs. Results document that acid-induced oesophagitis increases TRPV1 expression in both SP- and IB4-positive sensory neurons. The over expression of TRPV1 may contribute to oesophageal hypersensitivity observed in gastro-oesophageal reflux disease (GORD). PMID:17640184

Banerjee, B; Medda, B K; Lazarova, Z; Bansal, N; Shaker, R; Sengupta, J N

2007-08-01

123

Severe ulceration with impaired induction of growth factors and cytokines in keratinocytes after trichloroacetic acid application on TRPV1-deficient mice.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is a highly polymodal TRP channel activated by various stimuli, including capsaicin, heat and acids. TRPV1 expression can be detected widely but is highest in sensory neurons and its activation alerts the body to noxious signals via neurogenic pain. Although TRPV1 is reportedly localized in the epidermis, it remains unclear how TRPV1 is involved in the chemical peeling processes with cytotoxic acids. Therefore, in this study, the role of TRPV1 on the effects of trichloroacetic acid (TCA) peeling was assessed using TRPV1-deficient mice. Following the confirmation of TRPV1 expression in murine keratinocytes with reverse transcription-polymerase chain reaction and immunohistochemistry, the effects of TCA on TRPV1-deficient mouse skin were compared with those on wild-type mouse skin. Our results indicated that TRPV1 expression was not required for TCA-induced DNA damage, as shown by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, but was indispensable for the TCA-induced production of distinct growth factors and cytokines by keratinocytes. Ulceration after TCA peeling was actually more severe in the absence of TRPV1, suggesting that the TRPV1-mediated epidermal production of growth factors and cytokines affected the damaging and healing processes of TCA-peeled skin to induce rejuvenation. PMID:22858856

Li, Hong-jin; Kanazawa, Nobuo; Kimura, Ayako; Kaminaka, Chikako; Yonei, Nozomi; Yamamoto, Yuki; Furukawa, Fukumi

124

Anionic linear aliphatic surfactants activate TRPV1: a possible endpoint for estimation of detergent induced eye nociception?  

PubMed

The transient receptor potential vanilloid type 1 (TRPV1) has been reported as one of the key components in the pain pathway. Activation of the receptor causes a Ca(2+) influx in sensory C-fibres with secondary effects leading to neurogenic inflammation in the surrounding tissue. We have earlier reported specific activation of TRPV1 by surfactant-containing hygiene products. We have continued this project by investigating activation of the TRPV1 by shampoo and soap ingredients in low concentrations measured as intracellular Ca(2+) influxes in stably TRPV1-expressing neuroblastoma SH-SY5Y cells. As a TRPV1 specific control, the TRPV1 antagonist capsazepine was used. The response was quantified as the product induced Ca(2+) influx during 2 min in relation to the maximum response induced by the TRPV1 agonist capsaicin. The results show that anionic alkyl linear surfactant ingredients such as sodium lauryl sulphate, sodium laureth sulphate, ammonium lauryl sulphate, sodium C12-15 pareth sulphate and N-lauroylsarcosine concentration-dependently induced Ca(2+) influx that could be addressed to TRPV1. The cationic surfactants benzalkonium chloride and cetylpyridinium chloride induced a Ca(2+) influx that was not TRPV1 mediated as well as the zwitterionic surfactant cocamidopropyl betaine, the non-linear anionic surfactant sodium deoxycholate and the non-ionic surfactant Triton-X. These results reveal a new mechanistic pathway for surfactant-induced nociception. PMID:19540328

Lindegren, H; Mogren, H; El Andaloussi-Lilja, J; Lundqvist, J; Forsby, A

2009-06-18

125

TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids.  

PubMed

The capsaicin receptor, TRPV1, is regulated by phosphatidylinositol-4,5-bisphosphate (PIP(2)), although the precise nature of this effect (i.e., positive or negative) remains controversial. Here, we reconstitute purified TRPV1 into artificial liposomes, where it is gated robustly by capsaicin, protons, spider toxins, and, notably, heat, demonstrating intrinsic sensitivity of the channel to both chemical and thermal stimuli. TRPV1 is fully functional in the absence of phosphoinositides, arguing against their proposed obligatory role in channel activation. Rather, introduction of various phosphoinositides, including PIP(2), PI4P, and phosphatidylinositol, inhibits TRPV1, supporting a model whereby phosphoinositide turnover contributes to thermal hyperalgesia by disinhibiting the channel. Using an orthogonal chemical strategy, we show that association of the TRPV1 C terminus with the bilayer modulates channel gating, consistent with phylogenetic data implicating this domain as a key regulatory site for tuning stimulus sensitivity. Beyond TRPV1, these findings are relevant to understanding how membrane lipids modulate other "receptor-operated" TRP channels. PMID:23439120

Cao, Erhu; Cordero-Morales, Julio F; Liu, Beiying; Qin, Feng; Julius, David

2013-02-20

126

[Interaction of sea amemone Heteractis crispa Kunitz type polypeptides with pain vanilloid receptor TRPV1: in silico investigation].  

PubMed

Using methods of molecular biology we defined the structures of the 31 sea anemone Heteractis crispa genes encoding polypeptides which are structurally homologous to the Kunitz proteinase inhibitor family. Identified amino acid sequences have point residue substitutions, high degree of homology with sequences of known H. crispa Kunitz family members, and represent a combinatorial library of polypeptides. We generated their three-dimensional structures by homologous modeling methods. Analysis of their molecular electrostatic potential enabled us to divide given polypeptides into three clusters. One of them includes polypeptides APHC1, APHC2 and APHC3, which were earlier shown to possess a unique property of inhibiting of the pain vanilloid receptor TRPV1 in vitro and providing the analgesic effects in vivo in addition to their trypsin inhibitory activity. Molecular docking made possible establishing the spatial structure of the complexes, the nature of the polypeptides binding with TRPV1, as well as functionally important structural elements involved in the complex formation. Structural models have enabled us to propose a hypothesis contributing to understanding the APHC1-3 impact mechanism for the pain signals transduction by TRPV1: apparently, there is an increase of the receptor relaxation time resulted in binding of its two chains with the polypeptide molecule, which disrupt the functioning of the TRPV1 and leads to partial inhibition of signal transduction in electrophysiological experiments. PMID:22792722

Zelepuga, E A; Tabakmakher, V M; Chausova, V E; monastyrnaia, M M; Isaeva, M P; Kozlovskaia, É P

127

PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150  

PubMed Central

Activation of protein kinases and phosphatases at the plasma membrane often initiates agonist-dependent signalling events. In sensory neurons, AKAP150 (A-kinase-anchoring protein 150) orientates PKA (protein kinase A), PKC (protein kinase C) and the Ca2+/calmodulin-dependent PP2B (protein phosphatase 2B, also known as calcineurin) towards membrane-associated substrates. Recent evidence indicates that AKAP150-anchored PKA and PKC phosphorylate and sensitize the TRPV1 (transient receptor potential subfamily V type 1 channel, also known as the capsaicin receptor). In the present study, we explore the hypothesis that an AKAP150-associated pool of PP2B catalyses the dephosphorylation and desensitization of TRPV1. Biochemical, electrophysiological and cell-based experiments indicate that PP2B associates with AKAP150 and TRPV1 in cultured TG (trigeminal ganglia) neurons. Gene silencing of AKAP150 reduces basal phosphorylation of TRPV1. However, functional studies in neurons isolated from AKAP150?/? mice indicate that the anchoring protein is not required for pharmacological desensitization of TRPV1. Behavioural analysis of AKAP150?/? mice further support this notion, demonstrating that agonist-stimulated desensitization of TRPV1 is sensitive to PP2B inhibition and does not rely on AKAP150. These findings allow us to conclude that pharmacological desensitization of TRPV1 by PP2B may involve additional regulatory components.

Por, Elaine D.; Samelson, Bret K.; Belugin, Sergei; Akopian, Armen N.; Scott, John D.; Jeske, Nathaniel A.

2011-01-01

128

PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150.  

PubMed

Activation of protein kinases and phosphatases at the plasma membrane often initiates agonist-dependent signalling events. In sensory neurons, AKAP150 (A-kinase-anchoring protein 150) orientates PKA (protein kinase A), PKC (protein kinase C) and the Ca2+/calmodulin-dependent PP2B (protein phosphatase 2B, also known as calcineurin) towards membrane-associated substrates. Recent evidence indicates that AKAP150-anchored PKA and PKC phosphorylate and sensitize the TRPV1 (transient receptor potential subfamily V type 1 channel, also known as the capsaicin receptor). In the present study, we explore the hypothesis that an AKAP150-associated pool of PP2B catalyses the dephosphorylation and desensitization of TRPV1. Biochemical, electrophysiological and cell-based experiments indicate that PP2B associates with AKAP150 and TRPV1 in cultured TG (trigeminal ganglia) neurons. Gene silencing of AKAP150 reduces basal phosphorylation of TRPV1. However, functional studies in neurons isolated from AKAP150-/- mice indicate that the anchoring protein is not required for pharmacological desensitization of TRPV1. Behavioural analysis of AKAP150-/- mice further support this notion, demonstrating that agonist-stimulated desensitization of TRPV1 is sensitive to PP2B inhibition and does not rely on AKAP150. These findings allow us to conclude that pharmacological desensitization of TRPV1 by PP2B may involve additional regulatory components. PMID:20883208

Por, Elaine D; Samelson, Bret K; Belugin, Sergei; Akopian, Armen N; Scott, John D; Jeske, Nathaniel A

2010-12-15

129

Activation of NMDA receptors leads to phosphorylation of TRPV1 S800 by protein kinase C and A-Kinase anchoring protein 150 in rat trigeminal ganglia  

PubMed Central

A-Kinase anchoring protein 150 (AKAP150) is required for the phosphorylation of transient receptor potential cation channel subfamily V member 1 (TRPV1) by PKA or PKC in sensory neurons and, hence, affects TRPV1-dependent hyperalgesia under pathological conditions. Recently, we showed that the activation of N-methyl-d-aspartate (NMDA) receptors sensitizes TRPV1 by enhancing serine phosphorylation through PKC in trigeminal nociceptors. In this study, we extended this observation by investigating whether AKAP150 mediates NMDA-induced phosphorylation of TRPV1 via PKC in native sensory neurons in the rat. By adopting a phospho-specific antibody combined with a surface biotinylation assay, we first assessed NMDA-induced changes in the phosphorylation level of serine 800 residues (S800) in TRPV1 delimited to cell surface membrane in cultured trigeminal ganglia (TG). The biotinylation assay yielded that the application of NMDA significantly increased the phosphorylation of S800 (p-S800) of TRPV1 at time points correlating with the development of NMDA-induced mechanical hyperalgesia [10]. We then obtained a siRNA sequence against AKAP150 that dose-dependently down-regulated the AKAP150 protein. Pretreatment of TG culture with the siRNA, but not mismatch sequences, prevented the NMDA-induced phosphorylation of serine residues of total TRPV1 as well as S800 of membrane bound TRPV1. We confirmed that AKAP150 coimmunoprecipitated with TRPV1 and demonstrated that it also co-immunoprecipitated with NMDA receptor subunits (NR1 and NR2B) in TG. These data offer novel information that the activation of NMDA-induced TRPV1 sensitization involves p-S800 of TRPV1 in cell surface membrane in native sensory neurons and that AKAP150 is required for NMDA-and PKC-mediated phosphorylation of TRPV1 S800. Therefore, we propose that the NMDA receptor, AKAP150, and TRPV1 forms a signaling complex that underlies the sensitization of trigeminal nociceptors by modulating phosphorylation of specific TRPV1 residues.

Lee, Jongseok; Chung, Man-Kyo; Ro, Jin Y

2012-01-01

130

Structure-Activity Relationship of Capsaicin Analogs and Transient Receptor Potential Vanilloid 1-Mediated Human Lung Epithelial Cell ToxicityS?  

PubMed Central

Activation of intracellular transient receptor potential vanilloid-1 (TRPV1) in human lung cells causes endoplasmic reticulum (ER) stress, increased expression of proapoptotic GADD153 (growth arrest- and DNA damage-inducible transcript 3), and cytotoxicity. However, in cells with low TRPV1 expression, cell death is not inhibited by TRPV1 antagonists, despite preventing GADD153 induction. In this study, chemical variants of the capsaicin analog nonivamide were synthesized and used to probe the relationship between TRPV1 receptor binding, ER calcium release, GADD153 expression, and cell death in TRPV1-overexpressing BEAS-2B, normal BEAS-2B, and primary normal human bronchial epithelial lung cells. Modification of the 3-methoxy-4-hydroxybenzylamide vanilloid ring pharmacophore of nonivamide reduced the potency of the analogs and rendered several analogs mildly inhibitory. Correlation analysis of analog-induced calcium flux, GADD153 induction, and cytotoxicity revealed a direct relationship for all three endpoints in all three lung cell types for nonivamide and N-(3,4-dihydroxybenzyl)nonanamide. However, the N-(3,4-dihydroxybenzyl)nonanamide analog also produced cytotoxicity through redox cycling/reactive oxygen species formation, shown by inhibition of cell death by N-acetylcysteine. Molecular modeling of binding interactions between the analogs and TRPV1 agreed with data for reduced potency of the analogs, and only nonivamide was predicted to form a “productive” ligand-receptor complex. This study provides vital information on the molecular interactions of capsaicinoids with TRPV1 and substantiates TRPV1-mediated ER stress as a conserved mechanism of lung cell death by prototypical TRPV1 agonists.

Thomas, Karen C.; Ethirajan, Manivannan; Shahrokh, Kiumars; Sun, Hao; Lee, Jeewoo; Cheatham, Thomas E.; Yost, Garold S.

2011-01-01

131

TRPV1-mediated UCP2 upregulation ameliorates hyperglycemia-induced endothelial dysfunction  

PubMed Central

Background Diabetic cardiovascular complications are characterised by oxidative stress-induced endothelial dysfunction. Uncoupling protein 2 (UCP2) is a regulator of mitochondrial reactive oxygen species (ROS) generation and can antagonise oxidative stress, but approaches that enhance the activity of UCP2 to inhibit ROS are scarce. Our previous studies show that activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin can prevent cardiometabolic disorders. In this study, we conducted experiments in vitro and in vivo to investigate the effect of capsaicin treatment on endothelial UCP2 and oxidative stress. We hypothesised that TRPV1 activation by capsaicin attenuates hyperglycemia-induced endothelial dysfunction through a UCP2-mediated antioxidant effect. Methods TRPV1-/-, UCP2 -/- and db/db mice, as well as matched wild type (WT) control mice, were included in this study. Some mice were subjected to dietary capsaicin for 14 weeks. Arteries isolated from mice and endothelial cells were cultured. Endothelial function was examined, and immunohistological and molecular analyses were performed. Results Under high-glucose conditions, TRPV1 expression and protein kinase A (PKA) phosphorylation were found to be decreased in the cultured endothelial cells, and the effects of high-glucose on these molecules were reversed by the administration of capsaicin. Furthermore, high-glucose exposure increased ROS production and reduced nitric oxide (NO) levels both in endothelial cells and in arteries that were evaluated respectively by dihydroethidium (DHE) and DAF-2 DA fluorescence. Capsaicin administration decreased the production of ROS, restored high-glucose-induced endothelial dysfunction through the activation of TRPV1 and acted in a UCP2-dependent manner in vivo. Administration of dietary capsaicin for 14 weeks increased the levels of PKA phosphorylation and UCP2 expression, ameliorated the vascular oxidative stress and increased NO levels observed in diabetic mice. Prolonged dietary administration of capsaicin promoted endothelium-dependent relaxation in diabetic mice. However, the beneficial effect of capsaicin on vasorelaxation was absent in the aortas of UCP2 -/- mice exposed to high-glucose levels. Conclusion TRPV1 activation by capsaicin might protect against hyperglycemia-induced endothelial dysfunction through a mechanism involving the PKA/UCP2 pathway.

2013-01-01

132

Electroacupuncture Stimulation at CV12 Inhibits Gastric Motility via TRPV1 Receptor  

PubMed Central

Gastric dysmotility is one of the major pathophysiological factors in functional gastrointestinal disorders. Acupuncture, as one of the alternative approaches, is efficacious in the treatment of gastrointestinal motility disorders; however, the mechanism underlying its action is unclear. In the present study, we used both capsazepine, a TRPV1 antagonist, and TRPV1 knockout mice. Animals were divided into wild-type group (WT), capsazepine injection group (CZP, 0.5?mg/kg, i.p.), and TRPV1 knockout mice group (TRPV1?/?). Each of these three groups was divided into three subgroups, which were subjected to EA stimulation at acupoint Zhongwan (CV12) at a different intensity (1, 2, or 4?mA). We demonstrated that electroacupuncture at Zhongwan (CV12) markedly inhibited gastric motility at 2 and 4?mA in an intensity-dependent manner in wild-type mice. The inhibitory effect was also observed in capsazepine-injected and TRPV1?/? mice but was no longer intensity dependent, indicating that TRPV1 is partially involved in the electroacupuncture-mediated modulation of gastric motility.

Yu, Zhi; Cao, Xin; Xia, Youbing; Ren, Binbin; Feng, Hong; Wang, Yali; Jiang, Jingfeng; Xu, Bin

2013-01-01

133

Effect of Maillard Reacted Peptides on Human Salt Taste and the Amiloride-Insensitive Salt Taste Receptor (TRPV1t)  

Microsoft Academic Search

Maillard reacted peptides (MRPs) were synthesized by conjugating a peptide fraction (1000-5000 Da) purified from soy protein hydrolyzate with galacturonic acid, glucosamine, xylose, fructose, or glucose. The effect of MRPs was investigated on human salt taste and on the chorda tympani (CT) taste nerve responses to NaCl in Sprague-Dawley rats, wild-type, and transient receptor potential vanilloid 1 (TRPV1) knockout mice.

Tadayoshi Katsumata; Hiroko Nakakuki; Chikara Tokunaga; Noboru Fujii; Makoto Egi; Tam-Hao T. Phan; Shobha Mummalaneni; John A. DeSimone; Vijay Lyall

2008-01-01

134

Short Interfering (si)RNA Against Transient Receptor Potential Vanilloid-1 (TRPV1) Attenuates Cisplatin-Induced Hearing Loss in the Rat  

PubMed Central

Cisplatin, a chemotherapeutic agent of choice for the treatment of solid tumors, produces hearing loss in approximately half a million new cancer patients annually in the United States. The hearing loss is due, in part, to increased generation of reactive oxygen species (ROS) in the cochlea, leading to lipid peroxidation and damage or death of outer hair cells in the organ of Corti. The cochlea expresses the transient receptor potential vanilloid receptor 1 (TRPV1), which are normally expressed on small diameter neurons in the peripheral nervous system and mediate thermal sensitivity, but whose role in the cochlea is unclear. In this study, we show that TRPV1 is co-regulated along with the NADPH oxidase isoform, NOX3, by cisplatin. Induction of these proteins by cisplatin is dependent on ROS generation, since it is reversed by systemic lipoic acid administration. In organ of Corti hair cell cultures (UB/OC-1 cells), cisplatin activates and induces TRPV1 and NOX3, leading to apoptosis of these cells. Inhibition of TRPV1 by capsazepine or ruthenium red reduced the apoptosis, implicating TRPV1 in this process. Treatment of UB/OC-1 cultures with short interfering RNA (siRNA) against either TRPV1 or NOX3 reduced cisplatininduced apoptosis, while round window application of TRPV1 siRNA to rats reduced TRPV1 expression, decreased damage to outer hair cells and reduced cisplatin-induced hearing loss. These data provide a link between NOX3 and TRPV1 in cisplatin-induced hearing loss and suggest that targeting these proteins for knockdown by siRNA could serve as a novel approach in treating cisplatin ototoxicity.

Mukherjea, Debashree; Jajoo, Sarvesh; Whitworth, Craig; Bunch, Jennifer R.; Turner, Jeremy G.; Rybak, Leonard P.; Ramkumar, Vickram

2009-01-01

135

Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins  

Microsoft Academic Search

Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective

Tomoko Moriyama; Tomohiro Higashi; Kazuya Togashi; Tohko Iida; Eri Segi; Yukihiko Sugimoto; Tomoko Tominaga; Shuh Narumiya; Makoto Tominaga

2005-01-01

136

Transient activation of specific neurons in mice by selective expression of the capsaicin receptor  

PubMed Central

The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches.

Guler, Ali D.; Rainwater, Aundrea; Parker, Jones G.; Jones, Graham L.; Argilli, Emanuela; Arenkiel, Benjamin R.; Ehlers, Michael D.; Bonci, Antonello; Zweifel, Larry s.; Palmiter, Richard D.

2013-01-01

137

The hypothermic response to bacterial lipopolysaccharide critically depends on brain CB1, but not CB2 or TRPV1, receptors  

PubMed Central

Abstract Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide (AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22°C, a moderate dose of LPS (25–100 ?g kg?1i.v.) induced a fall in body temperature with a nadir at ?100 min postinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 ?g kg?1i.p.), by systemic TRPV1 antagonism with capsazepine (40 mg kg?1i.p.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kg?1i.p.). However, CB1 receptor antagonism by rimonabant (4.6 mg kg?1i.p.) or SLV319 (15 mg kg?1i.p.) blocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered i.c.v. at a dose (4.6 ?g) that was too low to produce systemic effects. The blockade of LPS hypothermia by i.c.v. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-?. In contrast to rimonabant, the i.c.v. administration of AEA (50 ?g) enhanced LPS hypothermia. Importantly, i.c.v. AEA did not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermoeffector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

Steiner, Alexandre A; Molchanova, Alla Y; Dogan, M Devrim; Patel, Shreya; Petervari, Erika; Balasko, Marta; Wanner, Samuel P; Eales, Justin; Oliveira, Daniela L; Gavva, Narender R; Almeida, M Camila; Szekely, Miklos; Romanovsky, Andrej A

2011-01-01

138

Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse  

PubMed Central

Sensory input from the periphery to the CNS is critically dependent on the strength of synaptic transmission at the first sensory synapse formed between primary afferent dorsal root ganglion (DRG) and superficial dorsal horn (DH) neurons of the spinal cord. Transient receptor potential vanilloid 1 (TRPV1) expressed on a subset of sensory neurons plays an important role in chronic inflammatory thermal nociception. Activation of protein kinase C (PKC) sensitizes TRPV1, which may contribute to the pathophysiology of chronic pain conditions. In this study, we have examined the modulation of TRPV1-mediated enhancement of excitatory synaptic transmission in response to PKC activation. Miniature excitatory postsynaptic currents (mEPSCs) from embryonic rat DRG–DH neuronal cocultures were recorded by patch clamping DH neurons. Capsaicin potently increased the frequency but not the amplitude of mEPSCs in a calcium-dependent manner, suggesting TRPV1-mediated glutamate release from presynaptic terminals of sensory neurons. Continued or repeated applications of capsaicin reduced the frequency of mEPSCs over time. The PKC activator phorbol 12,13-dibutyrate (PDBu) alone increased mEPSC events to a certain extent in a reversible manner but capsaicin further synergistically enhanced the frequency of mEPSCs. The PKC inhibitor bisindolylmaleimide (BIM) abolished PDBu-mediated potentiation of TRPV1-dependent increases in mEPSC frequency, suggesting modulation of TRPV1 by PKC-induced phosphorylation. In addition, at normal body temperatures (?37°C) PKC-mediated enhancement of mEPSC frequency is significantly decreased by a specific TRPV1 antagonist, suggesting a physiological role of TRPV1 at the central terminals. Furthermore, bradykinin (BK) significantly potentiated TRPV1-modulated synaptic responses by activating the PLC-PKC pathway. Our results indicate that TRPV1 activation can modulate excitatory synaptic transmission at the first sensory synapse and its effects can further be augmented by activation of PKC. Increased gain of sensory input by TRPV1-induced enhancement of glutamate release and its potentiation by various inflammatory mediators may contribute to persistent pain conditions. Selective targeting of TRPV1 expressed on the central terminals of sensory neurons may serve as a strategy to alleviate chronic intractable pain conditions.

Sikand, Parul; Premkumar, Louis S

2007-01-01

139

Expression of TRPV1 channels after nerve injury provides an essential delivery tool for neuropathic pain attenuation.  

PubMed

Increased expression of the transient receptor potential vanilloid 1 (TRPV1) channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP)--induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN) transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG) neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect dynamic changes in TRPV1 expression, in various pathological conditions. PMID:22962595

Zakir, Hossain Md; Mostafeezur, Rahman Md; Suzuki, Akiko; Hitomi, Suzuro; Suzuki, Ikuko; Maeda, Takeyasu; Seo, Kenji; Yamada, Yoshiaki; Yamamura, Kensuke; Lev, Shaya; Binshtok, Alexander M; Iwata, Koichi; Kitagawa, Junichi

2012-09-04

140

Vanilloid Receptors in Hearing: Altered Cochlear Sensitivity by Vanilloids and Expression of TRPV1 in the Organ of Corti  

PubMed Central

Capsaicin, the vanilloid that selectively activates vanilloid receptors (VRs) on sensory neurons for noxious perception, has been reported to increase cochlear blood flow (CBF). VR-related receptors have also been found in the inner ear. This study aims to address the question as to whether VRs exist in the organ of Corti and play a role in cochlear physiology. Capsaicin or the more potent VR agonist, resiniferatoxin (RTX), was infused into the scala tympani of guinea pig cochlea, and their effects on cochlear sensitivity were investigated. Capsaicin (20 µM) elevated the threshold of auditory nerve compound action potential and reduced the magnitude of cochlear microphonic and electrically evoked otoacoustic emissions. These effects were reversible and could be blocked by a competitive antagonist, capsazepine. Application of 2 µM RTX resulted in cochlear sensitivity alterations similar to that by capsaicin, which could also be blocked by capsazepine. A desensitization phenomenon was observed in the case of prolonged perfusion with either capsaicin or RTX. Brief increase of CBF by capsaicin was confirmed, and the endocochlear potential was not decreased. Basilar membrane velocity (BM) growth functions near the best frequency and BM tuning were altered by capsaicin. Immunohistochemistry study revealed the presence of vanilloid receptor type 1 of the transient receptor potential channel family in the hair cells and supporting cells of the organ of Corti and the spiral ganglion cells of the cochlea. The results indicate that the main action of capsaicin is on outer hair cells and suggest that VRs in the cochlea play a role in cochlear homeostasis.

Zheng, Jiefu; Dai, Chunfu; Steyger, Peter S.; Kim, Youngki; Vass, Zoltan; Ren, Tianying; Nuttall, Alfred L.

2013-01-01

141

Comparison of the transport of QX-314 through TRPA1, TRPM8, and TRPV1 channels  

PubMed Central

Background It has been demonstrated that N-ethyl-lidocaine (QX-314) can target the transient receptor protein vanilloid 1 (TRPV1) nociceptors when coadministered with capsaicin, resulting in a selective block of the nociceptors. Capsaicin is problematic in therapeutic use because it induces firing of nociceptors. The present study aimed to search for substitutes for capsaicin. We also examined the transportability of QX-314 into nociceptive neurons, through the pores of transient receptor potential ankyrin 1 (TRPA1), transient receptor potential melastatin-8 (TRPM8), and TRPV1. Methods To investigate the effect on TRPA1, injections of a vehicle, allyl isothiocyanate (AITC), QX-314, or AITC/QX-314 were made into the hind paws of rats. The effects of menthol and capsaicin on the opening of TRPM8 and TRPV1 were also examined and compared with the potency of QX-314. To examine inhibition of the antinociceptive effect by capsaicin/ QX-314, capsazepine (50 ?g/mL; 10 ?L) was injected 30 minutes prior to capsaicin/QX-314 (10 ?L) injection. Thermal sensitivity was investigated by the Hargreaves method. 5(6)-carboxyfluorescein (FAM)-conjugated QX-314 was used as a tracer to examine how many and which kind of dorsal root ganglia accumulate this molecule. QX-314-FAM, capsaicin/QX-314-FAM, AITC/QX-314-FAM, and menthol/QX-314-FAM were injected into the paw. Two weeks after injections, dorsal root ganglia were removed and sectioned with a cryostat. Results The capsaicin/QX-314 group induced longer withdrawal-response latency at 60 to 300 minutes after injection than the control. Both menthol only and menthol/QX-314 injections showed analgesia 10 to 60 minutes after injection. No significant difference was seen between the capsazepine/capsaicin/QX-314 group and the vehicle group. The fluorescence in small- and medium-sized neurons was conspicuous in only the dorsal root ganglia injected with capsaicin/ QX-314-FAM. Conclusion These results indicate that TRPA1 and TRPM8 are ineffective in the transport of QX-314 compared with TRPV1.

Nakagawa, Hiroshi; Hiura, Akio

2013-01-01

142

Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy  

PubMed Central

Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system.

Bhaskaran, Muthu D.; Smith, Bret N.

2010-01-01

143

Mechanisms of Prolonged Presynaptic Ca2+ Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons  

PubMed Central

TRPV1-mediated release of neuroactive peptides and neurotransmitters from the peripheral and central terminals of primary sensory neurons can critically contribute to nociceptive processing at the periphery and in the CNS. However, the mechanisms that link TRPV1 activation with Ca2+ signaling at the release sites and neurosecretion are poorly understood. Here we demonstrate that a brief stimulation of the receptor using either capsaicin or the endogenous TRPV1 agonist N-arachidonoyl-dopamine (NADA) induces a prolonged elevation of presynaptic [Ca2+]i and a concomitant enhancement of glutamate release at sensory synapses. Initiation of this response required Ca2+ entry, primarily via TRPV1. The sustained phase of the response was independent of extracellular Ca2+ and was prevented by inhibitors of mitochondrial Ca2+ uptake and release mechanisms. Measurements using a mitochondria-targeted Ca2+ indicator, mtPericam, revealed that TRPV1 activation elicits a long-lasting Ca2+ elevation in presynaptic mitochondria. The concentration of TRPV1 agonist determined the duration of mitochondrial and cytosolic Ca2+ signals in presynaptic boutons and, consequently, the period of enhanced glutamate release and action potential firing by postsynaptic neurons. These data suggest that mitochondria control vanilloid-induced neurotransmission by translating the strength of presynaptic TRPV1 stimulation into duration of the postsynaptic response.

Medvedeva, Yuliya V.; Kim, Man-Su; Usachev, Yuriy M.

2009-01-01

144

Functionally important amino acid residues in the transient receptor potential vanilloid 1 (TRPV1) ion channel - an overview of the current mutational data  

PubMed Central

This review aims to create an overview of the currently available results of site-directed mutagenesis studies on transient receptor potential vanilloid type 1 (TRPV1) receptor. Systematization of the vast number of data on the functionally important amino acid mutations of TRPV1 may provide a clearer picture of this field, and may promote a better understanding of the relationship between the structure and function of TRPV1. The review summarizes information on 112 unique mutated sites along the TRPV1, exchanged to multiple different residues in many cases. These mutations influence the effect or binding of different agonists, antagonists, and channel blockers, alter the responsiveness to heat, acid, and voltage dependence, affect the channel pore characteristics, and influence the regulation of the receptor function by phosphorylation, glycosylation, calmodulin, PIP2, ATP, and lipid binding. The main goal of this paper is to publish the above mentioned data in a form that facilitates in silico molecular modelling of the receptor by promoting easier establishment of boundary conditions. The better understanding of the structure-function relationship of TRPV1 may promote discovery of new, promising, more effective and safe drugs for treatment of neurogenic inflammation and pain-related diseases and may offer new opportunities for therapeutic interventions.

2013-01-01

145

Transcription factors Sp1 and Sp4 regulate TRPV1 gene expression in rat sensory neurons  

PubMed Central

Background The capsaicin receptor, transient receptor potential vanilloid type -1 (TRPV1) directs complex roles in signal transduction including the detection of noxious stimuli arising from cellular injury and inflammation. Under pathophysiologic conditions, TRPV1 mRNA and receptor protein expression are elevated in dorsal root ganglion (DRG) neurons for weeks to months and is associated with hyperalgesia. Building on our previous isolation of a promoter system for the rat TRPV1 gene, we investigated the proximal TRPV1 P2-promoter by first identifying candidate Sp1-like transcription factors bound in vivo to the P2-promoter using chromatin immunoprecipitation (ChIP) assay. We then performed deletion analysis of GC-box binding sites, and quantified promoter activity under conditions of Sp1 / Sp4 over-expression versus inhibition/knockdown. mRNA encoding Sp1, Sp4 and TRPV1 were quantified by qRT-PCR under conditions of Sp1/Sp4 over-expression or siRNA mediated knockdown in cultured DRG neurons. Results Using ChIP analysis of DRG tissue, we demonstrated that Sp1 and Sp4 are bound to the candidate GC-box site region within the endogenous TRPV1 P2-promoter. Deletion of GC-box "a" or "a + b" within the P2- promoter resulted in a complete loss of transcriptional activity indicating that GC-box "a" was the critical site for promoter activation. Co-transfection of Sp1 increased P2-promoter activity in cultured DRG neurons whereas mithramycin-a, an inhibitor of Sp1-like function, dose dependently blocked NGF and Sp1-dependent promoter activity in PC12 cells. Co-transfection of siRNA directed against Sp1 or Sp4 decreased promoter activity in DRG neurons and NGF treated PC12 cells. Finally, electroporation of Sp1 or Sp4 cDNA into cultures of DRG neurons directed an increase in Sp1/Sp4 mRNA and importantly an increase in TRPV1 mRNA. Conversely, combined si-RNA directed knockdown of Sp1/Sp4 resulted in a decrease in TRPV1 mRNA. Conclusion Based on these studies, we now propose a model of TRPV1 expression that is dependent on Sp1-like transcription factors with Sp4 playing a predominant role in activating TRPV1 RNA transcription in DRG neurons. Given that increases of TRPV1 expression have been implicated in a wide range of pathophysiologic states including persistent painful conditions, blockade of Sp1-like transcription factors represents a novel direction in therapeutic strategies.

2011-01-01

146

The effects of cannabinoid CB1, CB2 and vanilloid TRPV1 receptor antagonists on cocaine addictive behavior in rats.  

PubMed

There is evidence that indicates that tonic activation of cannabinoid CB1 receptors plays a role in extinction/reinstatement of cocaine seeking-behavior but is not involved in the maintenance of cocaine self-administration. To further explore the importance of other endocannabinoid-related receptors in an animal model of cocaine addiction, the present paper examines cannabinoid CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and the transient receptor potential vanilloid type-1 (TRPV1) receptor antagonist N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) on intravenous (i.v.) cocaine self-administration and extinction/reinstatement of cocaine-seeking behavior in rats. For comparison and reference purposes, the effect of the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was also examined. Moreover, for comparison effects of those drugs on operant lever responding for artificial (cocaine) vs. natural (food) reward, food self-administration was also evaluated. Our findings show that AM251 (1-3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.3-1mg/kg) did not affect cocaine self-administration. However, AM251 (0.1-1mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) decreased cocaine-induced reinstatement of cocaine-seeking behavior, and AM251 (0.3-1mg/kg) decreased cue-induced reinstatement. Moreover, AM251 (3mg/kg), SR144528 (0.1-1mg/kg) and SB366791 (0.1-1mg/kg) slightly decreased food self-administration behavior, but only AM251 (3mg/kg) reduced food reward. In conclusion, our results indicate for the first time, that tonic activation of CB2 or TRPV1 receptors is involved in cocaine-induced reinstatement of cocaine-seeking behavior, but their activity is not necessary for the rewarding effect of this psychostimulant. In contrast to CB1 receptors, neither CB2 nor TRPV1 receptors play a role in cue-induced reinstatement of cocaine-seeking behavior. PMID:22325096

Adamczyk, Przemys?aw; Miszkiel, Joanna; McCreary, Andrew C; Filip, Ma?gorzata; Papp, Mariusz; Przegali?ski, Edmund

2012-01-20

147

Opposite effect of capsaicin and capsazepine on behavioral thermoregulation in insects.  

PubMed

Transient receptor potential channels are implicated in thermosensation both in mammals and insects. The aim of our study was to assess the effect of mammalian vanilloid receptor subtype 1 (TRPV1) agonist (capsaicin) and antagonist (capsazepine) on insect behavioral thermoregulation. We tested behavioral thermoregulation of mealworms larvae intoxicated with capsaicin and capsazepine in two concentrations (10(-7) and 10(-4) M) in a thermal gradient system for 3 days. Our results revealed that in low concentration, capsaicin induces seeking lower temperatures than the ones selected by the insects that were not intoxicated. After application of capsazepine in the same concentration, the mealworms prefer higher temperatures than the control group. The observed opposite effect of TRPV1 agonist and antagonist on insect behavioral thermoregulation, which is similar to the effect of these substances on thermoregulation in mammals, indicates indirectly that capsaicin may act on receptors in insects that are functionally similar to TRPV1. PMID:21667066

Olszewska, Justyna; T?gowska, Eugenia

2011-06-11

148

Coexpression and activation of TRPV1 suppress the activity of the KCNQ2/3 channel  

PubMed Central

Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel expressed predominantly in peripheral nociceptors. By detecting and integrating diverse noxious thermal and chemical stimuli, and as a result of its sensitization by inflammatory mediators, the TRPV1 receptor plays a key role in inflammation-induced pain. Activation of TRPV1 leads to a cascade of pro-nociceptive mechanisms, many of which still remain to be identified. Here, we report a novel effect of TRPV1 on the activity of the potassium channel KCNQ2/3, a negative regulator of neuronal excitability. Using ion influx assays, we revealed that TRPV1 activation can abolish KCNQ2/3 activity, but not vice versa, in human embryonic kidney (HEK)293 cells. Electrophysiological studies showed that coexpression of TRPV1 caused a 7.5-mV depolarizing shift in the voltage dependence of KCNQ2/3 activation compared with control expressing KCNQ2/3 alone. Furthermore, activation of TRPV1 by capsaicin led to a 54% reduction of KCNQ2/3-mediated current amplitude and attenuation of KCNQ2/3 activation. The inhibitory effect of TRPV1 appears to depend on Ca2+ influx through the activated channel followed by Ca2+-sensitive depletion of phosphatidylinositol 4,5-bisphosphate and activation of protein phosphatase calcineurin. We also identified physical interactions between TRPV1 and KCNQ2/3 coexpressed in HEK293 cells and in rat dorsal root ganglia neurons. Mutation studies established that this interaction is mediated predominantly by the membrane-spanning regions of the respective proteins and correlates with the shift of KCNQ2/3 activation. Collectively, these data reveal that TRPV1 activation may deprive neurons from inhibitory control mediated by KCNQ2/3. Such neurons may thus have a lower threshold for activation, which may indirectly facilitate TRPV1 in integrating multiple noxious signals and/or in the establishment or maintenance of chronic pain.

Zhang, Xu-Feng; Han, Ping; Neelands, Torben R.; McGaraughty, Steve; Honore, Prisca; Surowy, Carol S.

2011-01-01

149

Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control  

PubMed Central

New studies have revealed an essential role for TRPA1, a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species and noxious constituents of smoke and smog, initiating irritation and airway reflex responses. Together with TRPV1, the capsaicin receptor, TRPA1 may contribute to chemical hypersensitivity, chronic cough and airway inflammation in asthma, COPD and reactive airway dysfunction syndrome.

Bessac, Bret F.; Jordt, Sven-Eric

2009-01-01

150

Breathtaking TRP Channels: TRPA1 and TRPV1 in Airway Chemosensation and Reflex Control  

NSDL National Science Digital Library

New studies have revealed an essential role for TRPA1, a sensory neuronal TRP ion channel, in airway chemosensation and inflammation. TRPA1 is activated by chlorine, reactive oxygen species, and noxious constituents of smoke and smog, initiating irritation and airway reflex responses. Together with TRPV1, the capsaicin receptor, TRPA1 may contribute to chemical hypersensitivity, chronic cough, and airway inflammation in asthma, COPD, and reactive airway dysfunction syndrome.

Bret Bessac (Yale University School of Medicine Pharmacology); Sven-Eric Jordt (Yale University School of Medicine)

2008-12-01

151

Discovery of novel pyrrolopyridazine scaffolds as transient receptor potential vanilloid (TRPV1) antagonists.  

PubMed

A novel indolizine class of compounds was identified as TRPV1 antagonist from an HTS campaign. However, this indolizine class proved to be unstable and reacted readily with glutathione when exposed to light and oxygen. Reactivity was reduced by the introduction of a nitrogen atom alpha to the indolizine nitrogen. The pyrrolopyridazine core obtained proved to be inert to the action of light and oxygen. The synthesis route followed the one used for the indolizine compounds, and the potency and ADMET profile proved to be similar. PMID:23058884

Dorange, Ismet; Forsblom, Rickard; Macsari, Istvan; Svensson, Mats; Bylund, Johan; Besidski, Yevgeni; Blid, Jan; Sohn, Daniel; Gravenfors, Ylva

2012-09-25

152

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries  

Microsoft Academic Search

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential\\u000a vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive\\u000a nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced\\u000a relaxations, with special emphasis on the role of CGRP,

Saurabh Gupta; Jair Lozano-Cuenca; Carlos M. Villalón; René de Vries; Ingrid M. Garrelds; Cees J. J. Avezaat; Jorge P. van Kats; Pramod R. Saxena; Antoinette MaassenVanDenBrink

2007-01-01

153

TRPV1 Channels Are Functionally Coupled with BK(mSlo1) Channels in Rat Dorsal Root Ganglion (DRG) Neurons  

PubMed Central

The transient receptor potential vanilloid receptor 1 (TRPV1) channel is a nonselective cation channel activated by a variety of exogenous and endogenous physical and chemical stimuli, such as temperature (?42 °C), capsaicin, a pungent compound in hot chili peppers, and allyl isothiocyanate. Large-conductance calcium- and voltage-activated potassium (BK) channels regulate the electric activities and neurotransmitter releases in excitable cells, responding to changes in membrane potentials and elevation of cytosolic calcium ions (Ca2+). However, it is unknown whether the TRPV1 channels are coupled with the BK channels. Using patch-clamp recording combined with an infrared laser device, we found that BK channels could be activated at 0 mV by a Ca2+ influx through TRPV1 channels not the intracellular calcium stores in submilliseconds. The local calcium concentration around BK is estimated over 10 ?M. The crosstalk could be affected by 10 mM BAPTA, whereas 5 mM EGTA was ineffectual. Fluorescence and co-immunoprecipitation experiments also showed that BK and TRPV1 were able to form a TRPV1-BK complex. Furthermore, we demonstrated that the TRPV1-BK coupling also occurs in dosal root ganglion (DRG) cells, which plays a critical physiological role in regulating the “pain” signal transduction pathway in the peripheral nervous system.

Yan, Zonghe; Kong, Wenjuan; Liu, Beiying; Li, Xia; Yao, Jing; Zhang, Yuexuan; Qin, Feng; Ding, Jiuping

2013-01-01

154

TRPV1 Channels Are Functionally Coupled with BK(mSlo1) Channels in Rat Dorsal Root Ganglion (DRG) Neurons.  

PubMed

The transient receptor potential vanilloid receptor 1 (TRPV1) channel is a nonselective cation channel activated by a variety of exogenous and endogenous physical and chemical stimuli, such as temperature (?42 °C), capsaicin, a pungent compound in hot chili peppers, and allyl isothiocyanate. Large-conductance calcium- and voltage-activated potassium (BK) channels regulate the electric activities and neurotransmitter releases in excitable cells, responding to changes in membrane potentials and elevation of cytosolic calcium ions (Ca(2+)). However, it is unknown whether the TRPV1 channels are coupled with the BK channels. Using patch-clamp recording combined with an infrared laser device, we found that BK channels could be activated at 0 mV by a Ca(2+) influx through TRPV1 channels not the intracellular calcium stores in submilliseconds. The local calcium concentration around BK is estimated over 10 ?M. The crosstalk could be affected by 10 mM BAPTA, whereas 5 mM EGTA was ineffectual. Fluorescence and co-immunoprecipitation experiments also showed that BK and TRPV1 were able to form a TRPV1-BK complex. Furthermore, we demonstrated that the TRPV1-BK coupling also occurs in dosal root ganglion (DRG) cells, which plays a critical physiological role in regulating the "pain" signal transduction pathway in the peripheral nervous system. PMID:24147119

Wu, Ying; Liu, Yongfeng; Hou, Panpan; Yan, Zonghe; Kong, Wenjuan; Liu, Beiying; Li, Xia; Yao, Jing; Zhang, Yuexuan; Qin, Feng; Ding, Jiuping

2013-10-16

155

Bicarbonate induces membrane reorganization and CBR1 and TRPV1 endocannabinoid receptor migration in lipid microdomains in capacitating boar spermatozoa.  

PubMed

Mammalian spermatozoa acquire full fertilizing ability only after a morphofunctional maturation called "capacitation." During this process the high level of bicarbonate present within the upper female genital tract or in culture medium induces a marked reorganization of sperm membranes characterized by a biphasic behavior: In a few minutes, it promotes membrane phospholipid scrambling preliminary to the apical translocation of sterol that, 2-4 h later, enables spermatozoa to recognize zona pellucida after albumin-mediated cholesterol extraction. In the present research it was demonstrated that spermatozoa incubated with bicarbonate in protein-free media underwent a marked reorganization of lipid microdomains present in a detergent-resistant membrane fraction (DRM) isolated by ultracentrifugation on sucrose density gradient. In fact, bicarbonate exposed sperm (ES) cells, compared with ejaculated spermatozoa (nonexposed sperm [nES] cells), displayed an increase in protein DRM content and, in particular, in Cav-1 and CD55, markers of caveolae and lipid rafts, as well in acrosin-2, a marker of the outer acrosomal membrane (OAM). Moreover, the amount of certain proteins involved in capacitation, such as the endocannabinoid system receptors cannabinoid receptor type 1 (CBR1) and transient receptor potential cation channel 1 (TRPV1), increased in DRM obtained from ES. These data allow us to hypothesize that sperm membrane reorganization takes place even in the absence of extracellular proteins; that not only the plasma membrane but also the OAM participate in this process; and that important molecules playing a key role in inside-out signaling, such as the endocannbinoid receptors TRPV1 and CBR1, are involved in this event, with potentially important consequences on sperm function. PMID:21104238

Botto, Laura; Bernabň, Nicola; Palestini, Paola; Barboni, Barbara

2010-11-23

156

Four Possible Itching Pathways Related to the TRPV1 Channel, Histamine, PAR-2 and Serotonin  

PubMed Central

The following four possible pathways for itching sensation have been suggested by recent reports. 1) Histaminergic TRPV1-positive pathway: Although histamine-positive nerve fibers cannot strictly be classified as “itch specific” due to their excitation also by pure algogens (making them itch-selective), the existence of a subpopulation of nociceptors responsible for itching is strongly suggested. Moreover, the TRPV1-expressing neurons have been suggested to be the main sensors and mediators of itching. 2) Histaminergic TRPV1-negative pathway: The scratching behavior caused by itching was not different between capsaicin-pre-treated and vehicle-treated (control) mast cell-rich NC mice. This result suggests the existence of a capsaicin-insensitive (TRPV1-negative) histaminergic pathway. 3) Non-histaminergic PAR-2 pathway: Protease-activated receptor 2 (PAR-2) has been shown to play a role in the itching of atopic dermatitis (AD). The itch evoked by cowhage (a non-histaminergic pruritogen that activates PAR-2) is very similar in characteristics to the itch evoked by conditions such as AD. 4) Non-histaminergic serotonin (5-HT) pathway: 5-HT alone applied to the human skin evokes an itching sensation and has been suggested to be involved in the itching associated with pruritic diseases, such as polycythemia vera and cholestasis.

NAKAGAWA, Hiroshi; HIURA, Akio

2013-01-01

157

Four Possible Itching Pathways Related to the TRPV1 Channel, Histamine, PAR-2 and Serotonin.  

PubMed

The following four possible pathways for itching sensation have been suggested by recent reports. 1) Histaminergic TRPV1-positive pathway: Although histamine-positive nerve fibers cannot strictly be classified as "itch specific" due to their excitation also by pure algogens (making them itch-selective), the existence of a subpopulation of nociceptors responsible for itching is strongly suggested. Moreover, the TRPV1-expressing neurons have been suggested to be the main sensors and mediators of itching. 2) Histaminergic TRPV1-negative pathway: The scratching behavior caused by itching was not different between capsaicin-pre-treated and vehicle-treated (control) mast cell-rich NC mice. This result suggests the existence of a capsaicin-insensitive (TRPV1-negative) histaminergic pathway. 3) Non-histaminergic PAR-2 pathway: Protease-activated receptor 2 (PAR-2) has been shown to play a role in the itching of atopic dermatitis (AD). The itch evoked by cowhage (a non-histaminergic pruritogen that activates PAR-2) is very similar in characteristics to the itch evoked by conditions such as AD. 4) Non-histaminergic serotonin (5-HT) pathway: 5-HT alone applied to the human skin evokes an itching sensation and has been suggested to be involved in the itching associated with pruritic diseases, such as polycythemia vera and cholestasis. PMID:24043991

Nakagawa, Hiroshi; Hiura, Akio

2013-07-01

158

Pharmacological blockade of TRPV1 receptors modulates the effects of 6-OHDA on motor and cognitive functions in a rat model of Parkinson's disease.  

PubMed

TRPV1 receptors and cannabinoid system are considered as important modulators of basal ganglia functions, and their pharmacologic manipulation represents a promising therapy to alleviate Parkinson-induced hypokinesia. Recent evidence suggests that the blockade of cannabinoid receptors might be beneficial to alleviate motor deficits observed in Parkinson's disease. In the present study, we have evaluated the effects of AMG9810 , a selective antagonist of TRPV1 receptors, on the motor and cognitive functions in a rat model of Parkinson's disease generated by an intracerebroventricular injection of 6- hydroxydopamine (6-OHDA) (200 ?g per animal). The injection of 10 nmol of AMG9810 for a single dose (AMG1) and for 2 weeks (AMG14) partially attenuated the hypokinesia shown by these animals in motor function evaluation tests, whereas chronic administration of AMG had destructive effects on learning and memory in 6-OHDA-treated rats. Animals in the AMG 1 and AMG 14 groups showed an increased latency to fall in rotarod and grasping tests in each trials compared with 6-OHDA-treated rats (P < 0.01) and DMSO 1 and 14 groups (P < 0.05). Our data indicate that pharmacological blockade of TRPV1 receptors by AMG 9810 attenuates the hypokinetic effects of 6-OHDA and that TRPV1 receptors play an important role in 6-OHDA-induced hypokinesia, athough elucidation of the neurochemical substrate involved in this process remains a major challenge for the future. PMID:23216087

Razavinasab, Moazamehosadat; Shamsizadeh, Ali; Shabani, Mohammad; Nazeri, Masoud; Allahtavakoli, Mohammad; Asadi-Shekaari, Majid; Esmaeli-Mahani, Saeed; Sheibani, Vahid

2012-12-05

159

The Role of TRPV1 in Mechanical and Chemical Visceral Hyperalgesia Following Experimental Colitis  

PubMed Central

The transient receptor potential vanilloid 1 receptor (TRPV1) is an important nociceptor involved in neurogenic inflammation. We aimed to examine the role of TRPV1 in experimental colitis and in the development of visceral hypersensitivity to mechanical and chemical stimulation. Male Sprague-Dawley rats received a single dose of trinitrobenzenesulfonic acid (TNBS) in the distal colon. In the pre-emptive group, rats received the TRPV1 receptor antagonist JYL1421 (10?mol/kg, iv) or vehicle 15 minutes prior to TNBS followed by daily doses for 7days. In the post-inflammation group, rats received JYL1421 daily for 7 days starting on day 7 following TNBS. The visceromotor response (VMR) to colorectal distension (CRD), intraluminal capsaicin, capsaicin vehicle (pH6.7) or acidic saline (pH5.0) was assessed in all groups and compared to controls and naďve rats. Colon inflammation was evaluated with H&E staining and myeloperoxidase (MPO) activity. TRPV1 immunoreactivity was assessed in the thoraco-lumbar (TL) and lumbo-sacral (LS) DRGs neurons. In the pre-emptive vehicle group, TNBS resulted in a significant increase in the VMR to CRD, intraluminal capsaicin and acidic saline compared the JYL1421 treated group (p<0.05). Absence of microscopic colitis and significantly reduced MPO activity was also evident compared to vehicle treated rats (p<0.05). TRPV1 immunoreactivity in the TL (69.1± 4.6%) and LS (66.4± 4.2%) DRG in vehicle treated rats was increased following TNBS but significantly lower in the pre-emptive JYL treated group (28.6±3.9 and 32.3±2.3 respectively, p<0.05). JYL1421 in the post-inflammation group improved microscopic colitis and significantly decreased the VMR to CRD compared to vehicle (p<0.05, ?30mmHg) but had no effect on the VMR to chemical stimulation. TRPV1 immunoreactivity in the TL and LS DRG was no different from vehicle or naďve controls. These results suggest an important role for TRPV1 channel in the development of inflammation and subsequent mechanical and chemical visceral hyperalgesia.

Miranda, Adrian; Nordstrom, Eric; Mannem, Arun; Smith, Cass; Banerjee, Banani; Sengupta, Jyoti N.

2007-01-01

160

Mediator mechanisms involved in TRPV1, TRPA1 and P2X receptor-mediated sensory transduction of pulmonary ROS by vagal lung C-fibers in rats.  

PubMed

We investigated the mediator mechanisms involved in the sensory transduction of pulmonary reactive oxygen species (ROS) by vagal lung C-fibers in anesthetized rats. Airway challenge of aerosolized H2O2 (0.4%) stimulated these afferent fibers. The H2O2-induced responses were reduced by a cyclooxygenase inhibitor or ATP scavengers and also attenuated by an antagonist of TRPV1, TRPA1 or P2X receptors. The suppressive effect of the cyclooxygenase inhibitor was not affected by a combined treatment with the TRPV1 or TRPA1 antagonist, but was amplified by a combined treatment with the P2X antagonists. The suppressive effect of ATP scavengers was not affected by a combined treatment with the P2X antagonist, but was amplified by a combined treatment with the TRPV1 or TRPA1 antagonist. Thus, the actions of cyclooxygenase metabolites are mediated through the functioning of the TRPV1 and TRPA1 receptors, whereas the action of ATP is mediated through the functioning of P2X receptors. PMID:23832015

Lin, Yu-Jung; Hsu, Hsao-Hsun; Ruan, Ting; Kou, Yu Ru

2013-07-05

161

2-(3-Fluoro-4-methylsulfonylaminophenyl) Propanamides as Potent Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists: Structure Activity Relationships of 2-Amino Derivatives in the N-(6-trifluoromethyl-pyridin-3-ylmethyl) C-region  

PubMed Central

A series of N-(2-amino-6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (Ki(CAP) = 0.2 nM; IC50(pH) = 6.3 nM) and was thus ca. 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice, but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region.

Kim, Myeong Seop; Ryu, HyungChul; Kang, Dong Wook; Cho, Seong-Hee; Seo, Sejin; Park, Young Soo; Kim, Mi-Yeon; Kwak, Eun Joo; Kim, Yong Soo; Bhondwe, Rahul S.; Kim, Ho Shin; Park, Seul-gi; Son, Karam; Choi, Sun; DeAndrea-Lazarus, Ian; Pearce, Larry V.; Blumberg, Peter M.; Frank, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Kogel, Babette Y.; Schiene, Klaus; Christoph, Thomas; Lee, Jeewoo

2012-01-01

162

2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent transient receptor potential vanilloid 1 (TRPV1) antagonists: structure-activity relationships of 2-amino derivatives in the N-(6-trifluoromethylpyridin-3-ylmethyl) C-region.  

PubMed

A series of N-(2-amino-6-trifluoromethylpyridin-3-ylmethyl)-2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were designed combining previously identified pharmacophoric elements and evaluated as hTRPV1 antagonists. The SAR analysis indicated that specific hydrophobic interactions of the 2-amino substituents in the C-region of the ligand were critical for high hTRPV1 binding potency. In particular, compound 49S was an excellent TRPV1 antagonist (K(i(CAP)) = 0.2 nM; IC(50(pH)) = 6.3 nM) and was thus approximately 100- and 20-fold more potent, respectively, than the parent compounds 2 and 3 for capsaicin antagonism. Furthermore, it demonstrated strong analgesic activity in the rat neuropathic model superior to 2 with almost no side effects. Compound 49S antagonized capsaicin induced hypothermia in mice but showed TRPV1-related hyperthermia. The basis for the high potency of 49S compared to 2 is suggested by docking analysis with our hTRPV1 homology model in which the 4-methylpiperidinyl group in the C-region of 49S made additional hydrophobic interactions with the hydrophobic region. PMID:22957803

Kim, Myeong Seop; Ryu, HyungChul; Kang, Dong Wook; Cho, Seong-Hee; Seo, Sejin; Park, Young Soo; Kim, Mi-Yeon; Kwak, Eun Joo; Kim, Yong Soo; Bhondwe, Rahul S; Kim, Ho Shin; Park, Seul-gi; Son, Karam; Choi, Sun; DeAndrea-Lazarus, Ian A; Pearce, Larry V; Blumberg, Peter M; Frank, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Kögel, Babette Y; Schiene, Klaus; Christoph, Thomas; Lee, Jeewoo

2012-09-20

163

Plasticity of TRPV1-Expressing Sensory Neurons Mediating Autonomic Dysreflexia Following Spinal Cord Injury  

PubMed Central

Spinal cord injury (SCI) triggers profound changes in visceral and somatic targets of sensory neurons below the level of injury. Despite this, little is known about the influence of injury to the spinal cord on sensory ganglia. One of the defining characteristics of sensory neurons is the size of their cell body: for example, nociceptors are smaller in size than mechanoreceptors or proprioceptors. In these experiments, we first used a comprehensive immunohistochemical approach to characterize the size distribution of sensory neurons after high- and low-thoracic SCI. Male Wistar rats (300?g) received a spinal cord transection (T3 or T10) or sham-injury. At 30?days post-injury, dorsal root ganglia (DRGs) and spinal cords were harvested and analyzed immunohistochemically. In a wide survey of primary afferents, only those expressing the capsaicin receptor (TRPV1) exhibited somal hypertrophy after T3 SCI. Hypertrophy only occurred caudal to SCI and was pronounced in ganglia far distal to SCI (i.e., in L4-S1 DRGs). Injury-induced hypertrophy was accompanied by a small expansion of central territory in the lumbar spinal dorsal horn and by evidence of TRPV1 upregulation. Importantly, hypertrophy of TRPV1-positive neurons was modest after T10 SCI. Given the specific effects of T3 SCI on TRPV1-positive afferents, we hypothesized that these afferents contribute to autonomic dysreflexia (AD). Rats with T3 SCI received vehicle or capsaicin via intrathecal injection at 2 or 28?days post-SCI; at 30?days, AD was assessed by recording intra-arterial blood pressure during colo-rectal distension (CRD). In both groups of capsaicin-treated animals, the severity of AD was dramatically reduced. While AD is multi-factorial in origin, TRPV1-positive afferents are clearly involved in AD elicited by CRD. These findings implicate TRPV1-positive afferents in the initiation of AD and suggest that TRPV1 may be a therapeutic target for amelioration or prevention of AD after high SCI.

Ramer, Leanne M.; van Stolk, A. Peter; Inskip, Jessica A.; Ramer, Matt S.; Krassioukov, Andrei V.

2012-01-01

164

Role of TRPV1 and P2X receptors in the activation of lung vagal C-fiber afferents by inhaled cigarette smoke in rats.  

PubMed

Inhaled cigarette smoke (CS) triggers airway reflexes that are thought to result from the activation of lung vagal C-fiber afferents (LVCAs) via the action of reactive oxygen species in rats. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) and P2X receptors in LVCA activation. Activities of LVCAs were recorded in anesthetized and artificially ventilated rats. Airway challenge of CS produced a concentration-dependent fiber stimulation. Pretreatment with dimethylthiourea [DMTU; a scavenger of hydroxyl radical (OH)], capsazepine (CPZ; a TRPV1 receptor antagonist) and iso-pyridoxalphosphate-6-azophenyl-2',5'-disulphonate (iso-PPADS; a P2X receptor antagonist) separately reduced the fiber responses by 64, 40 and 44%, respectively, whereas pretreatment with hexamethonium (a nicotinic acetylcholine receptor antagonist) failed to alter the response. A combination of CPZ and iso-PPADS exerted a greater inhibitory effect compared with the effect of either single pretreatment. However, a combination of DMTU, CPZ and iso-PPADS did not further reduce the fiber response compared with the combined effect of CPZ and iso-PPADS. It was concluded that both TRPV1 and P2X receptors, but not nicotinic acetylcholine receptors, participate in the stimulation of LVCAs by inhaled CS, possibly through the action of OH. PMID:23443231

Weng, Wen-Hui; Hsu, Chun-Chun; Chiang, Ling-Ling; Lin, Yi-Jiun Peter; Lin, You Shuei; Su, Chien-Ling

2013-01-30

165

DECREASED SENSORY RECEPTORS P2X 3 AND TRPV1 IN SUBUROTHELIAL NERVE FIBERS FOLLOWING INTRADETRUSOR INJECTIONS OF BOTULINUM TOXIN FOR HUMAN DETRUSOR OVERACTIVITY  

Microsoft Academic Search

PurposeBotulinum neurotoxin type A (BoNT\\/A) is effective in the treatment of intractable detrusor overactivity (DO). In addition to its known inhibitory effect on presynaptic release of acetylcholine by motor terminals, there is increasing evidence that BoNT\\/A may affect sensory fibers. We investigated a possible effect of BoNT\\/A on human bladder afferent mechanisms by studying the sensory receptors P2X3 and TRPV1

A. APOSTOLIDIS; R. POPAT; Y. YIANGOU; D. COCKAYNE; A. P. D. W. FORD; J. B. DAVIS; P. DASGUPTA; C. J. FOWLER; P. ANAND

2005-01-01

166

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol  

Microsoft Academic Search

BackgroundMyeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Methodology\\/Principal FindingsPolyclonal activation of T

Venkatesh L. Hegde; Prakash S. Nagarkatti; Mitzi Nagarkatti

2011-01-01

167

Identification of a Binding Motif in the S5 Helix That Confers Cholesterol Sensitivity to the TRPV1 Ion Channel*  

PubMed Central

The TRPV1 ion channel serves as an integrator of noxious stimuli with its activation linked to pain and neurogenic inflammation. Cholesterol, a major component of cell membranes, modifies the function of several types of ion channels. Here, using measurements of capsaicin-activated currents in excised patches from TRPV1-expressing HEK cells, we show that enrichment with cholesterol, but not its diastereoisomer epicholesterol, markedly decreased wild-type rat TRPV1 currents. Substitutions in the S5 helix, rTRPV1-R579D, and rTRPV1-F582Q, decreased this cholesterol response and rTRPV1-L585I was insensitive to cholesterol addition. Two human TRPV1 variants, with different amino acids at position 585, had different responses to cholesterol with hTRPV1-Ile585 being insensitive to this molecule. However, hTRPV1-I585L was inhibited by cholesterol addition similar to rTRPV1 with the same S5 sequence. In the absence of capsaicin, cholesterol enrichment also inhibited TRPV1 currents induced by elevated temperature and voltage. These data suggest that there is a cholesterol-binding site in TRPV1 and that the functions of TRPV1 depend on the genetic variant and membrane cholesterol content.

Picazo-Juarez, Giovanni; Romero-Suarez, Silvina; Nieto-Posadas, Andres; Llorente, Itzel; Jara-Oseguera, Andres; Briggs, Margaret; McIntosh, Thomas J.; Simon, Sidney A.; Ladron-de-Guevara, Ernesto; Islas, Leon D.; Rosenbaum, Tamara

2011-01-01

168

Phosphorylation regulates TRPV1 association with ?-arrestin-2.  

PubMed

Post-translational modifications in TRPV1 (transient receptor potential vanilloid 1) play a critical role in channel activity. Phosphorylation of serine/threonine residues within the N- and C-termini of TRPV1 are implicated in receptor sensitization and activation. Conversely, TRPV1 desensitization occurs via a calcium-dependent mechanism and leads to receptor de-phosphorylation. Importantly, we recently demonstrated that TRPV1 association with ?-arrestin-2 is critical to receptor desensitization via its ability to scaffold the phosphodiesterase PDE4D5 to the receptor, regulating TRPV1 phosphorylation. In the present study, we demonstrate that phosphorylation of TRPV1 and ?-arrestin-2 regulates this association at the membrane. Under serum-free media conditions, we observed a significant decrease in TRPV1 and ?-arrestin-2 association in transfected CHO (Chinese-hamster ovary) cells. Pharmacological activation of the kinases PKA (protein kinase A) and PKC (protein kinase C) led to a robust increase in TRPV1 and ?-arrestin-2 association, whereas inhibition of PKA and PKC decreased association. Previously, we identified potential PKA residues (Ser(116), Thr(370)) in the N-terminus of TRPV1 modulated by ?-arrestin-2. In the present study we reveal that the phosphorylation status of Thr(370) dictates the ?-arrestin-2 and TRPV1 association. Furthermore, we demonstrate that CK2 (casein kinase 2)-mediated phosphorylation of ?-arrestin-2 at Thr(382) is critical for its association with TRPV1. Taken together, the findings of the present study suggest that phosphorylation controls the association of TRPV1 with ?-arrestin-2. PMID:23360390

Por, Elaine D; Gomez, Ruben; Akopian, Armen N; Jeske, Nathaniel A

2013-04-01

169

Mechanisms involved in potentiation of transient receptor potential vanilloid 1 responses by ethanol  

Microsoft Academic Search

The transient receptor potential vanilloid 1 or TRPV1 is a calcium-permeable ion channel that is activated by capsaicin, the active component of hot chilli peppers, and is involved in the development of inflammatory and neuropathic hyperalgesias. Ethanol can sensitise TRPV1-mediated responses, but the pathways contributing to the potentiation of TRPV1 by ethanol have not been clearly defined. Since the ?

Irina Vetter; Bruce D Wyse; Sarah J Roberts-Thomson; Gregory R Monteith; Peter J Cabot

2008-01-01

170

Characterization of Functional TRPV1 Channels in the Sarcoplasmic Reticulum of Mouse Skeletal Muscle  

PubMed Central

TRPV1 represents a non-selective cation channel activated by capsaicin, acidosis and high temperature. In the central nervous system where TRPV1 is highly expressed, its physiological role in nociception is clearly identified. In skeletal muscle, TRPV1 appears implicated in energy metabolism and exercise endurance. However, how as a Ca2+ channel, it contributes to intracellular calcium concentration ([Ca2+]i) maintenance and muscle contraction remains unknown. Here, as in rats, we report that TRPV1 is functionally expressed in mouse skeletal muscle. In contrast to earlier reports, our analysis show TRPV1 presence only at the sarcoplasmic reticulum (SR) membrane (preferably at the longitudinal part) in the proximity of SERCA1 pumps. Using intracellular Ca2+ imaging, we directly accessed to the channel functionality in intact FDB mouse fibers. Capsaicin and resiniferatoxin, both agonists as well as high temperature (45°C) elicited an increase in [Ca2+]i. TRPV1-inhibition by capsazepine resulted in a strong inhibition of TRPV1-mediated functional responses and abolished channel activation. Blocking the SR release (with ryanodine or dantrolene) led to a reduced capsaicin-induced Ca2+ elevation suggesting that TRPV1 may participate to a secondary SR Ca2+ liberation of greater amplitude. In conclusion, our experiments point out that TRPV1 is a functional SR Ca2+ leak channel and may crosstalk with RyR1 in adult mouse muscle fibers.

Romestaing, Caroline; Legrand, Claude; Van Coppenolle, Fabien

2013-01-01

171

Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids.  

PubMed

Several studies have shown anxiolytic effects of cannabinoids after systemic or central injections. The periaqueductal gray matter is a midbrain structure involved in the control of anxiety states. Intra-cerebral administration of cannabidiol, a phytocannabinoid, or anandamide, an endocannabinoid, into the dorsolateral portion of periaqueductal gray (dlPAG) promotes anxiolytic-like effects in several animal models of anxiety with bell-shaped dose-response curves. The reasons for these curves are still unclear, but since these drugs can also activate TRPV1 receptors and increase glutamate release, we hypothesized that, at high doses, cannabidiol and WIN 55,212-2, a CB1 receptor agonist, could activate TRPV1 receptors, facilitating glutamate neurotransmission and anxiety responses. To test this hypothesis male Wistar rats with cannulae aimed toward the dlPAG were submitted to the following intra-dlPAG treatments: Experiment 1. Vehicle (0.2 microL) or WIN 55,212-2 (3-30 pmol); Experiment 2. Capsazepine (CPZ, 10 nmol, a TRPV1 receptor antagonist) or vehicle followed, 5 min later, by vehicle or WIN 55, 212-2 (10 or 30 pmol); Experiment 3. CPZ (10 nmol) or vehicle followed, 5 min later, by cannabidiol (30 or 60 nmol). Ten minutes after the last injection the animals were tested in the elevated plus maze (EPM). WIN 55,212-2 and cannabidiol induced anxiolytic effects at lower doses that disappeared at the higher dose. Although CPZ+WIN 10 or CPZ+WIN 30 pmol groups were not different from control (CPZ+V), capsazepine prevented the decrease in open arm exploration caused by the higher of dose of WIN 55,212-2 (30 nmol) relative to the lower dose of WIN 55,212-2 (10 nmol) and, in the case of cannabidiol (60 nmol), increased open arm exploration (V+CBD 60 group versus CPZ+CBD 60 group). These results suggest that TRPV1 receptors in the dlPAG modulate anxiety and that activation of these receptors by high doses of cannabinoids could be involved in the bell-shaped dose-response curves observed with these compounds. PMID:19735690

Campos, Alline Cristina; Guimarăes, Francisco Silveira

2009-09-06

172

Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs.  

PubMed

TRPA1 receptor is activated by endogenous inflammatory mediators and exogenous pollutant molecules relevant to respiratory diseases. Previous studies have implicated TRPA1 as a drug target for antitussive therapy. Here we evaluated the relative efficacy of TRPA1 activation to evoke cough. In conscious guinea pigs the TRPA1 agonist allyl-isothiocyanate (AITC) evoked cough with a maximally effective concentration of 10mM that was abolished by the selective TRPA1 antagonist AP-18. AITC (10mM) was approximately 3-times less effective in inducing cough than capsaicin (50 ?M). Ex vivo single fiber extracellular recordings revealed that, similarly to capsaicin, AITC evoked activation in airway jugular C-fibers, but not in airway nodose A?-fibers. Consistent with the cough studies, AITC was approximately 3-times less effective than capsaicin in evoking sustained activation of the jugular C-fibers. Another TRPA1 agonist, cinnamaldehyde, was approximately twofold more effective than AITC in inducing cough. However, the cinnamaldehyde (10mM)-induced cough was only partially inhibited by the TRPA1 antagonist AP-18, and was abolished by combination of AP-18 and the TRPV1 antagonist I-RTX. We conclude that in naďve guinea pigs, TRPA1 activation initiates cough that is relatively modest compared to the cough initiated by TRPV1, likely due to lower efficacy of TRPA1 stimulation to induce sustained activation of airway C-fibers. PMID:22683866

Brozmanova, Mariana; Mazurova, Lenka; Ru, Fei; Tatar, Milos; Kollarik, Marian

2012-06-07

173

Capsaicin-induced vasodilatation in human nasal vasculature is mediated by modulation of cyclooxygenase-2 activity and abrogated by sulprostone  

Microsoft Academic Search

Extensively based on evidence gained from experimental animal models, the transient receptor potential vanilloid receptor\\u000a type 1 (TRPV1)-activator capsaicin is regarded as a valuable tool in the research on neurogenic inflammation. Although capsaicin-related\\u000a drugs gained renewed interest as a therapeutic tool, there is also controversy as whether neurogenic inflammation actually\\u000a takes place in humans. In this study, we verified the

Koen Van Crombruggen; L. Van Nassauw; L. Derycke; J.-P. Timmermans; G. Holtappels; D. Hall; C. Bachert

2011-01-01

174

TRPV1: a therapeutic target for novel analgesic drugs?  

PubMed

The vanilloid receptor TRPV1 is now recognized as a molecular integrator of painful stimuli ranging from noxious heat to endovanilloids in inflammation. Pharmacological blockade of TRPV1 represents a new strategy in pain relief. TRPV1 antagonists are expected to prevent pain by silencing receptors where pain is generated rather than stopping the propagation of pain, as most-traditional pain killers do. This hypothesis has already being tested in the clinic by administering small molecule TRPV1 antagonists (e.g. GlaxoSmithKline SB-705498) for migraine and dental pain. Paradoxically, in some murine models of chronic pain, TRPV1-deficient mice exhibit more pain-related behavior than their wild-type littermates, indicating that the understanding of TRPV1 in pain is still incomplete. Moreover, there is mounting evidence to suggest the existence of functional TRPV1 both in the brain and in various non-neuronal tissues. The biological role of these receptors remains elusive, but their tissue distribution clearly indicates that they are involved in many more functions than just pain perception. Here, we review the potential therapeutic indications and adverse effects of TRPV1 antagonists. PMID:16996800

Szallasi, Arpad; Cruz, Francisco; Geppetti, Pierangelo

2006-09-25

175

Spinal 12-lipoxygenase-derived hepoxilin A3 contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors.  

PubMed

Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals. PMID:22493235

Gregus, Ann M; Doolen, Suzanne; Dumlao, Darren S; Buczynski, Matthew W; Takasusuki, Toshifumi; Fitzsimmons, Bethany L; Hua, Xiao-Ying; Taylor, Bradley K; Dennis, Edward A; Yaksh, Tony L

2012-04-09

176

Functional expression of TRPV1 and TRPA1 in rat vestibular ganglia.  

PubMed

Both TRPV1 and TRPA1 are non-selective cation channels. They are co-expressed, and interact in sensory neurons such as dorsal root ganglia (DRG) and trigeminal ganglia (TG), and are involved in nociception, being activated by nociceptive stimuli. Immunohistological localization of TRPV1 in vestibular ganglion (VG) neurons has been reported. Although TRPA1 is co-expressed with TRPV1 in DRG and TG neurons, it is unclear whether TRPA1 channels are expressed in VG neurons. Moreover, it is unknown whether TRPV1 and TRPA1 channels are functional in VG neurons. We investigated the expression of TRPV1 and TRPA1 in rat VG neurons by RT-PCR, in situ hybridization, immunohistochemistry, and Ca(2+) imaging experiments. Both TRPV1 and TRPA1 RT-PCR products were amplified from the mRNA of rat VG neurons. In situ hybridization experiments showed TRPV1 and TRPA1 mRNA expression in the majority of VG neurons. Immunohistochemistry experiments confirmed TRPV1 protein expression. In Ca(2+) imaging experiments, capsaicin, a TRPV1 agonist, induced a significant increase in intracellular calcium ion concentration ([Ca(2+)]i) in rat primary cultured VG neurons, which was almost completely blocked by capsazepine, a TRPV1-specific antagonist. Cinnamaldehyde, a TRPA1 agonist, also caused an increase in [Ca(2+)]i, which was completely inhibited by HC030031, a TRPA1-specific antagonist. Moreover, in some VG neurons, a [Ca(2+)]i increase was evoked by both capsaicin and cinnamaldehyde in the same neuron. In summary, our histological and physiological studies reveal that TRPV1 and TRPA1 are expressed in VG neurons. It is suggested that TRPV1 and TRPA1 in VG neurons might participate in vestibular function and/or dysfunction such as vertigo. PMID:23916509

Kamakura, Takefumi; Ishida, Yusuke; Nakamura, Yukiko; Yamada, Takahiro; Kitahara, Tadashi; Takimoto, Yasumitsu; Horii, Arata; Uno, Atsuhiko; Imai, Takao; Okazaki, Suzuyo; Inohara, Hidenori; Shimada, Shoichi

2013-08-03

177

Different types of toxins targeting TRPV1 in pain.  

PubMed

The transient receptor potential vanilloid 1(TRPV1) channels are members of the transient receptor potential (TRP) superfamily. Members of this family are expressed in primary sensory neurons and are best known for their role in nociception and sensory transmission. Multiple painful stimuli can activate these channels. In this review, we discussed the mechanisms of different types of venoms that target TRPV1, such as scorpion venom, botulinum neurotoxin, spider toxin, ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning (NSP). Some of these toxins activate TRPV1; however, some do not. Regardless of TRPV1 inhibition or activation, they occur through different pathways. For example, BoNT/A decreases TRPV1 expression levels by blocking TRPV1 trafficking to the plasma membrane, although the exact mechanism is still under debate. Vanillotoxins from tarantula (Psalmopoeus cambridgei) are proposed to activate TRPV1 via interaction with a region of TRPV1 that is homologous to voltage-dependent ion channels. Here, we offer a description of the present state of knowledge for this complex subject. PMID:23732125

Min, Jia-Wei; Liu, Wan-Hong; He, Xiao-Hua; Peng, Bi-Wen

2013-06-02

178

On the Mechanism of TBA Block of the TRPV1 Channel  

PubMed Central

The transient receptor potential vanilloid 1 (TRPV1) channel is a nonselective cation channel activated by capsaicin and responsible for thermosensation. To date, little is known about the gating characteristics of these channels. Here we used tetrabutylammonium (TBA) to determine whether this molecule behaves as an ion conduction blocker in TRPV1 channels and to gain insight into the nature of the activation gate of this protein. TBA belongs to a family of classic potassium channel blockers that have been widely used as tools for determining the localization of the activation gate and the properties of the pore of several ion channels. We found TBA to be a voltage-dependent pore blocker and that the properties of block are consistent with an open-state blocker, with the TBA molecule binding to multiple open states, each with different blocker affinities. Kinetics of channel closure and burst-length analysis in the presence of blocker are consistent with a state-dependent blocking mechanism, with TBA interfering with closing of an activation gate. This activation gate may be located cytoplasmically with respect to the binding site of TBA ions, similar to what has been observed in potassium channels. We propose an allosteric model for TRPV1 activation and block by TBA, which explains our experimental data.

Oseguera, Andres Jara; Islas, Leon D.; Garcia-Villegas, Refugio; Rosenbaum, Tamara

2007-01-01

179

Role of Myeloid-Derived Suppressor Cells in Amelioration of Experimental Autoimmune Hepatitis Following Activation of TRPV1 Receptors by Cannabidiol  

PubMed Central

Background Myeloid-derived suppressor cells (MDSCs) are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis. Methodology/Principal Findings Polyclonal activation of T cells, following injection of concanavalin A (ConA), in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST), induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD), a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b+Gr-1+ MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naďve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1?/?) thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ?2?1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury. Conclusions/Significance This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents such as CBD, which trigger MDSCs through activation of TRPV1 vanilloid receptors may constitute a novel therapeutic modality to treat inflammatory diseases.

Hegde, Venkatesh L.; Nagarkatti, Prakash S.; Nagarkatti, Mitzi

2011-01-01

180

Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels.  

PubMed

Glutathione (GSH) and N-acetylcysteine (NAC) are thiol-containing antioxidants, and also act through a direct reaction with free radicals. Transient receptor potential vanilloid 1 (TRPV1) is the principal transduction channel serving as a polymodal detector. Despite the importance of oxidative stress in pain sensitivity, its role in TRPV1 modulation is poorly understood. NAC may also have a regulator role on TRPV1 channel activity in the dorsal root ganglion (DRG) neuron. Therefore, we tested the effects of GSH and NAC on TRPV1 channel current, Ca(2+) influx, oxidative stress and caspase activity in the DRG of mice. DRG neurons were freshly isolated from mice and the neurons were incubated for 6 and 24h with buthionine sulfoximine (BSO). Pretreatment of cultured DRG neurons with NAC, results in a protection against oxidative damages. This neuroprotection is associated with the attenuation of a Ca(2+) influx triggered by oxidative agents such as H2O2, 5,5'-dithiobis-(2-nitrobenzoic acid) and GSH depletion via BSO. Here, we demonstrate the contribution of cytosolic factors (related to thiol group depletion) on the activation of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin (CAP), the pungent component of hot chili peppers, and are blocked by capsazepine. An oxidative environment also increased CAP-evoked TRPV1 currents in the neurons. When NAC and GSH were included in the patch pipette as well as extracellularly in the chamber, TRPV1 channels were not activated by CAP and H2O2. TRPV1 inhibitors, 2-aminoethyl diphenylborinate and N-(p-amylcinnamoyl)anthranilic acid strongly reduced BSO-induced oxidative toxicity and Ca(2+) influx, in a manner similar to pretreatment with NAC and GSH. Caspase-3 and -9 activities of all groups were not changed by the agonists or antagonists. In conclusion, in our experimental model, TRPV1 channels are involved in the oxidative stress-induced neuronal death, and negative modulation of this channel activity by GSH and NAC pretreatment may account for their neuroprotective activity against oxidative stress. PMID:23545271

Naz?ro?lu, M; Ci?, B; Ozgül, C

2013-03-29

181

Chronic alteration in phosphatidylinositol 4,5-bisphosphate levels regulates capsaicin and mustard oil responses  

PubMed Central

There is an agreement that acute (in minutes) hydrolysis and accumulation of phosphatidylinositol 4,5-bisphosphate (PIP2) modulate TRPV1 and TRPA1 activities. Since inflammation results in PIP2 depletion, persisting for long periods (hours-to-days) in pain models and in clinic, we examined whether chronic depletion and accumulation of PIP2 affects capsaicin and mustard oil responses. In addition we also wanted to evaluate whether the effects of PIP2 depend on TRPV1 and TRPA1 co-expression, and whether the PIP2 actions vary in expression cells versus sensory neurons. Chronic PIP2 production was stimulated by over-expression of phosphatidylinositol-4-phosphate-5-kinase, while PIP2-specific phospholipid 5?-phosphatase was selected to reduce plasma membrane levels of PIP2. Our results demonstrate that capsaicin (100 nM; CAP) responses and receptor tachyphylaxis are not significantly influenced by chronic changes in PIP2 levels in wild-type (WT) or TRPA1 null-mutant sensory neurons, as well as CHO cells expressing TRPV1 alone or with TRPA1. However, low concentrations of CAP (20 nM) produced a higher response after PIP2 depletion in cells containing TRPV1 alone, but not TRPV1 together with TRPA1. Mustard oil (25 ?M; MO) responses were also not affected by PIP2 in WT sensory neurons and cells co-expressing TRPA1 and TRPV1. In contrast, PIP2 reduction leads to pronounced tachyphylaxis to MO in cells with both channels. Chronic effect of PIP2 on TRPA1 activity depends on presence of the TRPV1 channel and cell type (CHO vs. sensory neurons). In summary, chronic alterations in PIP2 levels regulate magnitude of CAP and MO responses, as well as MO-tachyphylaxis. This regulation depends on co-expression profile of TRPA1 and TRPV1 and cell type.

Patil, Mayur J.; Belugin, Sergei; Akopian, Armen N.

2011-01-01

182

Discovery of novel 5,5-diarylpentadienamides as orally available transient receptor potential vanilloid 1 (TRPV1) antagonists.  

PubMed

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury. PMID:22394104

Saku, Osamu; Ishida, Hiroshi; Atsumi, Eri; Sugimoto, Yoshiyuki; Kodaira, Hiroshi; Kato, Yoshimitsu; Shirakura, Shiro; Nakasato, Yoshisuke

2012-03-22

183

Type III Nrg1 Back Signaling Enhances Functional TRPV1 along Sensory Axons Contributing to Basal and Inflammatory Thermal Pain Sensation  

PubMed Central

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs) [1]. Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of ?7* nicotinic acetylcholine receptors, along sensory axons [2]. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions [3]. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K [4], [5], [6], making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Canetta, Sarah E.; Luca, Edlira; Pertot, Elyse; Role, Lorna W.; Talmage, David A.

2011-01-01

184

Role of TRPV1 in renal hemodynamics and function in Dahl salt-sensitive hypertensive rats  

PubMed Central

This study tests the hypothesis that dysfunction of transient receptor potential vanilloid type 1 (TRPV1) channels occurs and contributes to the decrease in the glomerular filtration rate (GFR) and sodium/water excretion in Dahl salt-sensitive hypertensive rats. Recirculating Krebs-Henseleit buffer added with inulin was perfused at a constant flow in the isolated kidneys of Dahl salt-sensitive (DS) or Dahl salt-resistant (DR) rats fed a high salt (HS) or low salt (LS) diet for three weeks. Perfusion pressures (PP) were pre-adjusted to three levels (~100, ~150, ~190 mmHg) with or without phenylephrine. Capsaicin (Cap), a selective TRPV1 agonist, in the presence or absence of capsazepine (Capz), a selective TRPV1 antagonist, was perfused. Basal GFR, urine flow rate (UFR) and Na+ excretion (UNaV) were significantly lower in DS-HS than in DR-HS, DS-LS and DR-LS rats. Cap caused pressure-dependent decreases in PP and increases in GFR, UFR and UNaV in all groups, with less magnitude of decreases in PP and increases in GFR, UFR and UNaV in DS-HS than in DR-HS, DS-LS and DR-LS rats. Capz fully blocked the effect of Cap on PP, GFR, UFR and UNaV in all groups. Thus, these results show that TRPV1 function is impaired in the kidney of DS rats fed a high salt diet, which may contribute to the decrease in GFR and renal excretory function in DS rats in face of salt challenge.

Li, Jianping; Wang, Donna H.

2009-01-01

185

‘TRPing’ Synaptic Ribbon Function in the Rat Pineal Gland: Neuroendocrine Regulation Involves the Capsaicin Receptor TRPV1  

Microsoft Academic Search

Synaptic ribbons (SRs) are presynaptic structures thought to regulate and facilitate multivesicular release. In the pineal gland, they display a circadian rhythm with higher levels at night paralleling melatonin synthesis. To gain more insight into the processes involved and the possible functions of these structures, a series of experiments were conducted in rodents. We studied the regional distribution of a

Stefan Reuss; Ursula Disque-Kaiser; Uta Binzen; Wolfgang Greffrath; Elmar Peschke

2010-01-01

186

Cytosine arabinoside affects the heat and capsaicin receptor TRPV1 localisation and sensitivity in human sensory neurons  

Microsoft Academic Search

Background Cytosine arabinoside (Ara C) is a useful chemotherapy agent, used for treating acute myeloid leukaemia, although it may be\\u000a associated with side effects including painful neuropathy. It is also used for in vitro neuronal studies to limit the proliferation\\u000a of non-neuronal cells and thereby select nondividing neuronal cells. We studied the effects of Ara C on human dorsal root

Uma Anand; William R. Otto; Chas Bountra; Iain Chessell; Marco Sinisi; Rolfe Birch; Praveen Anand

2008-01-01

187

TRPV1 antagonist with high analgesic efficacy: 2-Thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides.  

PubMed

A series of 2-thio pyridine C-region analogues of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. Among them, compound 24S showed stereospecific and excellent TRPV1 antagonism of capsaicin-induced activation. Further, it demonstrated strong anti-allodynic in a rat neuropathic pain model. Consistent with its action in vitro being through TRPV1, compound 24S blocked capsaicin-induced hypothermia in mice. Docking analysis of 24S with our hTRPV1 homology model was performed to identify its binding mode. PMID:24035514

Ha, Tae-Hwan; Ryu, Hyungchul; Kim, Sung-Eun; Kim, Ho Shin; Ann, Jihyae; Tran, Phuong-Thao; Hoang, Van-Hai; Son, Karam; Cui, Minghua; Choi, Sun; Blumberg, Peter M; Frank, Robert; Bahrenberg, Gregor; Schiene, Klaus; Christoph, Thomas; Frormann, Sven; Lee, Jeewoo

2013-08-13

188

Jellyfish and other cnidarian envenomations cause pain by affecting TRPV1 channels  

Microsoft Academic Search

Cnidarian envenomations cause a burning-pain sensation of which the underlying mechanisms are unknown. Activation of TRPV1, a non-selective cation channel expressed in nociceptive neurons, leads to cell depolarisation and pain. Here, we show in vitro and in vivo evidence for desensitization-dependent TRPV1 activation in cnidarian envenomations. Cnidarian venom induced a nociceptive reactivity, comparable to capsaicin, in laboratory rats, which could

Eva Cuypers; Angel Yanagihara; Evert Karlsson; Jan Tytgat

2006-01-01

189

Jellyfish and other cnidarian envenomations cause pain by affecting TRPV1 channels  

PubMed Central

Cnidarian envenomations cause a burning-pain sensation of which the underlying mechanisms are unknown. Activation of TRPV1, a non-selective cation channel expressed in nociceptive neurons, leads to cell depolarisation and pain. Here, we show in vitro and in vivo evidence for desensitization-dependent TRPV1 activation in cnidarian envenomations. Cnidarian venom induced a nociceptive reactivity, comparable to capsaicin, in laboratory rats, which could be reduced by the selective TRPV1 antagonist, BCTC. These findings are the first to explain at least part of the symptomology of cnidarian envenomations and provide insights into the design of more effective treatments for this global public health problem.

Cuypers, Eva; Yanagihara, Angel; Karlsson, Evert; Tytgat, Jan

2007-01-01

190

Capsaicin Protects Mouse Neuromuscular Junctions from the Neuroparalytic Effects of Botulinum Neurotoxin A  

PubMed Central

Botulinum neurotoxin A (BoNT/A), the most toxic, naturally occurring protein, cleaves synapse-associated protein of 25 kDa and inhibits acetylcholine release from motor nerve endings (MNEs). This leads to paralysis of skeletal muscles. Our study demonstrates that capsaicin protects mouse neuromuscular junctions from the neuroparalytic effects of BoNT/A. Bilateral injection of BoNT/A near the innervation of the Extensor digitorum longus (EDL) muscle of adult Swiss-Webster mice inhibited the toe spread reflex (TSR). However, when capsaicin was coinjected bilaterally, or injected 4 or 8 h before injecting BoNT/A, the TSR remained normal. In animals that were pretreated with capsazepine, capsaicin failed to protect against the neuroparalytic effects of BoNT/A. In vivo analyses demonstrated that capsaicin protected muscle functions and electromygraphic activity from the incapacitating effects of BoNT/A. The twitch response to nerve stimulation was greater for EDL preparations isolated from mice injected with capsaicin before BoNT/A. Capsaicin pretreatment also prevented the inhibitory effects of BoNT/A on end-plate currents. Furthermore, pretreatment of Neuro 2a cells with capsaicin significantly preserved labeling of synaptic vesicles by FM 1-43. This protective effect of capsaicin was observed only in the presence of extracellular Ca2+ and was inhibited by capsazepine. Immunohistochemistry demonstrated that MNEs express transient receptor potential protein of the vanilloid subfamily, TRPV1, the capsaicin receptor. Capsaicin pretreatment, in vitro, reduced nerve stimulation or KCl-induced uptake of BoNT/A into motor nerve endings and cholinergic Neuro 2a cells. These data demonstrate that capsaicin interacts with TRPV1 receptors on MNEs to reduce BoNT/A uptake via a Ca2+-dependent mechanism.

Thyagarajan, Baskaran; Krivitskaya, Natalia; Potian, Joseph G.; Hognason, Kormakur; Garcia, Carmen C.

2009-01-01

191

Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats.  

PubMed

Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation. PMID:21550723

Hoffmeister, Carin; Trevisan, Gabriela; Rossato, Mateus Fortes; de Oliveira, Sara Marchesan; Gomez, Marcus Vinícius; Ferreira, Juliano

2011-05-07

192

Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.  

PubMed

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (? 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain. PMID:22570364

Reilly, Regina M; McDonald, Heath A; Puttfarcken, Pamela S; Joshi, Shailen K; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H; Segreti, Jason A; Neelands, Torben R; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R; Turner, Teresa M; Voight, Eric A; Daanen, Jerome F; Schmidt, Robert G; Gomtsyan, Arthur; Kort, Michael E; Faltynek, Connie R; Kym, Philip R

2012-05-08

193

In vitro hepatic and skin metabolism of capsaicin.  

PubMed

On the basis of the ability of capsaicin to activate the transient receptor potential vanilloid 1 receptor (TRPV1) expressed in nociceptive sensory neurons, topical and injectable high-concentration formulations are being developed as potential treatments for various pain syndromes. As much of the published literature on capsaicin is based on pepper extracts, which are typically a mixture of capsaicin and other capsaicinoids (including norhydrocapsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin), the purpose of this investigation was to study the in vitro metabolism of pure capsaicin. The metabolism of capsaicin was similar in human, rat, and dog microsomes and S9 fractions. In these assays, three major metabolites were detected and identified as 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-dehydrocapsaicin. In addition to these three metabolites, rat microsomes and S9 fractions also produced vanillylamine and vanillin. Biotransformation of capsaicin was slow in human skin in vitro, with the majority of the applied capsaicin remaining unchanged and a small fraction being metabolized to vanillylamine and vanillic acid. These data suggest that the metabolism of capsaicin by cytochrome P450 enzymes in skin is minimal, relative to hepatic metabolism. PMID:18180272

Chanda, Sanjay; Bashir, Mohammad; Babbar, Sunita; Koganti, Aruna; Bley, Keith

2008-01-07

194

Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice  

PubMed Central

Background and purpose: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy. Experimental approach: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB1, CB2 and TRPV1 receptor agonist); HU308 (CB2 receptor agonist), SR141716A (CB1 receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB2 receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively. Results: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin. Conclusions: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.

Avraham, Y; Grigoriadis, NC; Magen, I; Poutahidis, T; Vorobiav, L; Zolotarev, O; Ilan, Y; Mechoulam, R; Berry, EM

2009-01-01

195

Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety—two sides of one coin?  

Microsoft Academic Search

The transient receptor potential vanilloid type 1 channel (TRPV1; originally vanilloid receptor VR1) is activated in peripheral terminals of nociceptive fibers by noxious heat, low pH, and natural products such as capsaicin, the pungent ingredient of red-hot chilli peppers. Evidence has been accumulating that TRPV1 is expressed also in the brain, where it seems to be involved in antinociception, locomotor

F. A. Moreira; D. C. Aguiar; A. L. B. Terzian; F. S. Guimarăes; C. T. Wotjak

196

Thermoregulatory phenotype of the Trpv1 knockout mouse: thermoeffector dysbalance with hyperkinesis.  

PubMed

This study aimed at determining the thermoregulatory phenotype of mice lacking transient receptor potential vanilloid-1 (TRPV1) channels. We used Trpv1 knockout (KO) mice and their genetically unaltered littermates to study diurnal variations in deep body temperature (T(b)) and thermoeffector activities under basal conditions, as well as thermoregulatory responses to severe heat and cold. Only subtle alterations were found in the basal T(b) of Trpv1 KO mice or in their T(b) responses to thermal challenges. The main thermoregulatory abnormality of Trpv1 KO mice was a different pattern of thermoeffectors used to regulate T(b). On the autonomic side, Trpv1 KO mice were hypometabolic (had a lower oxygen consumption) and hypervasoconstricted (had a lower tail skin temperature). In agreement with the enhanced skin vasoconstriction, Trpv1 KO mice had a higher thermoneutral zone. On the behavioral side, Trpv1 KO mice preferred a lower ambient temperature and expressed a higher locomotor activity. Experiments with pharmacological TRPV1 agonists (resiniferatoxin and anandamide) and a TRPV1 antagonist (AMG0347) confirmed that TRPV1 channels located outside the brain tonically inhibit locomotor activity. With age (observed for up to 14 months), the body mass of Trpv1 KO mice exceeded that of controls, sometimes approaching 60 g. In summary, Trpv1 KO mice possess a distinct thermoregulatory phenotype, which is coupled with a predisposition to age-associated overweight and includes hypometabolism, enhanced skin vasoconstriction, decreased thermopreferendum, and hyperkinesis. The latter may be one of the primary deficiencies in Trpv1 KO mice. We propose that TRPV1-mediated signals from the periphery tonically suppress the general locomotor activity. PMID:21289181

Garami, Andras; Pakai, Eszter; Oliveira, Daniela L; Steiner, Alexandre A; Wanner, Samuel P; Almeida, M Camila; Lesnikov, Vladimir A; Gavva, Narender R; Romanovsky, Andrej A

2011-02-01

197

Effect of cholesterol depletion on the pore dilation of TRPV1.  

PubMed

The TRPV1 ion channel is expressed in nociceptors, where pharmacological modulation of its function may offer a means of alleviating pain and neurogenic inflammation processes in the human body. The aim of this study was to investigate the effects of cholesterol depletion of the cell on ion-permeability of the TRPV1 ion channel. The ion-permeability properties of TRPV1 were assessed using whole-cell patch-clamp and YO-PRO uptake rate studies on a Chinese hamster ovary (CHO) cell line expressing this ion channel. Prolonged capsaicin-induced activation of TRPV1 with N-methyl-D-glucamine (NMDG) as the sole extracellular cation, generated a biphasic current which included an initial outward current followed by an inward current. Similarly, prolonged proton-activation (pH 5.5) of TRPV1 under hypocalcemic conditions also generated a biphasic current including a fast initial current peak followed by a larger second one. Patch-clamp recordings of reversal potentials of TRPV1 revealed an increase of the ion-permeability for NMDG during prolonged activation of this ion channel under hypocalcemic conditions. Our findings show that cholesterol depletion inhibited both the second current, and the increase in ion-permeability of the TRPV1 channel, resulting from sustained agonist-activation with capsaicin and protons (pH 5.5). These results were confirmed with YO-PRO uptake rate studies using laser scanning confocal microscopy, where cholesterol depletion was found to decrease TRPV1 mediated uptake rates of YO-PRO. Hence, these results propose a novel mechanism by which cellular cholesterol depletion modulates the function of TRPV1, which may constitute a novel approach for treatment of neurogenic pain. PMID:23279936

Jansson, Erik T; Trkulja, Carolina L; Ahemaiti, Aikeremu; Millingen, Maria; Jeffries, Gavin Dm; Jardemark, Kent; Orwar, Owe

2013-01-02

198

Capsaicin-induced vasodilatation in human nasal vasculature is mediated by modulation of cyclooxygenase-2 activity and abrogated by sulprostone.  

PubMed

Extensively based on evidence gained from experimental animal models, the transient receptor potential vanilloid receptor type 1 (TRPV1)-activator capsaicin is regarded as a valuable tool in the research on neurogenic inflammation. Although capsaicin-related drugs gained renewed interest as a therapeutic tool, there is also controversy as whether neurogenic inflammation actually takes place in humans. In this study, we verified the involvement of capsaicin in vascular responses that are regarded to be implicated in the cascade of neurogenic inflammatory mechanisms. By means of ex vivo functional experiments on human nasal mucosal vascular beds, the effect and mechanism of action of capsaicin was assessed in the absence and presence of various agents that interfere with potentially related transduction pathways. Ten micromolars of capsaicin induced vasodilatations that were reduced by the selective EP(1) prostanoid receptor antagonist SC19220 (10 ?M) and almost abolished by the selective COX-2 inhibitor NS398 (1 ?M) and the EP(1/3) receptor agonist sulprostone (0.1-10 nM), but not affected by the TRPV1-antagonists capsazepine (5 ?M), the neurokinin NK(1) receptor antagonist GR20517A (1 ?M), and the calcitonin-gene-related peptide (CGRP) receptor antagonist CGRP8-37 (100 nM). Spontaneously released PGE(2) and PGD(2) levels were significantly reduced in the presence of capsaicin. In conclusion, capsaicin-at concentrations clinically applied or under investigation for diverse disease backgrounds-induces a vasodilatory response in human nasal mucosa via a mechanism involving TRPV1-independent reduction of PGE(2) production by modulation of COX-2 enzymatic activity. These vasodilatations can be suppressed by the EP(1/3) receptor agonist sulprostone at subnanomolar concentrations. PMID:21523557

Van Crombruggen, Koen; Van Nassauw, L; Derycke, L; Timmermans, J-P; Holtappels, G; Hall, D; Bachert, C

2011-04-28

199

Capsaicin- resistant arterial baroreceptors  

PubMed Central

Background Aortic baroreceptors (BRs) comprise a class of cranial afferents arising from major arteries closest to the heart whose axons form the aortic depressor nerve. BRs are mechanoreceptors that are largely devoted to cardiovascular autonomic reflexes. Such cranial afferents have either lightly myelinated (A-type) or non-myelinated (C-type) axons and share remarkable cellular similarities to spinal primary afferent neurons. Our goal was to test whether vanilloid receptor (TRPV1) agonists, capsaicin (CAP) and resiniferatoxin (RTX), altered the pressure-discharge properties of peripheral aortic BRs. Results Periaxonal application of 1 ?M CAP decreased the amplitude of the C-wave in the compound action potential conducting at <1 m/sec along the aortic depressor nerve. 10 ?M CAP eliminated the C-wave while leaving intact the A-wave conducting in the A-? range (<12 m/sec). These whole nerve results suggest that TRPV1 receptors are expressed along the axons of C- but not A-conducting BR axons. In an aortic arch – aortic nerve preparation, intralumenal perfusion with 1 ?M CAP had no effect on the pressure-discharge relations of regularly discharging, single fiber BRs (A-type) – including the pressure threshold, sensitivity, frequency at threshold, or maximum discharge frequency (n = 8, p > 0.50) but completely inhibited discharge of an irregularly discharging BR (C-type). CAP at high concentrations (10–100 ?M) depressed BR sensitivity in regularly discharging BRs, an effect attributed to non-specific actions. RTX (? 10 ?M) did not affect the discharge properties of regularly discharging BRs (n = 7, p > 0.18). A CAP-sensitive BR had significantly lower discharge regularity expressed as the coefficient of variation than the CAP-resistant fibers (p < 0.002). Conclusion We conclude that functional TRPV1 channels are present in C-type but not A-type (A-?) myelinated aortic arch BRs. CAP has nonspecific inhibitory actions that are unlikely to be related to TRV1 binding since such effects were absent with the highly specific TRPV1 agonist RTX. Thus, CAP must be used with caution at very high concentrations.

Reynolds, Patrick J; Fan, Wei; Andresen, Michael C

2006-01-01

200

Painful toxins acting at TRPV1.  

PubMed

Many plant and animal toxins cause aversive behaviors in animals due to their pungent or unpleasant taste or because they cause other unpleasant senstations like pain. This article reviews the current state of knowledge of toxins that act at the TRPV1 ion channel, which is expressed in primary sensory neurons, is activated by multiple painful stimuli and is thought to be a key pain sensor and integrator. The recent finding that painful peptide "vanillotoxin" components of tarantula toxin activate the TRPV1 ion channel to cause pain led us to survey what is known about toxins that act at this receptor. Toxins from plants, spiders and jellyfish are considered. Where possible, structural information about sites of interaction is considered in relation to toxin-binding sites on the Kv ion channel, for which more structural information exists. We discuss a developing model where toxin agonists such as resiniferatoxin and vanillotoxins are proposed to interact with a region of TRPV1 that is homologous to the "voltage sensor" in the Kv1.2 ion channel, to open the channel and activate primary sensory nerves, causing pain. PMID:18061640

Cromer, Brett A; McIntyre, Peter

2007-10-26

201

Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy  

PubMed Central

TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is best studied in peripheral sensory neurons as a pain receptor; however TRPV1 is expressed in numerous tissues and cell types including those of the cardiovascular system. TRPV1 expression is upregulated in the hypertrophic heart, and the channel is positioned to receive stimulatory signals in the hypertrophic heart. We hypothesized that TRPV1 has a role in regulating cardiac hypertrophy. Using transverse aortic constriction to model pressure overload cardiac hypertrophy we show that mice lacking functional TRPV1, compared to wild type, have improved heart function, and reduced hypertrophic, fibrotic and apoptotic markers. This suggests that TRPV1 plays a role in the progression of cardiac hypertrophy, and presents a possible therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Buckley, Cadie L

2011-01-01

202

Chronic alteration in phosphatidylinositol 4,5-biphosphate levels regulates capsaicin and mustard oil responses.  

PubMed

There is an agreement that acute (in minutes) hydrolysis and accumulation of phosphatidylinositol 4,5-bisphosphate (PIP(2) ) modulate TRPV1 and TRPA1 activities. Because inflammation results in PIP(2) depletion, persisting for long periods (hours to days) in pain models and in the clinic, we examined whether chronic depletion and accumulation of PIP(2) affect capsaicin (CAP) and mustard oil (MO) responses. In addition, we wanted to evaluate whether the effects of PIP(2) depend on TRPV1 and TRPA1 coexpression and whether the PIP(2) actions vary in expression cells vs. sensory neurons. Chronic PIP(2) production was stimulated by overexpression of phosphatidylinositol-4-phosphate-5-kinase, and PIP(2) -specific phospholipid 5'-phosphatase was selected to reduce plasma membrane levels of PIP(2) . Our results demonstrate that CAP (100 nM) responses and receptor tachyphylaxis are not significantly influenced by chronic changes in PIP(2) levels in wild-type (WT) or TRPA1 null-mutant sensory neurons as well as CHO cells expressing TRPV1 alone or with TRPA1. However, low concentrations of CAP (20 nM) produced a higher response after PIP(2) depletion in cells containing TRPV1 alone but not TRPV1 together with TRPA1. MO (25 ?M) responses were also not affected by PIP(2) in WT sensory neurons and cells coexpressing TRPA1 and TRPV1. In contrast, PIP(2) reduction leads to pronounced tachyphylaxis to MO in cells with both channels. Chronic effect of PIP(2) on TRPA1 activity depends on presence of the TRPV1 channel and cell type (CHO vs. sensory neurons). In summary, chronic alterations in PIP(2) levels regulate magnitude of CAP and MO responses as well as MO tachyphylaxis. This regulation depends on coexpression profile of TRPA1 and TRPV1 and cell type. PMID:21337373

Patil, Mayur J; Belugin, Sergei; Akopian, Armen N

2011-02-17

203

Activation of TRPV1 and TRPA1 leads to muscle nociception and mechanical hyperalgesia.  

PubMed

The involvement of TRPV1 and TRPA1 in mediating craniofacial muscle nociception and mechanical hyperalgesia was investigated in male Sprague-Dawley rats. First, we confirmed the expression of TRPV1 in masseter afferents in rat trigeminal ganglia (TG), and provided new data that TRPA1 is also expressed in primary afferents innervating masticatory muscles in double-labeling immunohistochemistry experiments. We then examined whether the activation of each TRP channel in the masseter muscle evokes acute nocifensive responses and leads to the development of masseter hypersensitivity to mechanical stimulation using the behavioral models that have been specifically designed and validated for the craniofacial system. Intramuscular injections with specific agonists for TRPV1 and TRPA1, capsaicin and mustard oil (MO), respectively, produced immediate nocifensive hindpaw responses followed by prolonged mechanical hyperalgesia in a concentration-dependent manner. Pretreatment of the muscle with a TRPV1 antagonist, capsazepine, effectively attenuated the capsaicin-induced muscle nociception and mechanical hyperalgesia. Similarly, pretreatment of the muscle with a selective TRPA1 antagonist, AP18, significantly blocked the MO-induced muscle nociception and mechanical hyperalgesia. We confirmed these data with another set of selective antagonist for TRPV1 and TRPA1, AMG9810 and HC030031, respectively. Collectively, these results provide compelling evidence that TRPV1 and TRPA1 can functionally contribute to muscle nociception and hyperalgesia, and suggest that TRP channels expressed in muscle afferents can engage in the development of pathologic muscle pain conditions. PMID:19464796

Ro, Jin Y; Lee, Jong-Seok; Zhang, Youping

2009-05-22

204

The capsaicin receptor: a heat-activated ion channel in the pain pathway  

Microsoft Academic Search

Capsaicin, the main pungent ingredient in ‘hot’ chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation

Michael J. Caterina; Mark A. Schumacher; Makoto Tominaga; Tobias A. Rosen; Jon D. Levine; David Julius

1997-01-01

205

The capsaicin receptor: a heat-activated ion channel in the pain pathway  

Microsoft Academic Search

Capsaicin, the main pungent ingredient in `hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation

Michael J. Caterina; Mark A. Schumacher; Makoto Tominaga; Tobias A. Rosen; Jon D. Levine; David Julius

1997-01-01

206

Trigeminal nociceptors express prostaglandin receptors.  

PubMed

Orofacial inflammation is associated with prostaglandin release and the sensitization of nociceptive receptors such as the transient receptor potential subtype V(1) (TRPV(1)). We hypothesized that certain PGE(2) receptor subtypes (EP1-EP4) are co-expressed with TRPV(1) in trigeminal nociceptors and sensitize responses to a TRPV(1) agonist, capsaicin. Accordingly, combined in situ hybridization was performed with immunohistochemistry on rat trigeminal ganglia. We next evaluated the effects of specific EP2 and EP3 agonists (butaprost and sulprostone) in cultured trigeminal ganglia neurons. The results showed that EP2 and EP3 are expressed in trigeminal neurons (58% and 53% of total neurons, respectively) and are co-expressed in TRPV(1)-positive neurons (64% and 67 % of TRPV(1)-positive neurons, respectively). Moreover, most of the cells expressing EP2 or EP3 mRNA were of small to medium diameter (< 30 microm). The application of butaprost and sulprostone triggered neuropeptide exocytosis, and butaprost sensitized capsaicin responses. Analysis of these data, collectively, supports the hypothesis that prostaglandins regulate trigeminal TRPV(1) nociceptors via activation of the EP2 and EP3 receptors. PMID:18296611

Patwardhan, A M; Vela, J; Farugia, J; Vela, K; Hargreaves, K M

2008-03-01

207

Capsaicin-induced depolarisation of mitochondria in dorsal root ganglion neurons is enhanced by vanilloid receptors  

Microsoft Academic Search

Capsaicin, a pungent ingredient of hot chilli peppers, triggered Ca2+ influx in dorsal root ganglion (DRG) neurons, which express specific vanilloid receptors of type 1, with ED50<100nM. An increase in capsaicin concentration to 10?M inhibited Ca2+ clearance from the cytosol, but did not affect the amplitude of intracellular Ca2+ elevation. In DRG neurons, 10?M capsaicin also produced a significant drop

V. N. Dedov; S. Mandadi; P. J. Armati; A. Verkhratsky

2001-01-01

208

Cough reflex and oral chemesthesis induced by capsaicin and capsiate in healthy never-smokers  

Microsoft Academic Search

BACKGROUND: Many tussive agents are components of foods, but little is known about the relationship between cough reflex and oral chemesthesis sensitivities. We investigated the relationships between cough reflex and oral chemesthesis in individuals using two transient receptor potential vanilloid 1 (TRPV1) agonists with different potencies: capsaicin and capsiate. METHODS: Twenty-eight healthy never-smokers were allocated to evaluate cough and oral

Miyako Yamasaki; Satoru Ebihara; Takae Ebihara; Shannon Freeman; Shinsuke Yamanda; Masanori Asada; Motoki Yoshida; Hiroyuki Arai

2007-01-01

209

Stimulatory effect of centrally injected capsaicin, an agonist of vanilloid receptors, on gastric acid secretion in rats  

Microsoft Academic Search

Capsaicin, the main pungent ingredient in chilli peppers, acts through specific vanilloid receptors on sensory neurons. The vanilloid receptors have been localized in the brain. We describe here a stimulatory effect of centrally injected capsaicin on gastric acid secretion in urethane-anesthetized rats. Injection of capsaicin (10–30 nmol per rat) into the lateral cerebroventricle markedly stimulated the secretion. Injection of capsazepine

Sachie Minowa; Shizuko Tsuchiya; Syunji Horie; Kazuo Watanabe; Toshihiko Murayama

2001-01-01

210

Coarse Architecture of the Transient Receptor Potential Vanilloid 1 (TRPV1) Ion Channel Determined by Fluorescence Resonance Energy Transfer.  

PubMed

The transient receptor potential vanilloid 1 ion channel is responsible for the perception of high temperatures and low extracellular pH, and it is also involved in the response to some pungent compounds. Importantly, it is also associated with the perception of pain and noxious stimuli. Here, we attempt to discern the molecular organization and location of the N and C termini of the transient receptor potential vanilloid 1 ion channel by measuring FRET between genetically attached enhanced yellow and cyan fluorescent protein to the N or C terminus of the channel protein, expressed in transfected HEK 293 cells or Xenopus laevis oocytes. The static measurements of the domain organization were mapped into an available cryo-electron microscopy density of the channel with good agreement. These measurements also provide novel insights into the organization of terminal domains and their proximity to the plasma membrane. PMID:23965996

De-la-Rosa, Víctor; Rangel-Yescas, Gisela E; Ladrón-de-Guevara, Ernesto; Rosenbaum, Tamara; Islas, León D

2013-08-21

211

Increased sensitivity of desensitized TRPV1 by PMA occurs through PKC?-mediated phosphorylation at S800  

Microsoft Academic Search

Important mechanisms that regulate inhibitory and facilitatory effects on TRPV1-mediated nociception are desensitization and phosphorylation, respectively. Using Ca2+-imaging, we have previously shown that desensitization of TRPV1 upon successive capsaicin applications was reversed by protein kinase C activation in dorsal root ganglion neurons and CHO cells. Here, using both Ca2+-imaging and patch-clamp methods, we show that PMA-induced activation of PKC? is

Sravan Mandadi; Tomoko Tominaga; Mitsuko Numazaki; Namie Murayama; Naoaki Saito; Patricia J. Armati; Basil D. Roufogalis; Makoto Tominaga

2006-01-01

212

Resolving TRPV1 and TNF-? Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1  

PubMed Central

Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 and TNF-?, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lacking Trpv1 the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP) in vivo is abolished in Trpv1 knockout mice. TNF-? also increases sEPSC frequency but not amplitude in spinal lamina IIo neurons, and this increase is abolished in Trpv1 knockout mice. Single-cell PCR analysis revealed that TNF-?-responding neurons in lamina IIo are exclusively excitatory (vGluT2+) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from omega-3 polyunsaturated fatty acid (docosahexaenoic acid) blocks TNF-?- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC50=0.4 nM) in dissociated dorsal root ganglion neurons, and this IC50 is ? 500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had not effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1–10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-?-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-?-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain.

Park, Chul-Kyu; Lu, Ning; Xu, Zhen-Zhong; Liu, Tong; Serhan, Charles N.; Ji, Ru-Rong

2011-01-01

213

AKAP150-mediated TRPV1 sensitization is disrupted by calcium/calmodulin  

PubMed Central

Background The transient receptor potential vanilloid type1 (TRPV1) is expressed in nociceptive sensory neurons and is sensitive to phosphorylation. A-Kinase Anchoring Protein 79/150 (AKAP150) mediates phosphorylation of TRPV1 by Protein Kinases A and C, modulating channel activity. However, few studies have focused on the regulatory mechanisms that control AKAP150 association with TRPV1. In the present study, we identify a role for calcium/calmodulin in controlling AKAP150 association with, and sensitization of, TRPV1. Results In trigeminal neurons, intracellular accumulation of calcium reduced AKAP150 association with TRPV1 in a manner sensitive to calmodulin antagonism. This was also observed in transfected Chinese hamster ovary (CHO) cells, providing a model for conducting molecular analysis of the association. In CHO cells, the deletion of the C-terminal calmodulin-binding site of TRPV1 resulted in greater association with AKAP150, and increased channel activity. Furthermore, the co-expression of wild-type calmodulin in CHOs significantly reduced TRPV1 association with AKAP150, as evidenced by total internal reflective fluorescence-fluorescence resonance energy transfer (TIRF-FRET) analysis and electrophysiology. Finally, dominant-negative calmodulin co-expression increased TRPV1 association with AKAP150 and increased basal and PKA-sensitized channel activity. Conclusions the results from these studies indicate that calcium/calmodulin interferes with the association of AKAP150 with TRPV1, potentially extending resensitization of the channel.

2011-01-01

214

Optical stimulation in mice lacking the TRPV1 channel  

NASA Astrophysics Data System (ADS)

Lasers can be used to stimulate neural tissue, including the sciatic nerve or auditory neurons. Wells and coworkers suggested that neural tissue is likely stimulated by heat.[1,2] Ion channels that can be activated by heat are the TRPV channels, a subfamily of the Transient Receptor Potential (TRP) ion channels. TRPV channels are nonselective cation channels found in sensory neurons involved in nociception. In addition to various chemicals, TRPV channels can also be thermally stimulated. The activation temperature for the different TRPV channels varies and is 43°C for TRPV1 and 39°C for TRPV3. By performing an immunohistochemical staining procedure on frozen 20 ?m cochlear slices using a primary TRPV1 antibody, we observed specific immunostaining of the spiral ganglion cells. Here we show that in mice that lack the gene for the TRPV1 channel optical radiation cannot evoke action potentials on the auditory nerve.

Suh, Eul; Izzo Matic, Agnella; Otting, Margarete; Walsh, Joseph T., Jr.; Richter, Claus-Peter

2009-02-01

215

Analysis of transient receptor potential ankyrin 1 (TRPA1) in frogs and lizards illuminates both nociceptive heat and chemical sensitivities and coexpression with TRP vanilloid 1 (TRPV1) in ancestral vertebrates.  

PubMed

Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1. PMID:22791718

Saito, Shigeru; Nakatsuka, Kazumasa; Takahashi, Kenji; Fukuta, Naomi; Imagawa, Toshiaki; Ohta, Toshio; Tominaga, Makoto

2012-07-12

216

Analysis of Transient Receptor Potential Ankyrin 1 (TRPA1) in Frogs and Lizards Illuminates Both Nociceptive Heat and Chemical Sensitivities and Coexpression with TRP Vanilloid 1 (TRPV1) in Ancestral Vertebrates*  

PubMed Central

Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1.

Saito, Shigeru; Nakatsuka, Kazumasa; Takahashi, Kenji; Fukuta, Naomi; Imagawa, Toshiaki; Ohta, Toshio; Tominaga, Makoto

2012-01-01

217

Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch  

PubMed Central

Summary Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug–drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as ‘defunctionalization’ of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies.

Anand, P.; Bley, K.

2011-01-01

218

Effect of PAR2 activation on single TRPV1 channel activities in rat vagal pulmonary sensory neurons  

PubMed Central

Protease-activated receptor-2 (PAR2) is involved in airway inflammation and airway hyperresponsiveness; both are the prominent features of asthma. Transient receptor potential vanilloid receptor 1 (TRPV1) is expressed in pulmonary sensory nerves, functions as a thermal and chemical transducer, and contributes to neurogenic inflammation. By using the cell-attached single-channel recordings, this study was carried out to investigate the effect of PAR2 activation on single TRPV1 channel activities in isolated pulmonary sensory neurons. Our immunohistochemical study demonstrated the expression of PAR2 in rat vagal pulmonary sensory neurons. Our patchclamp study further showed that intracellular application of capsaicin (0.75 µM) induced single-channel current that exhibited outward rectification in these neurons. The probability of the channel being open (Po) was significantly increased after the cells were pretreated with PAR2-activating peptide (100 µM, 2 min). Pretreatment with trypsin (0.1 µM, 2 min) also increased the single-channel Po and the effect was completely inhibited by soybean trypsin inhibitor (0.5 µM, 3 min). In addition, the effect of PAR2 activation was abolished by either U73122 (1 µM, 4 min), a phospholipase C inhibitor, or chelerythrine (10 µM, 4 min), a protein kinase C inhibitor. In conclusion, our data demonstrated that activation of PAR2 upregulated single-channel activities of TRPV1 and the effect was mediated through the protein kinase C-dependent transduction pathway.

Gu, Qihai; Lee, Lu-Yuan

2009-01-01

219

Oxidation of extracellular cysteines by mercury chloride reduces TRPV1 activity in rat dorsal root ganglion neurons  

Microsoft Academic Search

Transient receptor potential vanilloid type 1 (TRPV1) receptor plays an important role as a molecular detector of noxious signals in primary sensory neurons. Activity of TRPV1 can be modulated by the change in the environment such as redox state and extracellular cations. In the present study, we investigated the effect of the mercury chloride (HgCl2) on the activity of TRPV1

Yunju Jin; Jin Young Park; Jun Kim; Jiyeon Kwak

2011-01-01

220

[ 3H]Resiniferatoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR1) protein distribution  

Microsoft Academic Search

Knowledge of the distribution and function of the vanilloid receptor (VR-1 or TRPV1) in the CNS lacks the detailed appreciation of its role in the peripheral nervous system. The radiolabelled vanilloid agonist [3H]resiniferatoxin (RTX) has been used to indicate the presence of TRPV1 receptor protein in the brain but low specific binding has complicated interpretation of this data. Recently, support

Jennifer C Roberts; John B Davis; Christopher D Benham

2004-01-01

221

Capsaicin Pre-treatment Provides Neurovascular Protection Against Neonatal Hypoxic-Ischemic Brain Injury in Rats  

PubMed Central

Capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, has recently been shown to provide neuroprotection against brain injury in experimental adult models of cerebral ischemia. Accordingly, in this study, we investigated the way in which capsaicin-mediated TRPV1 modulation could attenuate damage in an experimental hypoxic-ischemic (HI) neonatal brain injury model. The Rice-Vannucci method was used in 10-day-old rat pups by performing unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37°C). Capsaicin was administered intraperitoneally (0.2 mg/kg or 2.0 mg/kg) at 3 h pre-HI or 1 h post-HI. Post assessment included measurement of infarction volume at 24 and 72 h in addition to an assessment of the vascular dynamics of the middle cerebral artery (MCA) at 6 h post-HI. The results indicated that pre-treatment with capsaicin reduced infarction volume significantly with either low-dose or high-dose treatment. Pre-treatment also improved myogenic tone and decreased apoptotic changes in the distal MCA. We concluded that capsaicin pre-treatment may provide neurovascular protection against neonatal HI.

Khatibi, Nikan H.; Jadhav, Vikram; Charles, Shelton; Chiu, Jeffrey; Buchholz, John; Zhang, John H.

2013-01-01

222

LPS from Porphyromonas gingivalis Sensitizes Capsaicin-Sensitive Nociceptors  

PubMed Central

Although odontogenic infections are often accompanied by pain, little is known about the potential mechanisms mediating this effect. In this study, we tested the hypothesis that trigeminal nociceptive neurons are directly sensitized by lipopolysaccharide (LPS) isolated from an endodontic pathogen, Porphyromonas gingivalis (P. gingivalis). In vitro studies conducted with cultures of rat trigeminal neurons demonstrated that pretreatment with LPS produced a significant increase in the capsaicin-evoked release of calcitonin gene-related peptide (CGRP) when compared to vehicle pretreatment, thus showing sensitization of the capsaicin receptor, TRPV1, by LPS. Furthermore, confocal microscopic examination of human tooth pulp samples showed the colocalization of the LPS receptor (toll-like receptor 4; TLR4) with CGRP containing nerve fibers. Collectively, these results suggest the direct sensitization of nociceptors by LPS at concentrations found in infected canal systems as one mechanism responsible for the pain associated with bacterial infections.

Ferraz, Caio Cezar Randi; Diogenes, Anibal; Henry, Michael A.; Hargreaves, Kenneth M.

2010-01-01

223

Contractile mechanisms coupled to TRPA1 receptor activation in rat urinary bladder  

Microsoft Academic Search

TRPA1 is a member of the transient receptor potential (TRP) channel family present in sensory neurons. Here we show that vanilloid receptor (TRPV1) stimulation with capsaicin and activation of TRPA1 with allyl isothiocyanate or cinnamaldehyde cause a graded contraction of the rat urinary bladder in vitro. Repeated applications of maximal concentrations of the agonists produce desensitization to their contractile effects.

Edinéia Lemos Andrade; Juliano Ferreira; Eunice André; Joăo B. Calixto

2006-01-01

224

A-kinase anchoring protein 150 mediates transient receptor potential family V type 1 sensitivity to phosphatidylinositol-4,5-bisphosphate.  

PubMed

A-kinase anchoring protein 150 (AKAP150) is a scaffolding protein that controls protein kinase A- and C-mediated phosphorylation of the transient receptor potential family V type 1 (TRPV1), dictating receptor response to nociceptive stimuli. The phospholipid phosphatidylinositol-4,5-bisphosphate (PIP(2)) anchors AKAP150 to the plasma membrane in naive conditions and also affects TRPV1 activity. In the present study, we sought to determine whether the effects of PIP(2) on TRPV1 are mediated through AKAP150. In trigeminal neurons and CHO cells, the manipulation of cellular PIP(2) led to significant changes in the association of AKAP150 and TRPV1. Following PIP(2) degradation, increased TRPV1:AKAP150 coimmunoprecipitation was observed, resulting in increased receptor response to capsaicin treatment. Phospholipase C activation in neurons isolated from AKAP150(-/-) animals indicated that PIP(2)-mediated inhibition of TRPV1 in the whole-cell environment requires expression of the scaffolding protein. Furthermore, the addition of PIP(2) to neurons isolated from AKAP150 wild-type mice reduced PKA sensitization of TRPV1 compared with isolated neurons from AKAP150(-/-) mice. These findings suggest that PIP(2) degradation increases AKAP150 association with TRPV1 in the whole-cell environment, leading to sensitization of the receptor to nociceptive stimuli. PMID:21653872

Jeske, Nathaniel A; Por, Elaine D; Belugin, Sergei; Chaudhury, Sraboni; Berg, Kelly A; Akopian, Armen N; Henry, Michael A; Gomez, Ruben

2011-06-01

225

TRPV1 activation by endogenous anandamide triggers postsynaptic LTD in dentate gyrus  

PubMed Central

The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. While TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been described in the brain where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. Here we show, however, that TRPV1 suppresses excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression is due to a Ca2+-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor-independent manner. Thus, our findings reveal a novel form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.

Chavez, Andres E.; Chiu, Chiayu Q.; Castillo, Pablo E.

2010-01-01

226

TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome.  

PubMed

The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK(1)-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state. PMID:22547700

Fernandes, Elizabeth S; Liang, Lihuan; Smillie, Sarah-Jane; Kaiser, Frank; Purcell, Robert; Rivett, Damian W; Alam, Saydul; Howat, Sarah; Collins, Helen; Thompson, Stephen J; Keeble, Julie E; Riffo-Vasquez, Yanira; Bruce, Kenneth D; Brain, Susan D

2012-04-30

227

Nociceptive transmitter release in the dorsal spinal cord by capsaicin-sensitive fibers after noxious gastric stimulation.  

PubMed

Little is known about transmitters that encode noxious gastric stimuli in the spinal cord. The release of glutamate, substance P, and CGRP from the spinal cord was therefore investigated in response to acid injury of the gastric mucosa. Dorsal halves of the caudal thoracic spinal cord (T7-T13) were removed 6 h after oral application of 0.5 M HCl or saline, transferred to a superfusion chamber, and the basal and capsaicin-stimulated (3.3 microM) transmitter release was determined. After acid injury, basal glutamate release increased 134% as compared to saline-treated animals. Capsaicin-stimulated release of CGRP and SP was 48% and 58% lower in acid- than in saline-treated animals, indicating that capsaicin-sensitive fibers in the dorsal spinal cord were already partially depleted by acid treatment. Capsaicin denervation reduced basal glutamate release by 33% after acid injury as compared to non-denervated acid-treated animals. Gastric origin and capsaicin sensitivity of glutamatergic, CGRP- and SP-containing primary afferents in thoracic dorsal root ganglia were then determined by retrograde tracing with True Blue and immunohistochemical labeling with the vanilloid receptor TRPV1. About 65% of True Blue-labeled cells were glutamatergic and more than 73% of this population expressed the TRPV1 receptor. Nearly all True Blue/CGRP (85%)- and True Blue/SP-positive cells (97%) coexpressed TRPV1. We conclude that noxious gastric stimulation with acid induces release of glutamate, SP, and CGRP from capsaicin-sensitive sensory afferents in the dorsal horn of the spinal cord where they may play an important role in gastric nociception and hyperalgesia. PMID:15781052

Schicho, Rudolf; Donnerer, Josef; Liebmann, Ingrid; Lippe, Irmgard Th

2005-03-28

228

Positive allosteric modulation of TRPV1 as a novel analgesic mechanism  

PubMed Central

Background The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly-myelinated A?-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. Results Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing nerve terminals. The loss of nerve endings was manifested by an increase in levels of axotomy markers assessed by qRT-PCR and colocalization of ATF3 in TRPV1+ cells visualized via immunohistochemistry. Conclusions The present observations suggest a novel, non-narcotic, selective, long-lasting TRPV1-based approach for analgesia that may be effective in acute, persistent, or chronic pain disorders.

2012-01-01

229

A role for TRPV1 in influencing the onset of cardiovascular disease in obesity.  

PubMed

Obesity induced by Western diets is associated with type 2 diabetes mellitus and cardiovascular diseases, although underlying mechanisms are unclear. We investigated a murine model of diet-induced obesity to determine the effect of transient potential receptor vanilloid 1 (TRPV1) deletion on hypertension and metabolic syndrome. Wild-type and TRPV1 knockout mice were fed normal or high-fat diet from 3 to 15 weeks. High-fat diet-fed mice from both genotypes became obese, with similar increases in body and adipose tissue weights. High-fat diet-fed TRPV1 knockout mice showed significantly improved handling of glucose compared with high-fat diet-fed wild-type mice. Hypertension, vascular hypertrophy, and altered nociception were observed in high-fat diet-fed wild-type but not high-fat diet-fed TRPV1 knockout mice. Wild-type, but not high-fat diet-fed TRPV1 knockout, mice demonstrated remodeling in terms of aortic vascular hypertrophy and increased heart and kidney weight, although resistance vessel responses were similar in each. Moreover, the wild-type mice had significantly increased plasma levels of leptin, interleukin 10 and interleukin 1?, whereas samples from TRPV1 knockout mice did not show significant increases. Our results do not support the concept that TRPV1 plays a major role in influencing weight gain. However, we identified a role of TRPV1 in the deleterious effects observed with high-fat feeding in terms of inducing hypertension, impairing thermal nociception sensitivity, and reducing glucose tolerance. The observation of raised levels of adipokines in wild-type but not TRPV1 knockout mice is in keeping with TRPV1 involvement in stimulating the proinflammatory network that is central to obesity-induced hypertension and sensory neuronal dysfunction. PMID:23150506

Marshall, Nichola J; Liang, Lihuan; Bodkin, Jennifer; Dessapt-Baradez, Cecile; Nandi, Manasi; Collot-Teixeira, Sophie; Smillie, Sarah-Jane; Lalgi, Kamal; Fernandes, Elizabeth S; Gnudi, Luigi; Brain, Susan D

2012-11-12

230

Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal  

PubMed Central

Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 ?m 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 ?m), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10–100 ?m) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1–10 ?m) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 ?m 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 ?m) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.

Taylor-Clark, T E; McAlexander, M A; Nassenstein, C; Sheardown, S A; Wilson, S; Thornton, J; Carr, M J; Undem, B J

2008-01-01

231

Capsaicin sensitivity is associated with the expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult rat sensory ganglia  

Microsoft Academic Search

A vanilloid receptor (VR1) has recently been cloned and shown to be a target for capsaicin, the excitotoxic component of capsicum peppers (Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D. and Julius, D., Nature, 389 (1997) 816–824). The effects of capsaicin appear to be selective for a subset of sensory neurones which includes polymodal nociceptors. The present study

Rachel J. A Helliwell; Linda M McLatchie; Melanie Clarke; Janet Winter; Stuart Bevan; Peter McIntyre

1998-01-01

232

Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain  

Microsoft Academic Search

BACKGROUND: Breast pain and tenderness affects 70% of women at some time. These symptoms have been attributed to stretching of the nerves with increase in breast size, but tissue mechanisms are poorly understood. METHODS: Eighteen patients (n = 12 breast reduction and n = 6 breast reconstruction) were recruited and assessed for breast pain by clinical questionnaire. Breast skin biopsies

Preethi Gopinath; Elaine Wan; Anita Holdcroft; Paul Facer; John B Davis; Graham D Smith; Chas Bountra; Praveen Anand

2005-01-01

233

TRPV1 is a novel target for omega-3 polyunsaturated fatty acids  

PubMed Central

Omega-3 (n-3) fatty acids are essential for proper neuronal function, and they possess prominent analgesic properties, yet their underlying signalling mechanisms are unclear. Here we show that n-3 fatty acids interact directly with TRPV1, an ion channel expressed in nociceptive neurones and brain. These fatty acids activate TRPV1 in a phosphorylation-dependent manner, enhance responses to extracellular protons, and displace binding of the ultrapotent TRPV1 ligand [3H]resiniferatoxin. In contrast to their agonistic properties, n-3 fatty acids competitively inhibit the responses of vanilloid agonists. These actions occur in mammalian cells in the physiological concentration range of 1–10 ?m. Significantly, docosahexaenoic acid exhibits the greatest efficacy as an agonist, whereas eicosapentaenoic acid and linolenic acid are markedly more effective inhibitors. Similarly, eicosapentaenoic acid but not docosahexaenoic acid profoundly reduces capsaicin-evoked pain-related behaviour in mice. These effects are independent of alterations in membrane elasticity because the micelle-forming detergent Triton X-100 only minimally affects TRPV1 properties. Thus, n-3 fatty acids differentially regulate TRPV1 and this form of signalling may contribute to their biological effects. Further, these results suggest that dietary supplementation with selective n-3 fatty acids would be most beneficial for the treatment of pain.

Matta, Jose A; Miyares, Rosa L; Ahern, Gerard P

2007-01-01

234

Spermatogonial stem cell sensitivity to capsaicin: An in vitro study  

PubMed Central

Background Conflicting reports have been published on the sensitivity of spermatogenesis to capsaicin (CAP), the pungent ingredient of hot chili peppers. Here, the effect of CAP on germ cell survival was investigated by using two testis germ cell lines as a model. As CAP is a potent agonist of the transient receptor potential vanilloid receptor 1 (TRPV1) and no information was available of its expression in germ cells, we also studied the presence of TRPV1 in the cultured cells and in germ cells in situ. Methods The rat spermatogonial stem cell lines Gc-5spg and Gc-6spg were used to study the effects of different concentrations of CAP during 24 and 48 h. The response to CAP was first monitored by phase-contrast microscopy. As germ cells appear to undergo apoptosis in the presence of CAP, the activation of caspase 3 was studied using an anti activated caspase 3 antibody or by quantifying the amount of cells with DNA fragmentation using flow cytometry. Immunolocalization was done with an anti-TRPV1 antibody either with the use of confocal microscopy to follow live cell labeling (germ cells) or on Bouin fixed paraffin embedded testicular tissues. The expression of TRPV1 by the cell lines and germ cells was confirmed by Western blots. Results Initial morphological observations indicated that CAP at concentrations ranging from 150 uM to 250 uM and after 24 and 48 h of exposure, had deleterious apoptotic-like effects on both cell lines: A large population of the CAP treated cell cultures showed signs of DNA fragmentation and caspase 3 activation. Quantification of the effect demonstrated a significant effect of CAP with doses of 150 uM in the Gc-5spg cell line and 200 uM in the Gc-6spg cell line, after 24 h of exposure. The effect was dose and time dependent in both cell lines. TRPV1, the receptor for CAP, was found to be expressed by the spermatogonial stem cells in vitro and also by premeiotic germ cells in situ. Conclusion CAP adversely affects spermatogonial survival in vitro by inducing apoptosis to those cells and TRPV-1, a CAP receptor, may be involved in this effect as this receptor is expressed by mitotic germ cells.

Mizrak, Sefika C; Gadella, Bart M; Erdost, Hatice; Ozer, Aytekin; van Pelt, Ana MM; van Dissel-Emiliani, Federica MF

2008-01-01

235

AKAP150-mediated TRPV1 sensitization is disrupted by calcium\\/calmodulin  

Microsoft Academic Search

Background  The transient receptor potential vanilloid type1 (TRPV1) is expressed in nociceptive sensory neurons and is sensitive to phosphorylation.\\u000a A-Kinase Anchoring Protein 79\\/150 (AKAP150) mediates phosphorylation of TRPV1 by Protein Kinases A and C, modulating channel\\u000a activity. However, few studies have focused on the regulatory mechanisms that control AKAP150 association with TRPV1. In the\\u000a present study, we identify a role for

Sraboni Chaudhury; Manjot Bal; Sergei Belugin; Mark S Shapiro; Nathaniel A Jeske

2011-01-01

236

TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis.  

PubMed

Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1(-/-) B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1(+) neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy. PMID:23689362

Paltser, Geoffrey; Liu, Xue Jun; Yantha, Jason; Winer, Shawn; Tsui, Hubert; Wu, Ping; Maezawa, Yuko; Cahill, Lindsay S; Laliberté, Christine L; Ramagopalan, Sreeram V; Deluca, Gabriele C; Sadovnick, A Dessa; Astsaturov, Igor; Ebers, George C; Henkelman, R Mark; Salter, Michael W; Dosch, H-Michael

2013-07-24

237

TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis  

PubMed Central

Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1?/? B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.

Paltser, Geoffrey; Liu, Xue Jun; Yantha, Jason; Winer, Shawn; Tsui, Hubert; Wu, Ping; Maezawa, Yuko; Cahill, Lindsay S; Laliberte, Christine L; Ramagopalan, Sreeram V; DeLuca, Gabriele C; Sadovnick, A Dessa; Astsaturov, Igor; Ebers, George C; Henkelman, R Mark; Salter, Michael W; Dosch, H-Michael

2013-01-01

238

A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic  

Microsoft Academic Search

Some members of the transient receptor potential (TRP) family of cation channels mediate sensory responses to irritant substances. Although it is well known that TRPA1 channels are activated by pungent compounds found in garlic, onion, mustard and cinnamon extracts, activation of TRPV1 by these extracts remains controversial. Here we establish that TRPV1 is activated by pungent extracts from onion and

Héctor Salazar; Itzel Llorente; Andrés Jara-Oseguera; Refugio García-Villegas; Mika Munari; Sharona E Gordon; León D Islas; Tamara Rosenbaum

2008-01-01

239

Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse  

Microsoft Academic Search

C-fiber nociceptors can be divided into two groups based on growth factor dependency and isolectin B4 (IB4) binding. IB4-negative nociceptors have been proposed to contribute to inflammatory pain. Since the TRPV1 receptor is critical for inflammatory heat hyperalgesia, we hypothesized that inflammation would sensitize IB4 negative but not IB4-positive small-diameter neurons to TRPV1 stimuli. Two days after complete Freund's adjuvant

Nicole M. Breese; Annette C. George; Laura E. Pauers; Cheryl L. Stucky

2005-01-01

240

Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior  

Microsoft Academic Search

BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1) channels are important membrane sensors on peripheral nerve endings and on supportive non-neuronal synoviocytes in the knee joint. TRPV 1 ion channels respond with activation of calcium and sodium fluxes to pH, thermal, chemical, osmotic, mechanical and other stimuli abundant in inflamed joints. In the present study, the kaolin\\/carrageenan (k\\/c) induced knee joint

Karin N Westlund; Mikhail Y Kochukov; Ying Lu; Terry A McNearney

2010-01-01

241

Diallyl sulfides in garlic activate both TRPA1 and TRPV1  

Microsoft Academic Search

We searched for novel agonists of TRP receptors especially for TRPA1 and TRPV1 in foods. We focused attention on garlic compounds, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS). In TRPA1 or TRPV1 heterogeneously expressed CHO cells, all of those compounds increased [Ca2+]i in concentration-dependent manner. The EC50 values of DADS and DATS were similar to that of

Kanako Koizumi; Yusaku Iwasaki; Masataka Narukawa; Yuji Iitsuka; Tomomi Fukao; Taiichiro Seki; Toyohiko Ariga; Tatsuo Watanabe

2009-01-01

242

TRPV1 mediates cell death in rat synovial fibroblasts through calcium entry-dependent ROS production and mitochondrial depolarization  

SciTech Connect

Synoviocyte hyperplasia is critical for rheumatoid arthritis, therefore, potentially an important target for therapeutics. It was found in this work that a TRPV1 agonist capsaicin, and acidic solution (pH 5.5) induced increases in cytosolic calcium concentration ([Ca{sup 2+}]{sub c}) and reactive oxygen species (ROS) production in synoviocytes isolated from a rat model of collagen-induced arthritis. The increases in both [Ca{sup 2+}]{sub c} and ROS production were completely abolished in calcium-free buffer or by a TRPV1 antagonist capsazepine. Further experiments revealed that capsaicin and pH 5.5 solution caused mitochondrial membrane depolarization and reduction in cell viability; such effects were inhibited by capsazepine, or the NAD(P)H oxidase inhibitor diphenylene iodonium. Both capsaicin and pH 5.5 buffer induced apoptosis as shown by nuclear condensation and fragmentation. Furthermore, RT-PCR readily detected TRPV1 mRNA expression in the isolated synoviocytes. Taken together, these data indicated that TRPV1 activation triggered synoviocyte death by [Ca{sup 2+}]{sub c} elevation, ROS production, and mitochondrial membrane depolarization.

Hu Fen; Sun Wenwu [Department of Biophysics, School of Physics, Ministry of Education Key Laboratory of Bioactive Materials, Nankai University, 94 Weijin Road, Nankai District, Tianjin 300071 (China); Zhao Xiao Ting [Institute of Cell Biology, Beijing Normal University, Beijing 100875 (China); Cui Zongjie [Institute of Cell Biology, Beijing Normal University, Beijing 100875 (China)], E-mail: zjcui@bnu.edu.cn; Yang Wenxiu [Department of Biophysics, The School of Physics, The Ministry of Education Key Laboratory of Bioactive Materials, Nankai University, 94 Weijin Road, Nankai District, Tianjin 300071 (China)], E-mail: yangwenx@nankai.edu.cn

2008-05-16

243

NOX3 NADPH Oxidase Couples Transient Receptor Potential Vanilloid 1 to Signal Transducer and Activator of Transcription 1-Mediated Inflammation and Hearing Loss  

PubMed Central

Abstract Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24?h, which recovered by 72?h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss. Antioxid. Redox Signal. 14, 999–1010.

Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly; Kaur, Tejbeer; Sheth, Sandeep; Bunch, Jennifer; Perro, Christopher; Rybak, Leonard P.

2011-01-01

244

Roles of Transient Receptor Potential Vanilloid Subtype 1 and Cannabinoid Type 1 Receptors in the Brain: Neuroprotection versus Neurotoxicity  

Microsoft Academic Search

Transient receptor potential vanilloid subtype 1 (TRPV1), also known as vanilloid receptor 1 (VR1), is a nonselective cation\\u000a channel that is activated by a variety of ligands, such as exogenous capsaicin (CAP) or endogenous anandamide (AEA), as well\\u000a as products of lipoxygenases. Cannabinoid type 1 (CB1) receptor belongs to the G protein-coupled receptor superfamily and\\u000a is activated by cannabinoids such

Sang R. Kim; Young C. Chung; Eun S. Chung; Keun W. Park; So Y. Won; E. Bok; Eun S. Park; Byung K. Jin

2007-01-01

245

mGlu and NMDA receptor contributions to capsaicin-induced thermal and mechanical hypersensitivity  

Microsoft Academic Search

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors, some of which are localized in the spinal cord dorsal horn, and are involved with pain perception. The anti-nociceptive effects of intrathecal (i.t.) pretreatment with various mGlu receptor agonists and antagonists were assessed in Long Evans rats with mechanical and thermal hypersensitivity after sub-dermal injection of capsaicin in the hindpaw. Selective group

Alexandra C. Soliman; Jonathan S. C. Yu; Terence J. Coderre

2005-01-01

246

A possible participation of transient receptor potential vanilloid type 1 channels in the antidepressant effect of fluoxetine.  

PubMed

The present study investigated the influence of transient receptor vanilloid type 1 (TRPV1) channel agonist (capsaicin) and antagonist (capsazepine) either alone or in combination with traditional antidepressant drug, fluoxetine; or a serotonin hydroxylase inhibitor, para-chlorophenylalanine; or a glutamate N-methyl-D-aspartate (NMDA) receptor agonist, NMDA on the forced swim test and tail suspension test using male Swiss mice. Results revealed that intracerebroventricular injections of capsaicin (200 and 300 ?g/mouse) and capsazepine (100 and 200 ?g/mouse) reduced the immobility time, exhibiting antidepressant-like activity that was comparable to the effects of fluoxetine (2.5-10 ?g/mouse) in both the tests. However, in the presence of inactive dose (10 ?g/mouse) of capsazepine, capsaicin (300 ?g/mouse) had no influence on the indices of both tests, signifying that the effects are TRPV1-mediated. Further, the antidepressant-like effects of both the TRPV1 ligands were neutralized in mice-pretreated with NMDA (0.1 ?g/mouse), suggestive of the fact that decreased glutamatergic transmission might contribute to the antidepressant-like activity. In addition, co-administration of sub-threshold dose of capsazepine (10 ?g/mouse) and fluoxetine (1.75 ?g/mouse) produced a synergistic effect in both the tests. In contrast, inactive doses of capsaicin (10 and 100 ?g/mouse) partially abolished the antidepressant effect of fluoxetine (10 ?g/mouse), while its effect was potentiated by active dose of capsaicin (200 ?g/mouse). Moreover, pretreatment of mice with para-chlorophenylalanine (300 mg/kg/day × 3 days, i.p.) attenuated the effects of capsaicin and capsazepine, demonstrating a probable interplay between serotonin and TRPV1, at least in parts. Thus, our data indicate a possible role of TRPV1 in depressive-like symptoms. PMID:22542657

Manna, Shyamshree S S; Umathe, Sudhir N

2012-04-20

247

Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor  

SciTech Connect

Capsaicin, the pungent constituent of chili peppers, represents the paradigm for the capsaicinoids or vanilloids, a family of compounds shown to stimulate and then desensitize specific subpopulations of sensory receptors, including C-polymodal nociceptors, A-delta mechanoheat nociceptors and warm receptors of the skin, as well as enteroceptors of thin afferent fibers. An exciting recent advance in the field has been the finding that resiniferatoxin (RTX), a naturally occurring diterpene containing a homovanillic acid ester, a key structural motif of capsaicin, functions as an ultrapotent capsaicin analog. For most of the responses characteristic of capsaicin, RTX is 100-10,000 fold more potent. Structure/activity analysis indicates, however, that RTX and related homovanillyl-diterpene esters display distinct spectra of activity. Specific ({sup 3}H)RTX binding provides the first direct proof for the existence of vanilloid receptors. We expect that the RTX class of vanilloids will promote rapid progress in understanding of vanilloid structure/activity requirements and mechanism.

Szallasi, A.; Blumberg, P.M. (National Institutes of Health, Bethesda, MD (USA))

1990-01-01

248

Acidic pH facilitates peripheral ??meATP-mediated nociception in rats: differential roles of P2X, P2Y, ASIC and TRPV1 receptors in ATP-induced mechanical allodynia and thermal hyperalgesia.  

PubMed

Peripheral ischemia is commonly associated with an increase in tissue ATP concentration and a decrease in tissue pH. Although in vitro data suggest that low tissue pH can affect ATP-binding affinities to P2 receptors, the mechanistic relationship between ATP and low pH on peripheral nociception has not been fully examined. This study was designed to investigate the potential role of an acidified environment on intraplantar ??meATP-induced peripheral pain responses in rats. The mechanical allodynia (MA) produced by injection of ??meATP was significantly increased in animals that received the drug diluted in pH 4.0 saline compared to those that received the drug diluted in pH 7.0 saline. Moreover, animals injected with ??meATP (100 nmol) in pH 4.0 saline developed thermal hyperalgesia (TH), which did not occur in animals treated with ??meATP diluted in pH 7.0 saline. To elucidate which receptors were involved in this pH-related facilitation of ??meATP-induced MA and TH, rats were pretreated with PPADS (P2 antagonist), TNP-ATP (P2X antagonist), MRS2179 (P2Y1 antagonist), AMG9810 (TRPV1 antagonist) or amiloride (ASIC blocker). Both PPADS and TNP-ATP dose-dependently blocked pH-facilitated MA, while TH was significantly reduced by pre-treatment with MRS2179 or AMG9810. Moreover, amiloride injection significantly reduced low pH-induced facilitation of ??meATP-mediated MA, but not TH. These results demonstrate that low tissue pH facilitates ATP-mediated MA via the activation of P2X receptors and ASICs, whereas TH induced by ATP under low pH conditions is mediated by the P2Y1 receptor and TRPV1, but not ASIC. Thus distinct mechanisms are responsible for the development of MA and TH under conditions of tissue acidosis and increased ATP. PMID:21172361

Seo, Hyoung-Sig; Roh, Dae-Hyun; Kwon, Soon-Gu; Yoon, Seo-Yeon; Kang, Suk-Yun; Moon, Ji-Young; Choi, Sheu-Ran; Beitz, Alvin J; Lee, Jang-Hern

2010-12-21

249

TRPA1 and TRPV1 are differentially involved in heat nociception of mice.  

PubMed

BACKGROUND: Two transient receptor potential (TRP) channels, TRPV1 and TRPA1, have been physiologically studied with regard to noxious heat transduction. Evidence argues against these channels as sole transducers of noxious heat or cold, respectively. Moreover, in submammalian species the TRPA1 orthologue shows heat sensitivity. METHODS: In vitro, single-fibre and compound action potential recordings from C-fibres as well as measurements of stimulated cutaneous CGRP release are combined with behavioural experiments to assess heat responsiveness in wild type mice, TRPA1 and TRPV1 as well as double-null mutants. RESULTS: Heat thresholds of cutaneous C-mechano-heat sensitive fibres were significantly higher in TRPA1-/- (43?°C) than +/+ (40?°C) mice, and averaged heat responses were clearly weaker, whereas TRPV1-/- showed normal heat thresholds and responses (up to 46?°C). Compound action potential recordings revealed much less activity-dependent slowing of conduction velocity upon noxious heat stimulation in TRPA1-/- and a delayed deficit in TRPV1-/- in comparison to controls. Heat-induced calcitonin gene-related peptide release was reduced in TRPV1-/- but not TRPA1-/- animals. Paw withdrawal latencies to radiant heat were significantly elevated in TRPA1-/-, more so in TRPV1-/- animals. In general, double-null mutants were similar to TRPV1-/- except for the single-fibre heat responses which appeared as weak as in TRPA1-/-. CONCLUSIONS: Our results indicate that in addition to TRPV1, TRPA1 plays a role in heat nociception, in particular in definition of the heat threshold, and might therefore serve as a therapeutic target in acute inflammatory pain. PMID:23720338

Hoffmann, T; Kistner, K; Miermeister, F; Winkelmann, R; Wittmann, J; Fischer, M J M; Weidner, C; Reeh, P W

2013-05-29

250

Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior.  

PubMed

Itch accompanies various skin diseases. As a number of mediators other than histamine can be involved in the itch sensation, H1 receptor antagonists are not necessarily effective in treating itch. External application of antipruritic drugs is occasionally used as an alternative therapy for pruritic skin conditions, such as pruritus on primary non-diseased, non-inflamed skin. Even so, the actual effects of these drugs on the itch sensation have yet to be studied in detail. To verify the antipruritic effects of crotamiton, capsaicin, and a corticosteroid on the itch sensation, we examined the inhibitory effects of these drugs on various pruritogen-induced scratching behaviors in mice. Topical application of 10% crotamiton moderately inhibited histamine-, serotonin-, and PAR-2 agonist-induced scratching behaviors. Topical capsaicin (0.025%) also exerted a moderate suppressive effect on histamine-, substance P-, and PAR-2 agonist-induced itch responses. Notably, topical corticosteroid (0.05% clobetasol propionate) remarkably inhibited the scratching behaviors induced by all of the pruritogenic agents tested. Therapeutic effects of capsaicin on substance P-induced pruritus did not seem to be mediated by desensitization of the TRPV1 (+) C fibers and/or by altered responsiveness of the mast cells. In addition, the antipruritic effects of crotamiton and corticosteroid appear to be, at least partly, associated with a TRPV1-independent pathway. This study examined the itch responses to pruritogens and demonstrated the mode of action of the externally applied antipruritic drugs. PMID:22379965

Sekine, Rika; Satoh, Takahiro; Takaoka, Ayumi; Saeki, Kazumi; Yokozeki, Hiroo

2012-03-01

251

Capsaicin mimics mechanical load-induced intracellular signaling events  

PubMed Central

Mechanical load-induced intracellular signaling events are important for subsequent skeletal muscle hypertrophy. We previously showed that load-induced activation of the cation channel TRPV1 caused an increase in intracellular calcium concentrations ([Ca2+]i) and that this activated mammalian target of rapamycin (mTOR) and promoted muscle hypertrophy. However, the link between mechanical load-induced intracellular signaling events, and the TRPV1-mediated increases in [Ca2+]i are not fully understood. Here we show that administration of the TRPV1 agonist, capsaicin, induces phosphorylation of mTOR, p70S6K, S6, Erk1/2 and p38 MAPK, but not Akt, AMPK or GSK3?. Furthermore, the TRPV1-induced phosphorylation patterns resembled those induced by mechanical load. Our results continue to highlight the importance of TRPV1-mediated calcium signaling in load-induced intracellular signaling pathways.

Ito, Naoki; Ruegg, Urs T.; Kudo, Akira; Miyagoe-Suzuki, Yuko; Takeda, Shin'ichi

2013-01-01

252

The Effects of Capsaicin and Capsiate on Energy Balance: Critical Review and Meta-analyses of Studies in Humans  

PubMed Central

Consumption of spicy foods containing capsaicin, the major pungent principle in hot peppers, reportedly promotes negative energy balance. However, many individuals abstain from spicy foods due to the sensory burn and pain elicited by the capsaicin molecule. A potential alternative for nonusers of spicy foods who wish to exploit this energy balance property is consumption of nonpungent peppers rich in capsiate, a recently identified nonpungent capsaicin analog contained in CH-19 Sweet peppers. Capsiate activates transient receptor potential vanilloid subtype 1 (TRPV1) receptors in the gut but not in the oral cavity. This paper critically evaluates current knowledge on the thermogenic and appetitive effects of capsaicin and capsiate from foods and in supplemental form. Meta-analyses were performed on thermogenic outcomes, with a systematic review conducted for both thermogenic and appetitive outcomes. Evidence indicates that capsaicin and capsiate both augment energy expenditure and enhance fat oxidation, especially at high doses. Furthermore, the balance of the literature suggests that capsaicin and capsiate suppress orexigenic sensations. The magnitude of these effects is small. Purposeful inclusion of these compounds in the diet may aid weight management, albeit modestly.

Ludy, Mary-Jon; Moore, George E.

2012-01-01

253

N-4-t-Butylbenzyl 2-(4-Methylsulfonylaminophenyl) Propanamide TRPV1 Antagonists : Structure Activity Relationships in the A-region  

PubMed Central

Structure activity relationships for the A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamides as TRPV1 antagonists have been investigated. Among them, the 3-fluoro analogue 54 showed high binding affinity and potent antagonism for both rTRPV1 and hTRPV1 in CHO cells. Its stereospecific activity was demonstrated with marked selectivity for the (S)-configuration (54S versus 54R). A docking study of 54S with our hTRPV1 homology model highlighted crucial hydrogen bonds between the ligand and the receptor contributing to its potency.

Kim, Yongsoo; Kil, Min-Jung; Kang, Sang-Uk; Choi, Hyun-Kyung; Ryu, HyungChul; Choi, Yeon-Sil; Cho, Sook-Hyun; Cho, Yongsung; Bhondwe, Rahul S.; Lee, Jin Hee; Choi, Sun; Pearce, Larry V.; Pavlyukovets, Vladimir A.; Morgan, Matthew A.; Tran, Richard; Lazar, Jozsef; Blumberg, Peter M.; Lee, Jeewoo

2013-01-01

254

Capsaicin Activation of the Pain Receptor, VR1: Multiple Open States from Both Partial and Full Binding  

PubMed Central

Capsaicin, the pungent ingredient of hot peppers, has long been used to identify nociceptors. Its molecular target, the vanilloid receptor VR1, was recently cloned and confirmed functionally as a polymodal detector of multiple pain stimuli: heat, acid, and vanilloids. Previous electrophysiology studies have focused on whole-cell characteristics of the receptor. Here, we provide the first in-depth single-channel kinetic study of VR1 to understand its activation mechanism. At low to medium concentrations, channel activity appeared as bursts. Not only did the durations of the interburst gaps vary with capsaicin, the bursts also appeared ligand-dependent, with high capsaicin prolonging bursts and stabilizing openings. Gating involved at least five closed and three open states, with strong correlations between short closures and long openings, and long closures and short openings. Increasing capsaicin reduced the long closures with little effect on short ones. The open time constants changed little with capsaicin concentration, though their relative proportions varied. These results suggest that 1), the channel contains multiple capsaicin binding sites; 2), both partial and full binding are capable of opening the channel; 3), when activated, multiple open states are accessible irrespective of the level of binding; and 4), capsaicin association occurs preferentially to the closed channel.

Hui, Kwokyin; Liu, Beiying; Qin, Feng

2003-01-01

255

Cannabinoid WIN 55,212-2 inhibits TRPV1 in trigeminal ganglion neurons via PKA and PKC pathways  

Microsoft Academic Search

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the\\u000a efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced\\u000a inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic\\u000a cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A “bell”-shaped concentration-dependent curve

Wei Wang; Xuehong Cao; Changjin Liu; Lieju Liu

256

Effect of the tachykinin receptor antagonists, SR 140333, FK 888, and SR 142801, on capsaicin-induced mouse ear oedema  

Microsoft Academic Search

We examined the effect of SR 140333, a nonpeptide NK1 receptor antagonist, FK 888, a peptide NK1 antagonist, and SR 142801, a non-peptide NK3 antagonist, on ear oedema induced by topical application of capsaicin (250 g\\/ear) in mice. SR 140333 (ED50: 39 g\\/kg, i.v.) dose-dependently inhibited the oedema response to capsaicin, whereas FK 888 (1.0 mg\\/kg, i.v.) and SR 142801

H. Inoue; N. Nagata; Y. Koshihara

1996-01-01

257

Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels  

PubMed Central

Background and purpose: Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-?-sanshool (?-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations. Experimental approach: The structure–activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds' aversive responses were measured in a taste brief-access test. Key results: For TRPA1 activation, the cis C6 double bond in the polyenic chain of ?-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to ?-SOH. Conclusions and implications: The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds.

Riera, CE; Menozzi-Smarrito, C; Affolter, M; Michlig, S; Munari, C; Robert, F; Vogel, H; Simon, SA; le Coutre, J

2009-01-01

258

Sex Differences in Serotonin Enhancement of Capsaicin-evoked Calcitonin Gene-Related Peptide Release from Human Dental Pulp  

PubMed Central

Serotonin (5HT) is a pronociceptive mediator in the periphery and evidence implicates involvement in trigeminal pain processing. However, the mechanism(s) by which 5HT modulates trigeminal nociceptors remains unclear. Trigeminal pain can be evoked by the transient receptor potential V1 channel (TRPV1), which is expressed by nociceptive trigeminal neurons and induces release of proinflammatory calcitonin gene-related peptide (CGRP). In our preclinical models, 5HT evoked thermal hyperalgesia and enhanced calcium influx and CGRP release from the TRPV1 population of trigeminal nociceptors. Whether this occurs in humans is unknown. As dental pulp is densely innervated by trigeminal nociceptors, routine tooth extractions offer a unique opportunity to examine whether 5HT enhances CGRP release from human nociceptors. Pulpal tissue was collected from 140 extracted molar teeth from men and women and basal release samples were collected prior to treatment with saline or 5HT 100 ?M. CGRP release was then stimulated with the TRPV1 agonist capsaicin 1 ?M and quantitated by enzyme immunoassay. Additional samples were collected for western blots to examine 5HT receptor expression. We report that 5HT induced a significant increase in capsaicin-evoked CGRP release and this enhancement was observed only in female dental pulp, with no effect of 5HT on male dental pulp. The greatest amount of CGRP release occurred in dental pulp from women in the luteal phase of the menstrual cycle. These results indicate that 5HT enhances capsaicin-evoked CGRP release from human trigeminal nociceptors in a sexually dimorphic manner providing a mechanistic basis for prevalence of trigeminal pain disorders in women.

Loyd, Dayna R.; Sun, Xiaoling X.; Locke, Erin E.; Salas, Margaux M.; Hargreaves, Kenneth M.

2012-01-01

259

Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide.  

PubMed

Calcitonin gene-related peptide (CGRP), the principal transmitter in sensory nerves, could also be expressed in vascular endothelium. Transient receptor potential vanilloid 1(TRPV1), which modulates the synthesis and release of CGRP in sensory nerves, is also present in endothelial cells. The present study tested whether TRPV1 modulates the release and synthesis of CGRP in endothelial cells, and evaluated the protective effect of endothelial cell-derived CGRP. Human umbilical vein endothelial cells (HUVECs) were treated with capsaicin or hyperthermia. The level of CGRP mRNA was detected by RT-PCR, and protein level was measured by radioimmunoassay. Endothelial cell injury was induced by lysophosphatidylcholine, and evaluated by cell viability and lactate dehydrogenase activity. HUVECs expressed CGRP, both alpha- and beta-subtype. Capsaicin increased the level of CGRP in the culture medium, and up-regulated the expression of CGRP in endothelial cells. Hyperthermia also increased the level of CGRP mRNA. These effects were abolished by capsazepine, a competitive antagonist of TRPV1. Capsaicin significantly attenuated the endothelial cell damage induced by LPC, which was prevented and aggravated by capsazepine or CGRP(8-37,) antagonist of CGRP receptor. These results indicate that TRPV1 also regulates the expression and secretion of endothelial cell-derived CGRP, which affords protective effects on endothelial cells. PMID:18584893

Luo, Dan; Zhang, Yi-Wei; Peng, Wei-Jie; Peng, Jun; Chen, Qing-Quan; Li, Dai; Deng, Han-Wu; Li, Yuan-Jian

2008-06-03

260

Capsaicin stimulates the non-store-operated Ca{sup 2+} entry but inhibits the store-operated Ca{sup 2+} entry in neutrophils  

SciTech Connect

Rat neutrophils express the mRNA encoding for transient receptor potential (TRP) V1. However, capsaicin-stimulated [Ca{sup 2+}]{sub i} elevation occurred only at high concentrations ({>=}100 {mu}M). This response was substantially decreased in a Ca{sup 2+}-free medium. Vanilloids displayed similar patterns of Ca{sup 2+} response with the rank order of potency as follows: scutigeral>resiniferatoxin>capsazepine>capsaicin=olvanil>isovelleral. Arachidonyl dopamine (AAD), an endogenous ligand for TRPV1, failed to desensitize the subsequent capsaicin challenge. Capsaicin-induced Ca{sup 2+} response was not affected by 8-bromo-cyclic ADP-ribose (8-Br-cADPR), the ryanodine receptor blocker, but was slightly attenuated by 1-[6-[17{beta}-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,= 5-dione (U-73122), the inhibitor of phospholipase C-coupled processes, 1-[{beta}-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole (SKF-96365), the blocker of receptor-gated and store-operated Ca{sup 2+} (SOC) channels, 2-aminoethyldiphenyl borate (2-APB), the blocker of D-myo-inositol 1,4,5-trisphospahte (IP{sub 3}) receptor and Ca{sup 2+} influx, and by ruthenium red, a blocker of TRPV channels, and enhanced by the Ca{sup 2+} channels blocker, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12330A) and Na{sup +}-deprivation. In addition, capsaicin had no effect on the plasma membrane Ca{sup 2+}-ATPase activity or the production of nitric oxide (NO) and reactive oxygen intermediates (ROI) or on the total thiols content. Capsaicin ({>=}100 {mu}M) inhibited the cyclopiazonic acid (CPA)-induced store-operated Ca{sup 2+} entry (SOCE). In the absence of external Ca{sup 2+}, the robust Ca{sup 2+} entry after subsequent addition of Ca{sup 2+} was decreased by capsaicin in CPA-activated cells. Capsaicin alone increased the actin cytoskeleton, and also increased the actin filament content in cell activation with CPA. These results indicate that capsaicin activates a TRPV1-independent non-SOCE pathway in neutrophils. The reorganization of the actin cytoskeleton is probably involved in the capsaicin inhibition of SOCE.

Wang, J.-P. [Department of Education and Research, Taichung Veterans General Hospital, 160, Sec. 3, Chung Kang Road, Taichung 407, Taiwan (China) and Graduate Institute of Pharmaceutical Chemistry, School of Pharmacy, Taichung, Taiwan (China)]. E-mail: w1994@vghtc.gov.tw; Tseng, C.-S. [Department of Anesthesiology, and Taichung Veterans General Hospital, Taichung, Taiwan (China); Sun, S.-P. [Department of Education and Research, Taichung Veterans General Hospital, 160, Sec. 3, Chung Kang Road, Taichung 407, Taiwan (China); Chen, Y.-S. [Department of Education and Research, Taichung Veterans General Hospital, 160, Sec. 3, Chung Kang Road, Taichung 407, Taiwan (China); Tsai, C.-R. [Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan (China); Hsu, M.-F. [Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan (China)

2005-12-01

261

TRPV1 and TRPV4 Play Pivotal Roles in Delayed Onset Muscle Soreness  

PubMed Central

Unaccustomed strenuous exercise that includes lengthening contraction (LC) often causes tenderness and movement related pain after some delay (delayed-onset muscle soreness, DOMS). We previously demonstrated that nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) are up-regulated in exercised muscle through up-regulation of cyclooxygenase (COX)-2, and they sensitized nociceptors resulting in mechanical hyperalgesia. There is also a study showing that transient receptor potential (TRP) ion channels are involved in DOMS. Here we examined whether and how TRPV1 and/or TRPV4 are involved in DOMS. We firstly evaluated a method to measure the mechanical withdrawal threshold of the deep tissues in wild-type (WT) mice with a modified Randall-Selitto apparatus. WT, TRPV1?/? and TRPV4?/? mice were then subjected to LC. Another group of mice received injection of murine NGF-2.5S or GDNF to the lateral gastrocnemius (LGC) muscle. Before and after these treatments the mechanical withdrawal threshold of LGC was evaluated. The change in expression of NGF, GDNF and COX-2 mRNA in the muscle was examined using real-time RT-PCR. In WT mice, mechanical hyperalgesia was observed 6–24 h after LC and 1–24 h after NGF and GDNF injection. LC induced mechanical hyperalgesia neither in TRPV1?/? nor in TRPV4?/? mice. NGF injection induced mechanical hyperalgesia in WT and TRPV4?/? mice but not in TRPV1?/? mice. GDNF injection induced mechanical hyperalgesia in WT but neither in TRPV1?/? nor in TRPV4?/? mice. Expression of NGF and COX-2 mRNA was significantly increased 3 h after LC in all genotypes. However, GDNF mRNA did not increase in TRPV4?/? mice. These results suggest that TRPV1 contributes to DOMS downstream (possibly at nociceptors) of NGF and GDNF, while TRPV4 is located downstream of GDNF and possibly also in the process of GDNF up-regulation.

Ota, Hiroki; Katanosaka, Kimiaki; Murase, Shiori; Kashio, Makiko; Tominaga, Makoto; Mizumura, Kazue

2013-01-01

262

Effect of capsaicin on potassium conductance and electromotility of guinea pig outer hair cell  

PubMed Central

Capsaicin, the classic activator of TRPV-1 channels in primary sensory neurons, evokes nociception. Interestingly, auditory reception is also modulated by this chemical, possibly by direct actions on outer hair cells (OHCs). Surprisingly, we find two novel actions of capsaicin unrelated to TRPV-1 channels, which likely contribute to its auditory effects in vivo. First, capsaicin is a potent blocker of OHC K conductances (IK and IK,n). Second, capsaicin substantially alters OHC nonlinear capacitance, the signature of electromotility – a basis of cochlear amplification. These new findings of capsaicin have ramifications for our understanding of the pharmacological properties of OHC IK, IK,n and electromotility and for interpretation of capsaicin pharmacological actions.

Wu, T; Song, L; Shi, X; Jiang, Z; Santos-Sacchi, J; Nuttall, A.L

2012-01-01

263

[Characterization of afferent neurons of spinal ganglions sensitive to capsaicin].  

PubMed

Morphological features of TRPV1(+)-, SP(+)-, CGRP(+)-, NF200(+)-neurons has been studied in thoracic spinal ganglions in 3-month-old rats under chemical deafferentation. The results have shown that from 6.5 up to 41.3% of ganglionic neurons of control group had markers mentioned above. The heterogeneity of nociceptive neurons in control group was kept in capsaicin-treated animals. In both groups, TRPV1(+)-neurons were prevailed, populations of SP(+)-, CGRP(+)- and NF200(+)-neurons formed smaller groups. Sensitivity to capsaicin was shown in largest neurons in each population; neurons in experimental group had smaller cross-sectional area, particularly in group of TRPV1(+)-neurons. PMID:23461032

Porseva, V V

2012-01-01

264

Identification of a Tetrameric Assembly Domain in the C Terminus of Heat-activated TRPV1 Channels*  

PubMed Central

Transient receptor potential (TRP) channels as cellular sensors are thought to function as tetramers. Yet, the molecular determinants governing channel multimerization remain largely elusive. Here we report the identification of a segment comprising 21 amino acids (residues 752–772 of mouse TRPV1) after the known TRP-like domain in the channel C terminus that functions as a tetrameric assembly domain (TAD). Purified recombinant C-terminal proteins of TRPV1–4, but not the N terminus, mediated the protein-protein interaction in an in vitro pulldown assay. Western blot analysis combined with electrophysiology and calcium imaging demonstrated that TAD exerted a robust dominant-negative effect on wild-type TRPV1. When fused with the membrane-tethered peptide Gap43, the TAD blocked the formation of stable homomultimers. Calcium imaging and current recordings showed that deletion of the TAD in a poreless TRPV1 mutant subunit suppressed its dominant-negative phenotype, confirming the involvement of the TAD in assembly of functional channels. Our findings suggest that the C-terminal TAD in TRPV1 channels functions as a domain that is conserved among TRPV1–4 and mediates a direct subunit-subunit interaction for tetrameric assembly.

Zhang, Feng; Liu, Shuang; Yang, Fan; Zheng, Jie; Wang, KeWei

2011-01-01

265

Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1.  

PubMed

Primary astrocytomas of grade 3 or 4 according to the classification system of the World Health Organization (high-grade astrocytomas or HGAs) are preponderant among adults and are almost invariably fatal despite the use of multimodal therapy. Here we show that the juvenile brain has an endogenous defense mechanism against HGAs. Neural precursor cells (NPCs) migrate to HGAs, reduce glioma expansion and prolong survival time by releasing endovanilloids that activate the vanilloid receptor (transient receptor potential vanilloid subfamily member-1 or TRPV1) on HGA cells. TRPV1 is highly expressed in tumor and weakly expressed in tumor-free brain. TRPV1 stimulation triggers tumor cell death through the branch of the endoplasmic reticulum stress pathway that is controlled by activating transcription factor-3 (ATF3). The antitumorigenic response of NPCs is lost with aging. NPC-mediated tumor suppression can be mimicked in the adult brain by systemic administration of the synthetic vanilloid arvanil, suggesting that TRPV1 agonists have potential as new HGA therapeutics. PMID:22820645

Stock, Kristin; Kumar, Jitender; Synowitz, Michael; Petrosino, Stefania; Imperatore, Roberta; Smith, Ewan St J; Wend, Peter; Purfürst, Bettina; Nuber, Ulrike A; Gurok, Ulf; Matyash, Vitali; Wälzlein, Joo-Hee; Chirasani, Sridhar R; Dittmar, Gunnar; Cravatt, Benjamin F; Momma, Stefan; Lewin, Gary R; Ligresti, Alessia; De Petrocellis, Luciano; Cristino, Luigia; Di Marzo, Vincenzo; Kettenmann, Helmut; Glass, Rainer

2012-07-22

266

Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain  

PubMed Central

Background Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Despite the availability of pharmacologic treatments, chronic inflammatory pain remains inadequately treated. Understanding the nociceptive signaling pathways of such pain is therefore important in developing long-acting treatments with limited side effects. High local proton concentrations (tissue acidosis) causing direct excitation or modulation of nociceptive sensory neurons by proton-sensing receptors are responsible for pain in some inflammatory pain conditions. We previously found that all four proton-sensing G-protein-coupled receptors (GPCRs) are expressed in pain-relevant loci (dorsal root ganglia, DRG), which suggests their possible involvement in nociception, but their functions in pain remain unclear. Results In this study, we first demonstrated differential change in expression of proton-sensing GPCRs in peripheral inflammation induced by the inflammatory agents capsaicin, carrageenan, and complete Freund's adjuvant (CFA). In particular, the expression of TDAG8, one proton-sensing GPCR, was increased 24 hours after CFA injection because of increased number of DRG neurons expressing TDAG8. The number of DRG neurons expressing both TDAG8 and transient receptor potential vanilloid 1 (TRPV1) was increased as well. Further studies revealed that TDAG8 activation sensitized the TRPV1 response to capsaicin, suggesting that TDAG8 could be involved in CFA-induced chronic inflammatory pain through regulation of TRPV1 function. Conclusion Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia.

Chen, Ying-Ju; Huang, Chia-Wei; Lin, Chih-Shin; Chang, Wen-Han; Sun, Wei-Hsin

2009-01-01

267

Effects of aerosol-applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats.  

PubMed Central

1. Capsaicin, prostaglandin E2 (PGE2) and histamine are potent stimuli for reflex coughing and bronchoconstriction in many species including man. We have studied the effects of solutions of capsaicin, PGE2 and histamine on airway sensory receptors when administered as inhaled aerosols to the lower respiratory tract in anaesthetized, paralysed and artificially ventilated cats. 2. Histamine, administered by aerosol (6 breaths of a 1 mg ml-1 solution) and intravenously (10 micrograms kg-1), caused an increase in the rate of discharge from rapidly adapting stretch receptors (RARs) and caused bronchoconstriction. 3. Six breaths of a capsaicin aerosol generated from solutions of 0.1 or 1 mg ml-1 stimulated six out of nine RARs tested. Bronchoconstriction occurred with and without RAR stimulation. The diluent for the capsaicin aerosol had no significant effect on pulmonary mechanics or rate of RAR discharge. 4. Administration of increasing concentrations (0.001-1 mg ml-1) of PGE2 aerosol given in six breaths (at 6 min intervals) caused a dose-dependent increase in the rate of discharge of eight RARs tested and caused bronchoconstriction. The diluent for the PGE2 aerosol had no effect on pulmonary mechanics or rate of RAR discharge. 5. Inhalation of aerosols of histamine (6 breaths of 1 mg ml-1 solution) and capsaicin (3 breaths of 0.1 mg ml-1 solution) stimulated all six lung C fibre endings studied (3 pulmonary and 3 bronchial). These aerosols of capsaicin and histamine also caused bronchoconstriction. 6. We conclude that solutions of capsaicin and PGE2, when delivered by aerosol to the airway epithelial surface, are not selective stimulants of C fibres. Both agents can stimulate RARs. Activation of some but not all RARs tested, by inhaled capsaicin, suggests that there are subpopulations of capsaicin-sensitive and -insensitive receptors. Stimulation of airway RARs by a range of pharmacologically active agents released by airway inflammation may contribute to reflex coughing and bronchoconstriction in man. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 Fig. 6

Mohammed, S P; Higenbottam, T W; Adcock, J J

1993-01-01

268

Association of genetic variations in neurokinin-2 receptor with enhanced cough sensitivity to capsaicin in chronic cough  

PubMed Central

Background Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non?productive chronic cough have not been reported. Methods Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin?1 and neurokinin?2 receptors (NK?1R and NK?2R, respectively). Informative non?synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK?1R and NK?2R genotypes was evaluated. Results Two informative SNPs were identified in NK?2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK?1R. After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p?=?0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p?=?0.003; OR 1.71 (95% CI 1.20 to 2.24)]. Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8)??M/l, p?=?0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0)??M/l, p?=?0.03). Conclusions The results of this study suggest that NK?2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.

Park, H-K; Oh, S-Y; Kim, T-B; Bahn, J-W; Shin, E-S; Lee, J-E; Oh, H-B; Kim, Y-K; Park, T; Cho, S-H; Min, K-U; Kim, Y-Y

2006-01-01

269

Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid  

Microsoft Academic Search

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured

M Fujimura; S Sakamoto; Y Kamio; T Matsuda

1992-01-01

270

Medium and large injured dorsal root ganglion cells increase TRPV-1, accompanied by increased alpha2C-adrenoceptor co-expression and functional inhibition by clonidine.  

PubMed

Some electrophysiologic studies demonstrate new, excitatory alpha2-adrenoceptors on peripheral nociceptors and their dorsal root ganglion (DRG) cell bodies after nerve injury, yet administration of alpha2-adrenoceptor agonists at these sites reduces hypersensitivity rather than worsens it. Since TRPV-1 expressing nociceptor afferents are important in many pain states, we examined the expression of this channel and its co-expression with alpha2C-adrenoceptors in injured DRG cell bodies and the ability of alpha2-adrenoceptors to inhibit responses to stimulation. Rats underwent tight ligation of the left L5 and L6 spinal nerves, followed by behavioral testing, removal of L5 and L6 DRGs, and either immunostaining for TRPV-1 channels and alpha2C-adrenoceptors or intracellular calcium videomicroscopy in response to electrical field stimulation before and after perfusion with clonidine and capsaicin. Spinal nerve ligation produced tactile allodynia. In normal and sham controls, about one-third of DRG neurons were TRPV-1-immunoreactive (IR), one half were alpha2C-adrenoceptor-IR and one-fourth co-expressed both. After nerve ligation there was a reduction in the number of small, strongly TRPV-1-IR or alpha2C-adrenoceptor-IR neurons, but an increase in medium and large, lightly stained cells and in their co-expression. The proportion of clonidine inhibited cells which responded to capsaicin increased 5 fold after injury. We conclude that TRPV-1 and alpha2C-adrenoceptors are up-regulated in some injured medium and large size neurons after nerve ligation. Increased co-expression by immunocytochemistry, and increased proportion of cells inhibited by clonidine and expressing functional TRPV-1 channels suggest that these cells may play an important role in the analgesic effects of alpha2-adrenoceptor agonists in neuropathic pain. PMID:15661448

Ma, Weiya; Zhang, Yong; Bantel, Carsten; Eisenach, James C

2005-02-01

271

Removing TRPV1-expressing Primary Afferent Neurons Potentiates the Spinal Analgesic Effect of ?-Opioid Agonists on Mechano-Nociception  

PubMed Central

Most ?-opioid receptors are located on the presynaptic terminals of primary afferent neurons in the spinal cord. However, their presence in different phenotypes of primary afferent neurons and their contribution to the analgesic effect of ?-opioid agonists are not fully known. Resiniferatoxin (RTX) is an ultra-potent transient receptor potential vanilloid type 1 channel (TRPV1) agonist and can selectively remove TRPV1-expressing primary afferent neurons. In this study, we determined the role of ?-opioid receptors expressed on TRPV1 sensory neurons in the antinociceptive effect of the ?-opioid receptor agonists [d-Pen2,d-Pen5]-enkephalin and [d-Ala2,Glu4]-deltorphin. Nociception was measured by testing the mechanical withdrawal threshold in the hindpaw of rats. Changes in the ?-opioid receptors were assessed using immunocytochemistry and the [3H]-naltrindole radioligand binding. In RTX-treated rats, the ?-opioid receptor on TRPV1-immunoreactive dorsal root ganglion neurons and afferent terminals in the spinal cord was diminished. RTX treatment also significantly reduced the maximal specific binding sites (31%) of the ?-opioid receptors in the dorsal spinal cord. Interestingly, intrathecal injection of [d-Pen2,d-Pen5]-enkephalin or [d-Ala2,Glu4]-deltorphin produced a large and prolonged increase in the nociceptive threshold in RTX-treated rats. These findings indicate that loss of TRPV1-expressing afferent neurons leads to a substantial reduction in presynaptic ?-opioid receptors in the spinal dorsal horn. However, the effect of ?-opioid agonists on mechano-nociception is paradoxically potentiated in the absence of TRPV1-expressing sensory neurons. This information is important to our understanding of the cellular sites and mechanisms underlying the spinal analgesic effect of ?-opioid agonists.

Chen, Shao-Rui; Pan, Hui-Lin

2008-01-01

272

Contribution of peripheral vanilloid receptor to the nociception induced by injection of spermine in mice  

Microsoft Academic Search

Polyamines (putrescine, spermidine and spermine) are important endogenous regulators of ion channels, such as vanilloid (TRPV1), glutamatergic (NMDA or AMPA\\/kainate) and acid-sensitive (ASIC) receptors. In the present study, we have investigated the possible nociceptive effect induced by polyamines and the mechanisms involved in this nociception in vivo. The subcutaneous (s.c.) injection of capsaicin (as positive control), spermine, spermidine or putrescine

Camila Gewehr; Mariane Arnoldi da Silva; Gabriela Trevisan dos Santos; Mateus Fortes Rossato; Sara Marchesan de Oliveira; Carine Cristiane Drewes; Andréia Martini Pazini; Gustavo Petri Guerra; Maribel A. Rubin; Juliano Ferreira

2011-01-01

273

Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain.  

PubMed

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model. PMID:23091405

Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B Yukihiro

2012-10-02

274

Aberrant TRPV1 Expression in Heat Hyperalgesia Associated with Trigeminal Neuropathic Pain  

PubMed Central

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B. Yukihiro

2012-01-01

275

Role of endogenous TRPV1 agonists in a postburn pain model of partial-thickness injury.  

PubMed

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24h after thermal injury, with allodynia being maintained for up to 7d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C(14)]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1. PMID:23891895

Green, Dustin P; Ruparel, Shivani; Roman, Linda; Henry, Michael A; Hargreaves, Kenneth M

2013-07-26

276

Developmental toxicity study of pure trans-capsaicin in rats and rabbits.  

PubMed

Human environmental and dietary exposure to trans-capsaicin--the pungent ingredient in chili peppers--is ubiquitous. Moreover, based on the highly selective agonism of trans-capsaicin for TRPV1 receptors, drug products containing high concentrations of trans-capsaicin are under development as analgesics. For instance, a high-concentration (8% w/w) pure trans-capsaicin dermal patch (designated NGX-4010) is in advanced clinical evaluation for the management of neuropathic pain of peripheral origin. Our objective was to investigate effects of trans-capsaicin on embryo/fetal development, consequent to maternal exposure, from implantation to closure of the hard palate. trans-Capsaicin was delivered systemically by means of either a patch [NGX-4010 (25, 37.5, or 50 cm(2))] to pregnant Sprague-Dawley rats on days of presumed gestation (DGs) 7 through 17, or via a 10% w/v capsaicin liquid formulation (CLF), at dosages of 3, 6.5 or 13 mul/cm(2) applied to a 200-cm(2) area on the back on DGs 7 though 19 to timed-mated New Zealand white rabbits. In rats, the maternal no-observable-effect level (NOEL) was less than 25 cm(2) but no cesarean-sectioning or litter parameters were affected by application of NGX-4010 at patch sizes as high as 50 cm(2). The only test article-related observations were delays in skeletal ossification, evident as significant reductions in the average number of metatarsals and ossified hindlimb and forelimb phalanges that occurred in the 50 cm(2) NGX-4010 dose group. Although the values for ossified metatarsals were outside the historical control range, ossified hindlimb and forelimb phalanges were within historical control ranges. No other gross external, soft tissue, or skeletal fetal alterations (malformations or variations) were caused by application of the NGX-4010. In rabbits, the maternal NOEL was less than 3 mul/cm(2) CLF (or 0.3 mg/cm(2)trans-capsaicin) per 200 cm(2), but no cesarean-sectioning or litter parameters were affected. No fetal alterations (malformations or variations) were caused by dosages of CLF as high as 13 mul/cm(2) (or 1.3 mg/cm(2)trans-capsaicin). Taken together, these data suggest that tran s-capsaicin should not be considered a developmental toxicant. PMID:16717036

Chanda, Sanjay; Sharper, Valerie; Hoberman, Alan; Bley, Keith

277

Novel vanilloid receptor-1 antagonists: 1. Conformationally restricted analogues of trans-cinnamides.  

PubMed

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughput screening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated the antihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailable cinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis and biological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound 9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitable isosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79 and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC50 = 4.5 and 0.6 nM, respectively) and human TRPV1 (IC50 = 7.4 and 3.7 nM, respectively). In addition, compound 74 was shown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia induced by complete Freund's adjuvant in rats. PMID:17585749

Norman, Mark H; Zhu, Jiawang; Fotsch, Christopher; Bo, Yunxin; Chen, Ning; Chakrabarti, Partha; Doherty, Elizabeth M; Gavva, Narender R; Nishimura, Nobuko; Nixey, Thomas; Ognyanov, Vassil I; Rzasa, Robert M; Stec, Markian; Surapaneni, Sekhar; Tamir, Rami; Viswanadhan, Vellarkad N; Treanor, James J S

2007-06-22

278

Locomotor Networks are Targets of Modulation by Sensory Transient Receptor Potential Vanilloid 1 and Transient Receptor Potential Melastatin 8 Channels  

PubMed Central

It is well recognized that proprioceptive afferent inputs can control the timing and pattern of locomotion. C and A? afferents can also affect locomotion but an unresolved issue is the identity of the subsets of these afferents that encode defined modalities. Over the last decade, the transient receptor potential (TRP) ion channels have emerged as a family of non-selective cation conductances that can label specific subsets of afferents. We focus on a class of TRPs known as ThermoTRPs which are well known to be sensor receptors that transduce changes in heat and cold. ThermoTRPs are known to help encode somatosensation and painful stimuli, and receptors have been found on C and A? afferents with central projections onto dorsal horn laminae. Here we show, using in vitro neonatal mouse spinal cord preparations, that activation of both spinal and peripheral transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential melastatin 8 (TRPM8) afferent terminals modulates central pattern generators (CPGs). Capsaicin or menthol and cooling modulated both sacrocaudal afferent (SCA) evoked and monoaminergic drug-induced rhythmic locomotor-like activity in spinal cords from wild type but not TRPV1-null (trpv1?/?) or TRPM8-null (trpm8?/?) mice, respectively. Capsaicin induced an initial increase in excitability of the lumbar motor networks, while menthol or cooling caused a decrease in excitability. Capsaicin and menthol actions on CPGs involved excitatory and inhibitory glutamatergic mechanisms, respectively. These results for the first time show that dedicated pathways of somatosensation and pain identified by TRPV1 or TRPM8 can target spinal locomotor CPGs.

Mandadi, S.; Nakanishi, S. T.; Takashima, Y.; Dhaka, A.; Patapoutian, A.; McKemy, D. D.; Whelan, P. J.

2010-01-01

279

Palvanil, a non-pungent capsaicin analogue, inhibits inflammatory and neuropathic pain with little effects on bronchopulmonary function and body temperature.  

PubMed

N-Palmitoyl-vanillamide (palvanil) is a non-pungent capsaicinoid, found in low amounts in Capsicum and shown to rapidly desensitize transient receptor potential vanilloid type-1 (TRPV1) channels to the action of capsaicin and to exert analgesic effects after local administration. We have investigated here if systemic administration of palvanil to mice causes two typical adverse events of TRPV1 agonists, i.e. profound changes in body temperature and bronchoconstriction, and if it can still produce effective inhibition of inflammatory and chronic pain in different experimental models. Varying doses of palvanil were tested subcutaneously and acutely on body temperature in vivo or, or as a bolus, on bronchopulmunary function ex vivo, in comparison with capsaicin. Intraperitoneal palvanil was also tested against formalin-induced nocifensive behavior and carrageenan-induced oedema and thermal hyperalgesia, acutely, and against mechanical allodynia and thermal hyperalgesia in mice with spared nerve injury (SNI) of the sciatic nerve, after repeated administration over 7 days from SNI. Palvanil, at therapeutically relevant doses, produced significantly less hypothermia and bronchoconstriction than capsaicin. Palvanil (0.5-2.5 mg/kg) abolished formalin-induced nocifensive behavior and strongly attenuated SNI-induced mechanical allodynia and thermal hyperalgesia and carrageenan-induced oedema and thermal hyperalgesia. Systemic administration of the non-pungent capsaicinoid, palvanil, produces, at least in mice, much less of those side effects typical of TRPV1 agonists (hypothermia and bronchoconstriction), whilst being very effective at reducing pain and oedema. Thus, palvanil might be developed further as a novel pharmacological treatment for chronic abnormal pain. PMID:22634607

Luongo, Livio; Costa, Barbara; D'Agostino, Bruno; Guida, Francesca; Comelli, Francesca; Gatta, Luisa; Matteis, Maria; Sullo, Nikol; De Petrocellis, Luciano; de Novellis, Vito; Maione, Sabatino; Di Marzo, Vincenzo

2012-05-24

280

Differential chemosensory function and receptor expression of splanchnic and pelvic colonic afferents in mice  

PubMed Central

Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here we determined whether these pathways also differ in their chemosensitivity and receptor expression. Using an in vitro mouse colon preparation, individual primary afferents were tested with selective P2X and transient receptor potential vanilloid receptor 1 (TRPV1) receptor ligands. Afferent cell bodies in thoracolumbar and lumbosacral dorsal root ganglia (DRG) were retrogradely labelled from the colon and analysed for P2X3- and TRPV1-like immunoreactivity (LI). Forty per cent of LSN afferents responded to ?,?-methylene adenosine 5?-triphosphate (?,?-meATP; 1 mm), an effect that was concentration dependent and reversed by the P2X antagonist pyridoxyl5-phosphate 6-azophenyl-2?,4?-disulphonic acid (PPADS) (100 ?m). Significantly fewer PN afferents (7%) responded to ?,?-meATP. Correspondingly, 36% of colonic thoracolumbar DRG neurones exhibited P2X3-LI compared with only 19% of colonic lumbosacral neurones. Capsaicin (3 ?m) excited 61% of LSN afferents and 47% of PN afferents; 82% of thoracolumbar and 50% of lumbosacral colonic DRG neurones displayed TRPV1-LI. Mechanically insensitive afferents were recruited by ?,?-meATP or capsaicin, and were almost exclusive to the LSN. Capsaicin-responsive LSN afferents displayed marked mechanical desensitization after responding to capsaicin, which did not occur in capsaicin-responsive PN afferents. Therefore, colonic LSN and PN pathways differ in their chemosensitivity to known noxious stimuli and their corresponding receptor expression. As these pathways relay information that may relate to symptoms in functional gastrointestinal disease, these results may have implications for the efficacy of therapies targeting receptor modulation.

Brierley, Stuart M; Carter, R; Jones, W; Xu, Linjing; Robinson, David R; Hicks, Gareth A; Gebhart, GF; Blackshaw, L Ashley

2005-01-01

281

Dietary agonists of TRPV1 inhibit gastric acid secretion in mice.  

PubMed

Capsaicin and 6-gingerol, pungent components of chilli pepper and ginger, are known as dietary agonists of transient receptor potential vanilloid-1. Transient receptor potential vanilloid-1 nerve fibers are recognized to play a role in gastric mucosal integrity in rats. In the present studies, we examined the acute effects of peroral administration of capsaicin and 6-gingerol on gastric acid secretion in conscious mice. These agents were given p.?o. 30?min before the pylorus was ligated. Oral administration of capsaicin (1.0-100?mg/kg) or 6-gingerol (1.5-50?mg/kg) significantly and dose-dependently inhibited basal acid secretion. Pretreatment with BCTC, a transient receptor potential vanilloid-1 antagonist, significantly reversed the reduced basal acid secretion by capsaicin or 6-gingerol. The combination of the lowest doses of capsaicin and 6-gingerol markedly inhibited basal acid secretion in conscious mice and this was also significantly reversed by BCTC. Moreover, the combination of the maximal dose of capsaicin and 6-gingerol inhibited basal acid secretion only to the level of a single administration of the maximal dose of capsaicin. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on the inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1. In separate experiments, intraduodenal administration of either capsaicin (30?mg/kg) or 6-gingerol (15?mg/kg), whose doses were observed to have a significant inhibitory effect by oral administration, tended to inhibit basal acid secretion compared with the vehicle. These results suggest that the combination of capsaicin and 6-gingerol has an additive effect on inhibition of gastric acid secretion through activation of transient receptor potential vanilloid-1, and oral administration of transient receptor potential vanilloid-1 agonists directly stimulates transient receptor potential vanilloid-1 in the gastric lumen, resulting in a potent reduction of gastric acid secretion. PMID:23047250

Okumi, Hirokuni; Tashima, Kimihito; Matsumoto, Kenjiro; Namiki, Takao; Terasawa, Katsutoshi; Horie, Syunji

2012-10-09

282

Particulate Matter Initiates Inflammatory Cytokine Release by Activation of Capsaicin and Acid Receptors in a Human Bronchial Epithelial Cell Line  

Microsoft Academic Search

Recent experiments have shown that human bronchial epithelial cells (i.e., BEAS-2B) release pro-inflammatory cytokines (i.e., IL-6 and TNF?) in a receptor-mediated fashion in response to the neuropeptides, substance P (SP), calcitonin gene-related protein (CGRP), and the prototype botanical irritant capsaicin. In the present experiments, we examined the relevance of these receptors to particulate matter (PM)-associated cellular inflammation. BEAS-2B cells, exposed

B. Veronesi; M. Oortgiesen; J. D. Carter; R. B. Devlin

1999-01-01

283

NF-?B feedback control of JNK1 activation modulates TRPV1-induced increases in IL-6 and IL-8 release by human corneal epithelial cells  

PubMed Central

Purpose The corneal wound healing response to an alkali burn results in dysregulated inflammation and opacity. Transient receptor potential vanilloid type1 (TRPV1) ion channel activation by such a stress contributes to this unfavorable outcome. Accordingly, we sought to identify potential drug targets for mitigating this response, in human corneal epithelial cells (HCEC). Methods SV40-immmortalized HCEC were transduced with lentiviral vectors to establish stable c-Jun N-terminal kinase1 (JNK1), nuclear factor-?B1 (NF-?B1), and dual specificity phsophatase1 (DUSP1) shRNAmir sublines. Immunoblotting evaluated the expression of NF-?B1, DUSP1, protein kinase C? (PKC?), and the phosphorylation status of cell signaling mediators. Enzyme-linked immunosorbent assay (ELISA) evaluated interleukin-6 (IL-6) and interleukin-8 (IL-8) release. Results Capsaicin (CAP; a selective TRPV1 agonist), induced time-dependent activation of transforming growth factor-activated kinase 1 (TAK1) and mitogen-activated protein kinase (MAPK) cascades temporally followed by increased nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (I?B?) phosphorylation, rises in both PKC? protein levels and IL-6 and IL-8 release. All of these responses were blocked by the TAK1 inhibitor 5z-7-oxozeaenol (5z-OX). In the JNK1 subline, CAP failed to increase IL-6/8 release, but still stimulated NF-?B by 50%. In the NF-?B1 subline, these IL-6/8 responses were absent, JNK1 activation was attenuated and there was a concomitant increase in DUSP1 expression compared to the control. In the DUSP1 subline, JNK1 phosphorylation was enhanced and prolonged and accompanied by larger increases in IL-6/8 release. Conclusions TRPV1 induced increases in IL-6/IL-8 release occur through TAK1 activation of JNK1-dependent and JNK1-independent signaling pathways. Their joint activation is required for NF-?B to elicit sufficient positive feedback control of JNK1/2 phosphorylation to elicit increases in IL-6/8 release. Such regulation depends on NF-?B modulation of DUSP1 expression levels and associated changes in PKC? protein levels.

Wang, Z.; Yang, Y.; Yang, H.; Capo-Aponte, J.E.; Tachado, S.D.; Wolosin, J.M.

2011-01-01

284

Identification of the plant steroid ?-spinasterol as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive properties.  

PubMed

The transient receptor potential vanilloid 1 (TRPV1) receptor is relevant to the perception of noxious information and has been studied as a therapeutic target for the development of new analgesics. The goal of this study was to perform in vivo and in vitro screens to identify novel, efficacious, and safe TRPV1 antagonists isolated from leaves of the medicinal plant Vernonia tweedieana Baker. All of the fractions and the hydroalcoholic extract produced antinociception in mice during the capsaicin test, but the dichloromethane fraction also had antioedematogenic effect. Among the compounds isolated from the dichloromethane fraction, only ?-spinasterol reduced the nociception and edema induced by capsaicin injection. Moreover, ?-spinasterol demonstrated good oral absorption and high penetration into the brain and spinal cord of mice. ?-Spinasterol was able to displace [3H]resiniferatoxin binding and diminish calcium influx mediated by capsaicin. Oral administration of the dichloromethane fraction and ?-spinasterol also produced antinociceptive effect in the noxious heat-induced nociception test; however, they did not change the mechanical threshold of naive mice. The treatment with ?-spinasterol did not produce antinociceptive effect in mice systemically pretreated with resiniferatoxin. In addition, ?-spinasterol and the dichloromethane fraction reduced the edema, mechanical, and heat hyperalgesia elicited by complete Freund's adjuvant paw injection. The dichloromethane fraction and ?-spinasterol did not affect body temperature or locomotor activity. In conclusion, ?-spinasterol is a novel efficacious and safe antagonist of the TRPV1 receptor with antinociceptive effect. PMID:22837009

Trevisan, Gabriela; Rossato, Mateus Fortes; Walker, Cristiani Isabel Banderó; Klafke, Jonatas Zeni; Rosa, Fernanda; Oliveira, Sara Marchesan; Tonello, Raquel; Guerra, Gustavo Petri; Boligon, Aline Augusti; Zanon, Ricardo Basso; Athayde, Margareth Linde; Ferreira, Juliano

2012-07-26

285

Nociceptors Lacking TRPV1 and TRPV2 Have Normal Heat Responses  

Microsoft Academic Search

Vanilloid receptor 1 (TRPV1) has been proposed to be the principal heat-responsive channel for nociceptive neurons. The skin of both rat and mouse receives major projections from primary sensory afferents that bind the plant lectin isolectin B4 (IB4). The majority of IB4-positive neurons are known to be heat-responsive nociceptors. Previous studies suggested that, unlike rat, mouse IB4-positive cutaneous afferents did

C. Jeffery Woodbury; Melissa Zwick; Shuying Wang; Jeffrey J. Lawson; Michael J. Caterina; Martin Koltzenburg; Kathryn M. Albers; H. Richard Koerber; Brian M. Davis

2004-01-01

286

The dual fatty acid amide hydrolase\\/TRPV1 blocker, N-arachidonoyl-serotonin, relieves carrageenan-induced inflammation and hyperalgesia in mice  

Microsoft Academic Search

Given that the pharmacological or genetic inactivation of fatty acid amide hydrolase (FAAH) counteracts pain and inflammation, and on the basis of the established involvement of transient receptor potential vanilloid type-1 (TRPV1) channels in inflammatory pain, we tested the capability of a dual FAAH\\/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT), to relieve oedema and pain in a model of acute inflammation, and compared

Barbara Costa; Isabella Bettoni; Stefania Petrosino; Francesca Comelli; Gabriella Giagnoni; Vincenzo Di Marzo

2010-01-01

287

Cigarette smoke-induced neurogenic inflammation is mediated by ?,?-unsaturated aldehydes and the TRPA1 receptor in rodents  

PubMed Central

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 ?,?-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify ?,?-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.

Andre, Eunice; Campi, Barbara; Materazzi, Serena; Trevisani, Marcello; Amadesi, Silvia; Massi, Daniela; Creminon, Christophe; Vaksman, Natalya; Nassini, Romina; Civelli, Maurizio; Baraldi, Pier Giovanni; Poole, Daniel P.; Bunnett, Nigel W.; Geppetti, Pierangelo; Patacchini, Riccardo

2008-01-01

288

Role of TRPV1 and TRPA1 in visceral hypersensitivity to colorectal distension during experimental colitis in rats.  

PubMed

The aim of the present study is to investigate the effects of TRPV1 and TRPA1 receptor antagonists and their synergism on the visceromotor responses during experimental colitis in rats. Colitis was induced in rats by a TNBS/ethanol enema at day 0 and was assessed at day 3 using endoscopy, histology and a myeloperoxidase assay. The visceromotor response to colorectal distension (10-80 mmHg) was evaluated in conscious rats before (control condition) and 3 days after 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration (colitis condition). At day 3, visceromotor responses were assessed before and after treatment with a TRPV1 (BCTC) or TRPA1 (TCS-5861528) receptor antagonist either alone or in combination and either after intraperitoneal or intrathecal administration. Endoscopy, microscopy and myeloperoxidase activity indicated severe colonic tissue damage 3 days after TNBS administration. Colorectal distension-evoked visceromotor responses demonstrated a 2.9-fold increase during acute colitis (day 3) compared to control conditions. Intraperitoneal and intrathecal administration of BCTC or TCS-5861528 partially reversed the colitis-induced increase in visceromotor responses compared to control conditions (P<0.05). Intraperitoneal blockade of TRPA1 plus TRPV1 further decreased the enhanced visceromotor responses at high distension pressures (40-80 mmHg) compared to blockade of either TRPV1 or TRPA1 alone. This synergistic effect was not seen after combined intrathecal blockade of TRPA1 plus TRPV1. The present study demonstrates that in the rat, TRPV1 and TRPA1 play a pivotal role in visceral hypersensitivity at the peripheral and spinal cord level during acute TNBS colitis. Target interaction, however, is presumably mediated via a peripheral site of action. PMID:23099257

Vermeulen, Wim; De Man, Joris G; De Schepper, Heiko U; Bult, Hidde; Moreels, Tom G; Pelckmans, Paul A; De Winter, Benedicte Y

2012-10-23

289

Anandamide capacitates bull spermatozoa through CB1 and TRPV1 activation.  

PubMed

Anandamide (AEA), a major endocannabinoid, binds to cannabinoid and vanilloid receptors (CB1, CB2 and TRPV1) and affects many reproductive functions. Nanomolar levels of anandamide are found in reproductive fluids including mid-cycle oviductal fluid. Previously, we found that R(+)-methanandamide, an anandamide analogue, induces sperm releasing from bovine oviductal epithelium and the CB1 antagonist, SR141716A, reversed this effect. Since sperm detachment may be due to surface remodeling brought about by capacitation, the aim of this paper was to investigate whether anandamide at physiological concentrations could act as a capacitating agent in bull spermatozoa. We demonstrated that at nanomolar concentrations R(+)-methanandamide or anandamide induced bull sperm capacitation, whereas SR141716A and capsazepine (a TRPV1 antagonist) inhibited this induction. Previous studies indicate that mammalian spermatozoa possess the enzymatic machinery to produce and degrade their own AEA via the actions of the AEA-synthesizing phospholipase D and the fatty acid amide hydrolase (FAAH) respectively. Our results indicated that, URB597, a potent inhibitor of the FAAH, produced effects on bovine sperm capacitation similar to those elicited by exogenous AEA suggesting that this process is normally regulated by an endogenous tone. We also investigated whether anandamide is involved in bovine heparin-capacitated spermatozoa, since heparin is a known capacitating agent of bovine sperm. When the spermatozoa were incubated in the presence of R(+)-methanandamide and heparin, the percentage of capacitated spermatozoa was similar to that in the presence of R(+)-methanandamide alone. The pre-incubation with CB1 or TRPV1 antagonists inhibited heparin-induced sperm capacitation; moreover the activity of FAAH was 30% lower in heparin-capacitated spermatozoa as compared to control conditions. This suggests that heparin may increase endogenous anandamide levels. Our findings indicate that anandamide induces sperm capacitation through the activation of CB1 and TRPV1 receptors and could be involved in the same molecular pathway as heparin in bovines. PMID:21347292

Gervasi, María Gracia; Osycka-Salut, Claudia; Caballero, Julieta; Vazquez-Levin, Mónica; Pereyra, Elba; Billi, Silvia; Franchi, Ana; Perez-Martinez, Silvina

2011-02-11

290

Anandamide Capacitates Bull Spermatozoa through CB1 and TRPV1 Activation  

PubMed Central

Anandamide (AEA), a major endocannabinoid, binds to cannabinoid and vanilloid receptors (CB1, CB2 and TRPV1) and affects many reproductive functions. Nanomolar levels of anandamide are found in reproductive fluids including mid-cycle oviductal fluid. Previously, we found that R(+)-methanandamide, an anandamide analogue, induces sperm releasing from bovine oviductal epithelium and the CB1 antagonist, SR141716A, reversed this effect. Since sperm detachment may be due to surface remodeling brought about by capacitation, the aim of this paper was to investigate whether anandamide at physiological concentrations could act as a capacitating agent in bull spermatozoa. We demonstrated that at nanomolar concentrations R(+)-methanandamide or anandamide induced bull sperm capacitation, whereas SR141716A and capsazepine (a TRPV1 antagonist) inhibited this induction. Previous studies indicate that mammalian spermatozoa possess the enzymatic machinery to produce and degrade their own AEA via the actions of the AEA-synthesizing phospholipase D and the fatty acid amide hydrolase (FAAH) respectively. Our results indicated that, URB597, a potent inhibitor of the FAAH, produced effects on bovine sperm capacitation similar to those elicited by exogenous AEA suggesting that this process is normally regulated by an endogenous tone. We also investigated whether anandamide is involved in bovine heparin-capacitated spermatozoa, since heparin is a known capacitating agent of bovine sperm. When the spermatozoa were incubated in the presence of R(+)-methanandamide and heparin, the percentage of capacitated spermatozoa was similar to that in the presence of R(+)-methanandamide alone. The pre-incubation with CB1 or TRPV1 antagonists inhibited heparin-induced sperm capacitation; moreover the activity of FAAH was 30% lower in heparin-capacitated spermatozoa as compared to control conditions. This suggests that heparin may increase endogenous anandamide levels. Our findings indicate that anandamide induces sperm capacitation through the activation of CB1 and TRPV1 receptors and could be involved in the same molecular pathway as heparin in bovines.

Gervasi, Maria Gracia; Osycka-Salut, Claudia; Caballero, Julieta; Vazquez-Levin, Monica; Pereyra, Elba; Billi, Silvia; Franchi, Ana; Perez-Martinez, Silvina

2011-01-01

291

Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents.  

PubMed

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases. PMID:18568077

Andrč, Eunice; Campi, Barbara; Materazzi, Serena; Trevisani, Marcello; Amadesi, Silvia; Massi, Daniela; Creminon, Christophe; Vaksman, Natalya; Nassini, Romina; Civelli, Maurizio; Baraldi, Pier Giovanni; Poole, Daniel P; Bunnett, Nigel W; Geppetti, Pierangelo; Patacchini, Riccardo

2008-07-01

292

Different uptake of gentamicin through TRPV1 and TRPV4 channels determines cochlear hair cell vulnerability  

PubMed Central

Hair cells at the base of the cochlea appear to be more susceptible to damage by the aminoglycoside gentamicin than those at the apex. However, the mechanism of base-to-apex gradient ototoxicity by gentamicin remains to be elucidated. We report here that gentamicin caused rodent cochlear hair cell damages in a time- and dose-dependent manner. Hair cells at the basal turn were more vulnerable to gentamicin than those at the apical turn. Gentamicin-conjugated Texas Red (GTTR) uptake was predominant in basal turn hair cells in neonatal rats. Transient receptor potential vanilloid 1 (TRPV1) and 4 (TRPV4) expression was confirmed in the cuticular plate, stereocilia and hair cell body of inner hair cells and outer hair cells. The involvement of TRPV1 and TRPV4 in gentamicin trafficking of hair cells was confirmed by exogenous calcium treatment and TRPV inhibitors, including gadolinium and ruthenium red, which resulted in markedly inhibited GTTR uptake and gentamicin-induced hair cell damage in rodent and zebrafish ototoxic model systems. These results indicate that the cytotoxic vulnerability of cochlear hair cells in the basal turn to gentamicin may depend on effective uptake of the drug, which was, in part, mediated by the TRPV1 and TRPV4 proteins.

Lee, Jeong-Han; Park, Channy; Kim, Se-Jin; Kim, Hyung-Jin; Oh, Gi-Su; Shen, AiHua; So, Hong-Seob; Park, Raekil

2013-01-01

293

Synergistic Role of TRPV1 and TRPA1 in Pancreatic Pain and Inflammation  

PubMed Central

Background & Aims The transient receptor potential (TRP) channels TRPV1 and TRPA1 have each been associated with regulation of efferent properties of primary afferent neurons that initiate neurogenic inflammation and are required for the development of inflammatory hyperalgesia. To evaluate the role of these channels in producing pain during pancreatic inflammation, we studied pancreatic nodose (NG) and dorsal root (DRG) ganglion sensory neurons (identified by content of retrograde tracer) and behavioral outcomes in a mouse model of acute pancreatitis. Methods Pancreatic inflammation was induced by 8 hourly injections of caerulein (50 ?g/kg). The extent of inflammation, pancreatic neuron TRP channel expression and function and excitability, and pain-related behaviors were evaluated over the course of the following week. Results Histology and myeloperoxidase activity confirmed pancreatic inflammation that was associated with increased excitability and mRNA expression of the TRP channels in NG and DRG pancreatic neurons. Calcium imaging of pancreatic NG and DRG neurons from mice given caerulein revealed increased responses to TRP agonists. TRPV1 and TRPA1 antagonists attenuated caerulein-induced pain behaviors and pancreatic inflammation; they had a synergistic effect. Conclusions Pancreatic inflammation significantly increased the expression and functional properties of TRPV1 and TRPA1, as well as the excitability of pancreatic sensory neurons in vagal and spinal pathways. TRP channel antagonists acted synergistically to reverse pancreatic inflammation and associated pain behaviors; reagents that target interactions between these channels might be developed to reduce pain in patients with acute pancreatitis.

Schwartz, Erica S.; Christianson, Julie A.; Chen, Xiaowei; La, Jun-Ho; Davis, Brian M.; Albers, Kathryn M.; Gebhart, G.F.

2011-01-01

294

Regulation of calcitonin gene-related peptide and TRPV1 in a rat model of osteoarthritis.  

PubMed

Pain in osteoarthritis (OA) remains an intractable problem in a majority of patients, with many of the commonly prescribed analgesics providing insufficient relief and considerable side effects. However, the structural or mechanistic cause of OA pain is still unknown. Animal models to address this issue have only recently been established, with much of the research to date focused on tissue pathology rather than pain. We have previously compared the surgically induced partial medial meniscectomy and chemically induced intra-articular iodoacetate injection rat models of OA in the rat, with reference to pain behaviour. This demonstrated relevant tissue pathology in both models, but greater evidence of pain related behaviour in the iodoacetate induced model. Here we further investigate the iodoacetate model using Fast Blue backlabelling from the articular joint space to identify the cell bodies of primary sensory afferents from the knee at the L4 dorsal root ganglion. Expression of calcitonin gene-related peptide (CGRP) and the vanilloid receptor TRPV1 was quantified in these backlabelled cells and was enriched in the knee afferents in all animals studied, compared to the expression in neurons across the whole dorsal root ganglia (DRG). Analysis of the backlabelled population in the osteoarthritis model and controls showed an increase in both CGRP and TRPV1 expression in the iodoacetate model compared with control animals. Therefore, there is a potential role for CGRP and TRPV1 in the manifestation of pain behaviour accompanied by OA changes in the knee in the iodoacetate induced model. PMID:16039054

Fernihough, Janet; Gentry, Clive; Bevan, Stuart; Winter, Janet

2005-11-11

295

Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats.  

PubMed

Vampire bats (Desmodus rotundus) are obligate blood feeders that have evolved specialized systems to suit their sanguinary lifestyle. Chief among such adaptations is the ability to detect infrared radiation as a means of locating hotspots on warm-blooded prey. Among vertebrates, only vampire bats, boas, pythons and pit vipers are capable of detecting infrared radiation. In each case, infrared signals are detected by trigeminal nerve fibres that innervate specialized pit organs on the animal's face. Thus, vampire bats and snakes have taken thermosensation to the extreme by developing specialized systems for detecting infrared radiation. As such, these creatures provide a window into the molecular and genetic mechanisms underlying evolutionary tuning of thermoreceptors in a species-specific or cell-type-specific manner. Previously, we have shown that snakes co-opt a non-heat-sensitive channel, vertebrate TRPA1 (transient receptor potential cation channel A1), to produce an infrared detector. Here we show that vampire bats tune a channel that is already heat-sensitive, TRPV1, by lowering its thermal activation threshold to about 30?°C. This is achieved through alternative splicing of TRPV1 transcripts to produce a channel with a truncated carboxy-terminal cytoplasmic domain. These splicing events occur exclusively in trigeminal ganglia, and not in dorsal root ganglia, thereby maintaining a role for TRPV1 as a detector of noxious heat in somatic afferents. This reflects a unique organization of the bat Trpv1 gene that we show to be characteristic of Laurasiatheria mammals (cows, dogs and moles), supporting a close phylogenetic relationship with bats. These findings reveal a novel molecular mechanism for physiological tuning of thermosensory nerve fibres. PMID:21814281

Gracheva, Elena O; Cordero-Morales, Julio F; González-Carcacía, José A; Ingolia, Nicholas T; Manno, Carlo; Aranguren, Carla I; Weissman, Jonathan S; Julius, David

2011-08-03

296

Fetal ethanol exposure attenuates aversive oral effects of TrpV1, but not TrpA1 agonists in rats.  

PubMed

In humans, fetal ethanol exposure is highly predictive of adolescent ethanol use and abuse. Prior work in our labs indicated that fetal ethanol exposure results in stimulus-induced chemosensory plasticity in the taste and olfactory systems of adolescent rats. In particular, we found that increased ethanol acceptability could be attributed, in part, to an attenuated aversion to ethanol's aversive odor and quinine-like bitter taste quality. Here, we asked whether fetal ethanol exposure also alters the oral trigeminal response of adolescent rats to ethanol. We focused on two excitatory ligand-gated ion channels, TrpV1 and TrpA1, which are expressed in oral trigeminal neurons and mediate the aversive orosensory response to many chemical irritants. To target TrpV1, we used capsaicin, and to target TrpA1, we used allyl isothiocyanate (or mustard oil). We assessed the aversive oral effects of ethanol, together with capsaicin and mustard oil, by measuring short-term licking responses to a range of concentrations of each chemical. Experimental rats were exposed in utero by administering ethanol to dams through a liquid diet. Control rats had ad libitum access to an iso-caloric iso-nutritive liquid diet. We found that fetal ethanol exposure attenuated the oral aversiveness of ethanol and capsaicin, but not mustard oil, in adolescent rats. Moreover, the increased acceptability of ethanol was directly related to the reduced aversiveness of the TrpV1-mediated orosensory input. We propose that fetal ethanol exposure increases ethanol avidity not only by making ethanol smell and taste better, but also by attenuating ethanol's capsaicin-like burning sensations. PMID:22378825

Glendinning, John I; Simons, Yael M; Youngentob, Lisa; Youngentob, Steven L

2012-02-29

297

Attenuation of TRPV1 and TRPV4 Expression and Function in Mouse Inflammatory Pain Models Using Electroacupuncture.  

PubMed

Although pain is a major human affliction, our understanding of pain mechanisms is limited. TRPV1 (transient receptor potential vanilloid subtype 1) and TRPV4 are two crucial receptors involved in inflammatory pain, but their roles in EA- (electroacupuncture-) mediated analgesia are unknown. We injected mice with carrageenan (carra) or a complete Freund's adjuvant (CFA) to model inflammatory pain and investigated the analgesic effect of EA using animal behavior tests, immunostaining, Western blotting, and a whole-cell recording technique. The inflammatory pain model mice developed both mechanical and thermal hyperalgesia. Notably, EA at the ST36 acupoint reversed these phenomena, indicating its curative effect in inflammatory pain. The protein levels of TRPV1 and TRPV4 in DRG (dorsal root ganglion) neurons were both increased at day 4 after the initiation of inflammatory pain and were attenuated by EA, as demonstrated by immunostaining and Western blot analysis. We verified DRG electrophysiological properties to confirm that EA ameliorated peripheral nerve hyperexcitation. Our results indicated that the AP (action potential) threshold, rise time, and fall time, and the percentage and amplitude of TRPV1 and TRPV4 were altered by EA, indicating that EA has an antinociceptive role in inflammatory pain. Our results demonstrate a novel role for EA in regulating TRPV1 and TRPV4 protein expression and nerve excitation in mouse inflammatory pain models. PMID:23258994

Chen, Wei-Hsin; Tzen, Jason T C; Hsieh, Ching Liang; Chen, Yung Hsiang; Lin, Tzu-Jou; Chen, Shih-Yin; Lin, Yi-Wen

2012-11-13

298

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors.  

PubMed

The sensitization of capsaicin-sensitive lung vagal (CSLV) afferents by inflammatory mediators is important in the development of airway hypersensitivity. Hydrogen sulfide (H2S) is an endogenous mediator inducing hyperalgesia through transient receptor potential ankyrin 1 (TRPA1) receptors located on nociceptors. We conducted this study to determine whether H2S elevates the sensitivity of rat CSLV afferents. In anesthetized, artificially ventilated rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a H2S donor) caused no significant changes in the baseline activity of CSLV afferents. However, the afferent responses to right atrial injection of capsaicin or phenylbiguanide and to lung inflation were all markedly potentiated after NaHS inhalation. By contrast, the inhalation of its vehicle or NaOH (with a similar pH to NaHS) failed to enhance the afferent responses. Additionally, the potentiating effect on the afferent responses was found in rats inhaling l-cysteine (a substrate of H2S synthase) that slowly releases H2S. The potentiating effect of NaHS on the sensitivity of CSLV afferents was completely blocked by pretreatment of HC-030031 (a TRPA1 receptor antagonist) but was unaffected by its vehicle. In isolated rat CSLV neurons, the perfusion of NaHS alone did not influence the intracellular Ca(2+) concentration but markedly potentiated the Ca(2+) transients evoked by capsaicin. The NaHS-caused effect was totally abolished by HC-030031 pretreatment. These results suggest that H2S induces a nonspecific sensitizing effect on CSLV fibers to both chemical and mechanical stimulation in rat lungs, which appears mediated through an action on the TRPA1 receptors expressed on the nerve endings of CSLV afferents. PMID:23842678

Hsu, Chun-Chun; Lin, Ruei-Lung; Lee, Lu-Yuan; Lin, You Shuei

2013-07-10

299

Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists.  

PubMed

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition. PMID:21315587

Schmidt, Robert G; Bayburt, Erol K; Latshaw, Steven P; Koenig, John R; Daanen, Jerome F; McDonald, Heath A; Bianchi, Bruce R; Zhong, Chengmin; Joshi, Shailen; Honore, Prisca; Marsh, Kennan C; Lee, Chih-Hung; Faltynek, Connie R; Gomtsyan, Arthur

2011-01-21

300

TRPV1 Activation Is Required for Hypertonicity-Stimulated Inflammatory Cytokine Release in Human Corneal Epithelial Cells  

PubMed Central

Purpose. To determine whether hypertonic stress promotes increases in inflammatory cytokine release through transient receptor potential vanilloid channel type 1 (TRPV1) signaling pathway activation in human corneal epithelial cells (HCECs). Methods. Hyperosmotic medium was prepared by supplementing isotonic Ringers solution with sucrose. Ca2+ signaling was measured in fura2-AM–loaded HCECs using a single-cell fluorescence imaging system. Western blot analysis evaluated the phosphorylation status of EGFR, ERK, p38 MAPK, and nuclear factor (NF)-?B. ELISA assessed the effect of TRPV1 activation on the release of IL-6 and IL-8. Results. A 450 mOsm hypertonic stress elicited 2-fold Ca2+ transients that were suppressed by the TRPV1-selective antagonists capsazepine and JYL 1421. Such transients were enhanced by PGE2. Hypertonicity-induced EGF receptor (EGFR) transactivation was suppressed by preincubating HCECs with capsazepine, matrix metalloproteinase 1 (MMP1) inhibitor TIMP-1, broad-spectrum MMP inhibitor GM 6001, heparin-bound (HB)-EGF inhibitor CRM 197, or EGFR inhibitor AG 1478. ERK and p38 MAPK and NF-?B activation after EGFR transactivation occurred in tonicity and in a time-dependent manner. Hypertonicity-induced increases in IL-6 and IL-8 releases were suppressed by exposure to capsazepine, AG 1478, ERK inhibitor PD 98059, p38 inhibitor SB 203580, or NF-?B inhibitor PDTC. Conclusions. Hypertonic stress–elicited TRPV1 channel stimulation mediates increases in a proinflammatory cytokine IL-6 and a chemoattractant IL-8 by eliciting EGFR transactivation, MAPK, and NF-?B activation. Selective drug modulation of either TRPV1 activity or its signaling mediators may yield a novel approach to suppressing inflammatory responses occurring in dry eye syndrome.

Wang, Zheng; Yang, Hua; Zhang, Fan; Reinach, Peter S.

2011-01-01

301

Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors  

PubMed Central

The transient receptor potential V1 channel (vanilloid receptor, TRPV1) represents a promising therapeutic target for inflammatory pain and other conditions involving C-fiber sensory afferent neurons. Sensitivity of TRPV1 is known to be subject to modulation by numerous signaling pathways, in particular by phosphorylation, and we wished to determine whether TRPV1 structure-activity relations could be differentially affected. We demonstrate here that the structure activity relations of TRPV1, as determined by 45Ca2+ uptake, were substantially altered by treatment of the cells with cyclosporin A, an inhibitor of protein phosphatase 2B. Whereas the potency of resiniferatoxin for stimulation of 45Ca2+ was not altered by cyclosporin A treatment, the potencies of some other agonists were increased up to 8-fold. Among antagonists examined, potencies were reduced to a lesser extent, ranging from 1–2.5 fold. Finally, the efficacy of partial agonists was increased. In contrast to cyclosporin A, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, had little effect on agonist potencies, and calyculin A, an inhibitor of protein phosphatases 1 and 2A but with somewhat different selectivity from that of okadaic acid, caused changes in structure activity relations distinct from those induced by cyclosporin A. Because phosphatase activity differentially modulates the structure activity relations of TRPV1 agonists and antagonists, our findings predict that it may be possible to design agonist and antagonists selective for TRPV1 in a specific regulatory environment. A further implication is that it may be desirable to tailor screening approaches for drug discovery to reflect the desired regulatory state of the targeted TRPV1.

Pearce, Larry V.; Toth, Attila; Ryu, HyungChul; Kang, Dong Wook; Choi, Hyun-Kyung; Jin, Mi-Kyoung; Lee, Jeewoo; Blumberg, Peter M.

2008-01-01

302

Recent progress in the development of selective TRPV1 antagonists for pain.  

PubMed

As last year marked the tenth anniversary of the cloning of TRPV1, no attenuation has been observed in the intense interest surrounding this ion channel by both academic labs and pharmaceutical companies alike. Patent searches provide an extensive list of novel TRPV1 antagonists generated within the last 7 years, while literature searches reveal a diverse collection of TRPV1 antagonists that have progressed into pre-clinical in vivo profiling and even clinical development. This review serves to summarize the current knowledge of TRPV1 and TRPV1 antagonists as pain therapeutics and to highlight how use of divergent TRPV1 antagonists is helping to further define the physiological and pathological role of TRPV1 and the scope for TRPV1 antagonist therapies. PMID:18991729

Broad, Lisa M; Keding, Stacy J; Blanco, Maria-Jesus

2008-01-01

303

TRPV1 Potentiates TGF?-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop.  

PubMed

Injuring mouse corneas with alkali causes myofibroblast expression leading to tissue opacification. However, in transient receptor potential vanilloid 1 channel (TRPV1-/-) knockout mice healing results in transparency restoration. Since TGF? is the primary inducer of the myofibroblast phenotype, we examined the mechanism by which TRPV1 affects TGF?-induced myofibroblast development. Experiments were performed in pig corneas and human corneal fibroblasts (HCFs). Immunohistochemical staining of ?-smooth muscle actin (?-SMA) stress fibers was used to visualize myofibroblasts. Protein and phosphoprotein were determined by Western blotting. siRNA transfection silenced TRPV1 gene expression. Flow cytometry with a reactive oxygen species (ROS) reporting dye analyzed intracellular ROS. [Ca2+]I was measured by loading HCF with fura2. In organ cultured corneas, the TRPV1 antagonist capsazepine drastically reduced by 75% wound-induced myofibroblast development. In HCF cell culture, TGF-?1 elicited rapid increases in Ca2+ influx, phosphorylation of SMAD2 and MAPKs (ERK1/2, JNK1/2 and p38), ROS generation and, after 72 hrs myofibroblast development. SMAD2 and p38 activation continued for more than 16 h, whereas p-ERK1/2 and p-JNK1/2 waned within 90 min. The long-lived SMAD2 activation was dependent on activated p38 and vice versa, and it was essential to generate a > 13-fold increase in ?-SMA protein and a fully developed myofibroblast phenotype. These later changes were markedly reduced by inhibition of TRPV1 or reduction of the ROS generation rate. Taken together our results indicate that in corneal derived fibroblasts, TGF?- induced myofibroblast development is highly dependent on a positive feedback loop where p-SMAD2-induced ROS activates TRPV1, TRPV1 causes activation of p38, the latter in turn further enhances the activation of SMAD2 to establish a recurrent loop that greatly extends the residency of the activated state of SMAD2 that drives myofibroblast development. PMID:24098582

Yang, Yuanquan; Wang, Zheng; Yang, Hua; Wang, Lingyan; Gillespie, Stephanie R; Wolosin, J Mario; Bernstein, Audrey M; Reinach, Peter S

2013-10-02

304

TRPV1 Potentiates TGF?-Induction of Corneal Myofibroblast Development through an Oxidative Stress-Mediated p38-SMAD2 Signaling Loop  

PubMed Central

Injuring mouse corneas with alkali causes myofibroblast expression leading to tissue opacification. However, in transient receptor potential vanilloid 1 channel (TRPV1-/-) knockout mice healing results in transparency restoration. Since TGF? is the primary inducer of the myofibroblast phenotype, we examined the mechanism by which TRPV1 affects TGF?-induced myofibroblast development. Experiments were performed in pig corneas and human corneal fibroblasts (HCFs). Immunohistochemical staining of ?-smooth muscle actin (?-SMA) stress fibers was used to visualize myofibroblasts. Protein and phosphoprotein were determined by Western blotting. siRNA transfection silenced TRPV1 gene expression. Flow cytometry with a reactive oxygen species (ROS) reporting dye analyzed intracellular ROS. [Ca2+]I was measured by loading HCF with fura2. In organ cultured corneas, the TRPV1 antagonist capsazepine drastically reduced by 75% wound-induced myofibroblast development. In HCF cell culture, TGF-?1 elicited rapid increases in Ca2+ influx, phosphorylation of SMAD2 and MAPKs (ERK1/2, JNK1/2 and p38), ROS generation and, after 72 hrs myofibroblast development. SMAD2 and p38 activation continued for more than 16 h, whereas p-ERK1/2 and p-JNK1/2 waned within 90 min. The long-lived SMAD2 activation was dependent on activated p38 and vice versa, and it was essential to generate a > 13-fold increase in ?-SMA protein and a fully developed myofibroblast phenotype. These later changes were markedly reduced by inhibition of TRPV1 or reduction of the ROS generation rate. Taken together our results indicate that in corneal derived fibroblasts, TGF?- induced myofibroblast development is highly dependent on a positive feedback loop where p-SMAD2-induced ROS activates TRPV1, TRPV1 causes activation of p38, the latter in turn further enhances the activation of SMAD2 to establish a recurrent loop that greatly extends the residency of the activated state of SMAD2 that drives myofibroblast development.

Yang, Yuanquan; Wang, Zheng; Yang, Hua; Wang, Lingyan; Gillespie, Stephanie R.; Wolosin, J. Mario; Bernstein, Audrey M.; Reinach, Peter S.

2013-01-01

305

A novel non-CB1/TRPV1 endocannabinoid-mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons  

PubMed Central

Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well the involvement of group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the non-hydrolysable anandamide analogue R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by approximately 50%. The group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10?M) but not by the mGluR1 antagonist CPCCOEt (50 ?M). Interestingly, however, neither DHPG-mediated nor R-methanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 ?M), the CB1 antagonist AM-251 (2 ?M) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.

Edwards, Jeffrey G.; Gibson, Helen E.; Jensen, Tyron; Nugent, Fereshteh; Walther, Curtis; Blickenstaff, Jacob; Kauer, Julie A.

2010-01-01

306

Solid-phase synthesis of a library of amphipatic hydantoins. Discovery of new hits for TRPV1 blockade.  

PubMed

Some heterocyclic systems, called privileged scaffolds, appear frequently in bioactive products and marketed drugs. The combination of a recognized privileged scaffold (hydantoin) and a functional group with high incidence in bioactive molecules (guanidine) guided the design of a library of amphipatic compounds, which allowed the discovery of novel TRPV1 ion channel blockers. The library was synthesized by parallel solid-phase synthesis from an orthogonally protected resin-bound Lys-Lys skeleton. Key steps of the synthetic procedure were the construction of the hydantoin ring, by reaction of the N-terminal amino group with N,N-disuccinimidyl carbonate (DSC) and subsequent base-induced cyclization, and the guanidinylation of the C-terminal Lys side-chain after removal of the Alloc protecting-group. The preliminary biological studies have allowed the identification of some of the key structural features directing the blockage of capsaicin-induced Ca(2+) influx through TRPV1 channels, particularly, the strong preference showed for highly lipophilic acyl groups and substituted guanidine moieties. Active compounds based on this new pharmacophoric scaffold that display in vitro and in vivo inhibitory activity. PMID:21671576

Gerona-Navarro, Guillermo; González-Muńiz, Rosario; Fernández-Carvajal, Asia; González-Ros, José M; Ferrer-Montiel, Antonio; Carreńo, Cristina; Albericio, Fernando; Royo, Miriam

2011-07-08

307

Pungent qualities of sanshool-related compounds evaluated by a sensory test and activation of rat TRPV1.  

PubMed

The detection threshold and taste characteristics of sanshools were examined by sensory evaluation, after isolating four sanshools (alpha-, beta-, gamma-, and delta-), and two hydroxy sanshools (alpha- and beta-) from the pericarp of Japanese pepper. The Scoville unit (SU) values of the four sanshools were in the range of 80,000-110,000, while those of hydroxy sanshools were 3-5 fold lower than corresponding sanshools. The pungent qualities of each sanshool were different. Burning and tingling were predominantly perceived and lasted for the longest time with alpha-sanshool. Burning and fresh for gamma-sanshool, and tingling and numbing for hydroxy alpha-sanshool were perceived. Tests on the activation of rat TRPV1 were also performed. All of them were weak agonists. Among them, gamma-sanshool was the most potent agonist, although its EC50 value of 5.3 microM was 230 fold higher than that of capsaicin. These results indicate that it would be difficult to explain the pungent quality of each sanshool simply in terms of TRPV1 activation. PMID:16244447

Sugai, Etsuko; Morimitsu, Yasujiro; Iwasaki, Yusaku; Morita, Akihito; Watanabe, Tatsuo; Kubota, Kikue

2005-10-01

308

Cough Receptor Sensitivity to Capsaicin and Tartaric Acid in Patients with Mycoplasma Pneumonia  

Microsoft Academic Search

.   There has been no detailed study of cough sensitivity during acute lower respiratory infection. The aim of this study was\\u000a to clarify cough sensitivity in Mycoplasma pneumonia, which is a well known acute lower respiratory infection with persistent nonproductive cough. We examined cough\\u000a sensitivity to inhaled capsaicin and tartaric acid in both the acute and the convalescent phases of

M. Fujimura; S. Myou; M. Matsuda; T. Amemiya; Y. Kamio; K. Iwasa; Y. Ishiura; M. Yasui; A. Tagami; T. Matsuda

1998-01-01

309

Differential TRPV1 and TRPV2 Channel Expression in Dental Pulp  

PubMed Central

Hypersensitivity to thermal and mechanical stimuli can occur in painful pulpitis. To explore the neuro-anatomical basis of heat and mechanical sensitivity, we evaluated expression of TRPV1 (heat) and TRPV2 (heat/mechanical) channels in the cell bodies and terminal arborizations of neurons that innervate the dental pulp (DP) and periodontal tissues (PDL). We report that ~50% of trigeminal ganglion (TG) neurons retrogradely labeled from the DP express TRPV2, and this was significantly greater than the general expression of this channel in the TG (15%) and slightly more than what is expressed in the PDL by retrograde labeling (40%). The TRPV1 receptor, however, was less prevalent in neurons innervating the DP than their general expression in the TG (17% vs. 26%) and was more extensively expressed in neurons innervating the PDL (26%). Co-labeling studies showed that 70% of neurons that innervate the DP are myelinated. Approximately 1/3 of the retrogradely labeled neurons from the DP were calcitonin-gene-related-peptide-positive (peptide-expressing), but very few expressed the IB4 marker of non-peptidergic unmyelinated afferents. These findings suggest that the DP has a unique neurochemical innervation with regard to TRP receptor expression, which has significant implications for the mechanisms contributing to odontogenic pain and management strategies.

Gibbs, J.L.; Melnyk, J.L.; Basbaum, A.I.

2011-01-01

310

3D-QSAR analysis of TRPV1 inhibitors reveals a pharmacophore applicable to diverse scaffolds and clinical candidates.  

PubMed

TRPV1 (Transient Receptor Potential Vanilloid Type 1) receptor, a member of Transient Receptor Potential Vanilloid subfamily of ion channels, occurs in the peripheral and central nervous system, and plays a key role in transmission of pain. Consequently, this has been the target for discovery of several pain relieving agents which have undergone clinical trials. Though several TRPV1 antagonists have progressed to become clinical candidates, many are known to cause temperature elevation in humans, halting their further advancement, and signifying the need for new chemotypes. Different chemical classes of TRPV1 antagonists share three important features: an amide or an isostere flanked by an aromatic (or fused aromatic) ring with polar substitutions on one side, and a hydrophobic group on the other. Recent work identified new series of compounds with these and additional features, leading to improvement of properties, and development of clinical candidates. Herein, we describe a 3D-QSAR model (n=62; R(2)=0.9 and Q(2)=0.75) developed from the piperazinyl-aryl series of compounds and a novel 5-point pharmacophore model is shown to fit several diverse scaffolds, six clinical candidates, five pre-clinical candidates and three lead compounds. The pharmacophore model can aid in finding new chemotypes as starting points that can be developed further. PMID:24036505

Kristam, Rajendra; Parmar, Vinod; Viswanadhan, Vellarkad N

2013-08-28

311

Using novel in vitro NociOcular assay based on TRPV1 channel activation for prediction of eye sting potential of baby shampoos.  

PubMed

The transient receptor potential vanilloid type 1 (TRPV1) channel is one of the most well-characterized pain-inducing receptors. The purpose of this study was to predict human eye stinging of 19 baby bath and shampoo formulations by studying TRPV1 activity, as measured by increase in intracellular free Ca(2+). The NociOcular test, a novel recombinant neuronal in vitro model with high expression of functional TRPV1 channels, was used to test formulations containing a variety of surfactants, preservatives, and fragrances. TRPV1-specific Ca(2+) influx was abolished when the TRPV1 channel antagonist capsazepine was applied to the cells prior to shampoo samples. The positive control, an adult shampoo that contains cocamide monoethanolamine (CMEA), a known stinging ingredient, was the most active sample tested in the NociOcular test. The negative control, a marketed baby shampoo, was negative in the NociOcular and human tests. Seven of the formulations induced stinging in the human test, and of those six were positive in the NociOcular test. Twelve formulations were classified as nonstinging in the human test, and of those ten were negative in the NociOcular test. There was no correlation between the clinical stinging results for the baby formulations and the data generated from other in vitro eye irritation assays (cytosensor microphysiometer, neutral red uptake, EpiOcular, transepithelial permeability). Our data support that the TRPV1 channel is a principal mediator of eye-stinging sensation induced by baby bath and shampoo formulations and that the NociOcular test may be a valuable in vitro tool to predict human eye-stinging sensation. PMID:22705807

Forsby, Anna; Norman, Kimberly G; El Andaloussi-Lilja, Johanna; Lundqvist, Jessica; Walczak, Vincent; Curren, Rodger; Martin, Katharine; Tierney, Neena K

2012-06-15

312

Involvement of central 5-HT1A receptors in the reflex activation of pulmonary vagal motoneurones by inhaled capsaicin in anaesthetized cats.  

PubMed Central

1. The aim of the present experiments was to determine whether 5-HT1A receptors play a role in the control of the reflex activation of pulmonary vagal motoneurones. This was carried out by investigating the effects of intracisternal injections (i.c.) of the 5-HT1A receptor ligands, 8-OH-DPAT (50 micrograms kg-1), buspirone (200 micrograms kg-1), WAY-100635 (100 micrograms kg-1), methiothepin (200 micrograms kg-1) and (-)-pindolol (100 micrograms kg-1) and the 5-HT2 receptor antagonist, cinanserin (200 micrograms kg-1), on the reflex bronchoconstriction evoked by inhaled capsaicin aerosol in alpha-chloralose anaesthetized, neuromuscularly blocked and artificially ventilated cats. Recordings were made of heart rate, blood pressure and upper tracheal pressure. 2. Central application of all the 5-HT1A receptor antagonists (methiothepin, WAY-100635 and (-)-pindolol) attenuated the reflex bronchoconstriction in the upper trachea. However, the same dose of WAY-100635 given i.v. had no effect on this reflex bronchoconstriction. The 5-HT1A receptor agonist, 8-OH-DPAT (50 micrograms kg-1) given i.c., potentiated the capsaicin-evoked reflex bronchoconstriction, whereas buspirone (200 micrograms kg-1) i.c. had no effect. The 5-HT2 receptor antagonist, cinanserin (200 micrograms kg-1) also had no effect. 3. It is concluded that the reflex excitation of pulmonary vagal motoneurones by inhaled capsaicin in alpha-chloralose anaesthetized cats involves the activation of central 5-HT1A receptors.

Bootle, D. J.; Adcock, J. J.; Ramage, A. G.

1996-01-01

313

Epidermal keratinocyte polarity and motility require Ca2+ influx through TRPV1.  

PubMed

Ca(2+) has long been known to play an important role in cellular polarity and guidance. We studied the role of Ca(2+) signaling during random and directed cell migration to better understand whether Ca(2+) directs cell motility from the leading edge and which ion channels are involved in this function by using primary zebrafish keratinocytes. Rapid line-scan and time-lapse imaging of intracellular Ca(2+) (Ca(2+)i) during migration and automated image alignment enabled us to characterize and map the spatiotemporal changes in Ca(2+)i. We show that asymmetric distributions of lamellipodial Ca(2+) sparks are encoded in frequency, not amplitude, and that they correlate with cellular rotation during migration. Directed migration during galvanotaxis increases the frequency of Ca(2+) sparks over the entire lamellipod; however, these events do not give rise to asymmetric Ca(2+)i signals that correlate with turning. We demonstrate that Ca(2+)-permeable channels within these cells are mechanically activated and include several transient receptor potential family members, including TRPV1. Last, we demonstrate that cell motility and Ca(2+)i activity are affected by pharmacological agents that target TRPV1, indicating a novel role for this channel during cell migration. PMID:23943873

Graham, David M; Huang, Ling; Robinson, Kenneth R; Messerli, Mark A

2013-08-13

314

Spinal Nerve Ligation in Mouse Upregulates TRPV1 Heat Function in Injured IB4 Positive Nociceptors  

PubMed Central

Peripheral nerve injury leads to neuropathic pain, but the underlying mechanisms are not clear. The TRPV1 channel expressed by nociceptors is one receptor for noxious heat and inflammatory molecules. Lumbar 4 spinal nerve ligation (SNL) in mice induced persistent heat hyperalgesia 4–10 days following injury. The heat hypersensitivity was completely reversed by the TRPV1 antagonist A-425619. Furthermore, DRG neurons were isolated from the injured L4 ganglia or adjacent L3 ganglia 4–10 days after L4 SNL. Whole-cell patch clamp recordings were performed and heat stimuli (22–50°C/3 sec) were applied to the soma. Neurons were classified by soma size and isolectin-B4 (IB4) binding. Among directly injured L4 neurons, SNL increased the percentage of small-diameter IB4 positive neurons that were heat sensitive from 13% (naive controls) to 56% and conversely, decreased the proportion of small IB4-negative neurons that were heat sensitive from 66% (naive controls) to 34%. There was no change in IB4 binding in neurons from the injured ganglia. Surprisingly, in neurons from the adjacent L3 ganglia, SNL had no effect on the heat responsiveness of either IB4 positive or negative small neurons. Also, SNL had no effect on heat responses in medium-large diameter neurons from either the injured or adjacent ganglia.

Vilceanu, Daniel; Honore, Prisca; Hogan, Quinn H.; Stucky, Cheryl L.

2009-01-01

315

Capsaicin sensitive afferent neurons from peripheral glucose receptors mediate the insulin-induced increase in adrenaline secretion  

Microsoft Academic Search

1.The effect of insulin and of 2-deoxy-d-glucose (2-DG) on adrenaline secretion was compared in rats pretreated as neonates with capsaicin and in rats pretreated with the drug-vehicle.2.Capsaicin-pretreatment did not inhibit the fall in blood glucose concentrations induced by insulin or by fasting, nor did it affect the increase in blood glucose concentrations in response to 2-DG or restraint stress.3.Capsaicin greatly

Rainer Amann; Fred Lembeck

1986-01-01

316

Sensitization of capsaicin and icilin responses in oxaliplatin treated adult rat DRG neurons  

PubMed Central

Background Oxaliplatin chemotherapy induced neuropathy is a dose related cumulative toxicity that manifests as tingling, numbness, and chronic pain, compromising the quality of life and leading to discontinued chemotherapy. Patients report marked hypersensitivity to cold stimuli at early stages of treatment, when sensory testing reveals cold and heat hyperalgesia. This study examined the morphological and functional effects of oxaliplatin treatment in cultured adult rat DRG neurons. Results 48 hour exposure to oxaliplatin resulted in dose related reduction in neurite length, density, and number of neurons compared to vehicle treated controls, using Gap43 immunostaining. Neurons treated acutely with 20 ?g/ml oxaliplatin showed significantly higher signal intensity for cyclic AMP immunofluorescence (160.5 ± 13 a.u., n = 3, P < 0.05), compared to controls (120.3 ± 4 a.u.). Calcium imaging showed significantly enhanced capsaicin (TRPV1 agonist), responses after acute 20 ?g/ml oxaliplatin treatment where the second of paired capsaicin responses increased from 80.7 ± 0.6% without oxaliplatin, to 171.26 ± 29% with oxaliplatin, (n = 6 paired t test, P < 0.05); this was reduced to 81.42 ± 8.1% (P < 0.05), by pretretreatment with the cannabinoid CB2 receptor agonist GW 833972. Chronic oxaliplatin treatment also resulted in dose related increases in capsaicin responses. Similarly, second responses to icilin (TRPA1/TRPM8 agonist), were enhanced after acute (143.85 ± 7%, P = 0.004, unpaired t test, n = 3), and chronic (119.7 ± 11.8%, P < 0.05, n = 3) oxaliplatin treatment, compared to control (85.3 ± 1.7%). Responses to the selective TRPM8 agonist WS-12 were not affected. Conclusions Oxaliplatin treatment induces TRP sensitization mediated by increased intracellular cAMP, which may cause neuronal damage. These effects may be mitigated by co-treatment with adenylyl cyclase inhibitors, like CB2 agonists, to alleviate the neurotoxic effects of oxaliplatin.

2010-01-01

317

Nitric oxide induces apoptosis associated with TRPV1 channel-mediated Ca(2+) entry via S-nitrosylation in osteoblasts.  

PubMed

The high-level production of nitric oxide (NO) induced by inflammatory cytokines has been shown to play a key role in the pathogenesis of inflammation-mediated osteoporosis. In the present work, we observed that 1mM of the NO donor sodium nitroprusside (SNP) induced an increase of the cytosolic calcium concentration ([Ca(2+)]c) in osteoblasts, which was completely abolished by applying an extracellular Ca(2+)-free buffer. Further experiments showed that the SNP-induced [Ca(2+)]c increase was specifically blocked by potent antagonists of the transient receptor potential vanilloid subtype 1 (TRPV1) channel: capsazepine, ruthenium red, and La(3+) in Ca(2+)-containing buffer. However, nifedipine, an L-type voltage sensitive Ca(2+)-channel blocker, failed to suppress the [Ca(2+)]c elevation caused by SNP. Additionally, 1mM SNP induced osteoblast apoptosis, which was largely inhibited by the blockers of TRPV1, capsazepine and ruthenium red. Interestingly, our data showed that the SNP-induced [Ca(2+)]c increase was significantly inhibited by N-ethylmaleimide, the blocker of S-nitrosylation modification, instead of inhibitors of the NO-cGMP-PKG pathway. Taken together, our data clearly demonstrated that the NO donor SNP resulted in apoptosis associated with TRPV1 channel-mediated Ca(2+) entry via S-nitrosylation in osteoblasts. PMID:23707350

Pan, Leiting; Song, Kun; Hu, Fen; Sun, Wenwu; Lee, Imshik

2013-05-23

318

TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms  

PubMed Central

The mechanisms that generate itch are poorly understood at both the molecular and cellular levels despite its clinical importance. To explore the peripheral neuronal mechanisms underlying itch, we assessed the behavioral responses (scratching) produced by s.c. injection of various pruritogens in PLC?3- or TRPV1-deficient mice. We provide evidence that at least 3 different molecular pathways contribute to the transduction of itch responses to different pruritogens: 1) histamine requires the function of both PLC?3 and the TRPV1 channel; 2) serotonin, or a selective agonist, ?-methyl-serotonin (?-Me-5-HT), requires the presence of PLC?3 but not TRPV1, and 3) endothelin-1 (ET-1) does not require either PLC?3 or TRPV1. To determine whether the activity of these molecules is represented in a particular subpopulation of sensory neurons, we examined the behavioral consequences of selectively eliminating 2 nonoverlapping subsets of nociceptors. The genetic ablation of MrgprD+ neurons that represent ?90% of cutaneous nonpeptidergic neurons did not affect the scratching responses to a number of pruritogens. In contrast, chemical ablation of the central branch of TRPV1+ nociceptors led to a significant behavioral deficit for pruritogens, including ?-Me-5-HT and ET-1, that is, the TRPV1-expressing nociceptor was required, whether or not TRPV1 itself was essential. Thus, TRPV1 neurons are equipped with multiple signaling mechanisms that respond to different pruritogens. Some of these require TRPV1 function; others use alternate signal transduction pathways.

Imamachi, Noritaka; Park, Goon Ho; Lee, Hyosang; Anderson, David J.; Simon, Melvin I.; Basbaum, Allan I.; Han, Sang-Kyou

2009-01-01

319

The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats  

Microsoft Academic Search

Although it is well known that cannabinoids produce antinociception in acute pain models, there is less information on the ability of cannabinoids to alleviate hyperalgesia. In the present study, we determined whether cannabinoids attenuated the development of hyperalgesia produced by intraplantar injection of capsaicin in rats. In normal, untreated animals, intraplantar injection of 10 ?g capsaicin produces nocifensive behavior (elevation

Jun Li; Randy S Daughters; Christopher Bullis; Rimon Bengiamin; Mark W Stucky; John Brennan; Donald A Simone

1999-01-01

320

Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional differences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment  

Microsoft Academic Search

Vanilloid (capsaicin) receptors were visualized by [3H]resiniferatoxin (RTX) autoradiography in the brain of newborn as well as adult (both control and colchicine-treated) rats. Specific labelling was seen in the brain stem only, in the nucleus of the solitary tract extending into the area postrema and the spinal sensory nucleus of the trigeminal nerve. Also, a strong signal was seen in

Arpad Szallasi; Siv Nilsson; Tunde Farkas-Szallasi; Peter M. Blumberg; Tomas Hökfelt; Jan M. Lundberg

1995-01-01

321

The dual fatty acid amide hydrolase/TRPV1 blocker, N-arachidonoyl-serotonin, relieves carrageenan-induced inflammation and hyperalgesia in mice.  

PubMed

Given that the pharmacological or genetic inactivation of fatty acid amide hydrolase (FAAH) counteracts pain and inflammation, and on the basis of the established involvement of transient receptor potential vanilloid type-1 (TRPV1) channels in inflammatory pain, we tested the capability of a dual FAAH/TRPV1 blocker, N-arachidonoyl-serotonin (AA-5-HT), to relieve oedema and pain in a model of acute inflammation, and compared its efficacy with that of a single FAAH inhibitor (URB597) or TRPV1 antagonist (capsazepine). Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice and the anti-inflammatory and anti-nociceptive actions of AA-5-HT were assessed at different doses, time points and treatment schedule. In addition, endocannabinoid levels were measured in paw skin and spinal cord. Systemic administration of AA-5-HT elicited dose-dependent anti-oedemigen and anti-nociceptive effects, whereas it was devoid of efficacy when given locally. When tested in a therapeutic regimen, the compound retained comparable anti-inflammatory effects. TRPV1 receptor mediated the anti-inflammatory property of AA-5-HT, whereas both CB(1) and TRPV1 receptors were involved in its anti-hyperalgesic activity. These effects were accompanied by an increase of the levels of the endocannabinoid anandamide (AEA) in both inflamed paw and spinal cord. AA-5-HT was more potent than capsazepine as anti-oedemigen and anti-hyperalgesic drug, whereas it shows an anti-oedemigen property similar to URB597, which was, however, devoid of the anti-nociceptive effect. AA-5-HT did not induce unwanted effects on locomotion and body temperature. In conclusion AA-5-HT has both anti-inflammatory and anti-hyperalgesic properties and its employment offers advantages, in terms of efficacy and lack of adverse effects, deriving from its dual activity. PMID:20138997

Costa, Barbara; Bettoni, Isabella; Petrosino, Stefania; Comelli, Francesca; Giagnoni, Gabriella; Di Marzo, Vincenzo

2010-02-06

322

Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization*S?  

PubMed Central

TRPV1 is a nociceptive, Ca2+-selective ion channel involved in the development of several painful conditions. Sensitization of TRPV1 responses by cAMP-dependent PKA crucially contributes to the development of inflammatory hyperalgesia. However, the pathways involved in potentiation of TRPV1 responses by cAMP-dependent PKA remain largely unknown. Using HEK cells stably expressing TRPV1 and the ? opioid receptor, we demonstrated that treatment with the adenylate cyclase activator forskolin significantly increased the multimeric TRPV1 species. Pretreatment with the ? opioid receptor agonist morphine reversed this increased TRPV1 multimerization. FRET analysis revealed that treatment with forskolin did not cause multimerization of pre-existing TRPV1 monomers on the plasma membrane and that intracellular pools of TRPV1 exist mostly as monomers in this model. This suggests that increased TRPV1 multimerization occurred from an intracellular store of inactive TRPV1 monomers. Treatment with forskolin also caused an increase in TRPV1 expression on the plasma membrane not resulting from increased TRPV1 expression, and this rapid TRPV1 translocation was inhibited by treatment with morphine. Thus, potentiation of TRPV1 responses by cAMP-dependent PKA involves plasma membrane insertion of functional TRPV1 multimers formed from an intracellular store of inactive TRPV1 monomers. This potentiation occurs rapidly and can be dynamically modulated by activation of the ? opioid receptor under conditions where cAMP levels are raised, such as with inflammation. Increased translocation and multimerization of TRPV1 channels provide a cellular mechanism for finetuning of nociceptive responses that allow for rapid modulation of TRPV1 responses independent of transcriptional changes.

Vetter, Irina; Cheng, Wei; Peiris, Madusha; Wyse, Bruce D.; Roberts-Thomson, Sarah J.; Zheng, Jie; Monteith, Gregory R.; Cabot, Peter J.

2008-01-01

323

Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease  

PubMed Central

Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.

Kerstein, Patrick C.; Vilceanu, Daniel; Barabas, Marie E.; Retherford, Dawn; Brandow, Amanda M.; Wandersee, Nancy J.

2011-01-01

324

TRPV1 activation is not an all-or-none event: TRPV1 partial agonism/antagonism and its regulatory modulation  

PubMed Central

TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all be exploited through drug design.

Blumberg, Peter M.; Pearce, Larry V.; Lee, Jeewoo

2012-01-01

325

Ultraviolet irradiation of the eye and Fos-positive neurons induced in trigeminal brainstem after intravitreal or ocular surface transient receptor potential vanilloid 1 activation.  

PubMed

The interior structures of the eye are well supplied by the trigeminal nerve; however, the function of these afferent fibers is not well defined. The aim of this study was to use c-fos like immunohistochemistry (Fos-LI) to map the trigeminal brainstem complex after intravitreal microinjection or ocular surface application of capsaicin, a selective transient receptor potential vanilloid 1 (TRPV1) agonist in male rats under barbiturate anesthesia. The effect of ocular inflammation on Fos-LI was tested 2 or 7 days after UV irradiation of the eye. In non-inflamed controls, intravitreal capsaicin produced peaks of Fos-LI at the trigeminal subnucleus interpolaris/caudalis (Vi/Vcvl) transition and in superficial laminae at the caudalis/upper cervical cord (Vc/C1) junction regions. At the Vc/C1 junction intravitreal capsaicin induced Fos-LI in a dose-dependent manner, while at the Vi/Vcvl transition responses were similar after vehicle or capsaicin injections. Two days, but not 7 days, after UV irradiation intravitreal and ocular surface capsaicin-evoked Fos-LI at the Vc/C1 junction and nucleus tractus solitarius (NTS) were markedly enhanced, whereas the responses at the Vi/Vcvl transition were not different from non-inflamed controls. More than 80% of trigeminal ganglion neurons labeled after intravitreal microinjection of Fluorogold also expressed immunoreactivity for the TRPV1 receptor. These findings suggested that most intraocular trigeminal sensory nerves serve as nociceptors. The similar pattern and magnitude of Fos-LI after capsaicin suggested that TRPV1-responsive trigeminal nerves that supply intraocular and ocular surface tissues form a unified integrative circuit in the caudal brainstem. Intensity coding of capsaicin concentration and facilitation of Fos-LI expression after UV irradiation strongly supported the hypothesis that the Vc/C1 junction was critical for nociceptive processing related to ocular pain, whereas the Vi/Vcvl transition region likely served other functions in ocular homeostasis under naďve and inflamed conditions. PMID:20643195

Chang, Z; Okamoto, K; Tashiro, A; Bereiter, D A

2010-07-17

326

Role of Peptidergic Nerve Terminals in the Skin: Reversal of Thermal Sensation by Calcitonin Gene-Related Peptide in TRPV1-Depleted Neuropathy  

PubMed Central

To investigate the contribution of peptidergic intraepidermal nerve fibers (IENFs) to nociceptive responses after depletion of the thermal-sensitive receptor, transient receptor potential vanilloid subtype 1 (TRPV1), we took advantage of a resiniferatoxin (RTX)-induced neuropathy which specifically affected small-diameter dorsal root ganglion (DRG) neurons and their corresponding nerve terminals in the skin. Thermal hypoalgesia (p<0.001) developed from RTX-treatment day 7 (RTXd7) and became normalized from RTXd56 to RTXd84. Substance P (SP)(+) and TRPV1(+) neurons were completely depleted (p?=?0.0001 and p<0.0001, respectively), but RTX had a relatively minor effect on calcitonin gene-related peptide (CGRP)(+) neurons (p?=?0.029). Accordingly, SP(+) (p<0.0001) and TRPV1(+) (p?=?0.0008) IENFs were permanently depleted, but CGRP(+) IENFs (p?=?0.012) were only transiently reduced and had recovered by RTXd84 (p?=?0.83). The different effects of RTX on peptidergic neurons were attributed to the higher co-localization ratio of TRPV1/SP than of TRPV1/CGRP (p?=?0.029). Thermal hypoalgesia (p?=?0.0018) reappeared with an intraplantar injection of botulinum toxin type A (botox), and the temporal course of withdrawal latencies in the hot-plate test paralleled the innervation of CGRP(+) IENFs (p?=?0.0003) and CGRP contents in skin (p?=?0.01). In summary, this study demonstrated the preferential effects of RTX on depletion of SP(+) IENFs which caused thermal hypoalgesia. In contrast, the skin was reinnervated by CGRP(+) IENFs, which resulted in a normalization of nociceptive functions.

Chiang, Hao; Fu, Yaw-Syan; Lue, June-Horng; Hsieh, Sung-Tsang

2012-01-01

327

Endothelin receptor-mediated responses in trigeminal ganglion neurons.  

PubMed

Recent evidence implicates endothelin in nociception, but it is unclear how endothelin activates trigeminal ganglion (TRG) neurons. In the present study, we investigated the expression of the endothelin receptors ETA and ETB and endothelin-induced responses in rat TRG neurons. Double-immunofluorescence studies demonstrated that ETA and ETB were expressed in TRG neurons and that 26% of ETA- or ETB-expressing neurons expressed both receptors. During whole-cell patch-clamp recording, endothelin-1 enhanced an induced current in response to capsaicin, a TRPV1 agonist, in approximately 20% of dissociated neurons. The enhancement was blocked by the PKC inhibitor chelerythrine and by the ETA antagonist BQ-123, but not by the ETB antagonist BQ-788. Ca(2+)-imaging showed that endothelin-1 increased the intracellular Ca(2+) concentration in more than 20% of the dissociated neurons. Importantly, unlike the effect of endothelin-1 on capsaicin-induced current, the Ca(2+) response was largely suppressed by BQ-788 but not by BQ-123. These results suggest that ETA-mediated TRPV1 hyperactivation via PKC activation and ETB-mediated Ca(2+) mobilization occurs in different subsets of TRG neurons. These endothelin-induced responses may contribute to the induction of orofacial pain. The ETB-mediated function in TRG neurons is a special feature in the trigeminal system because of no ETB expression in dorsal root ganglion neurons. PMID:23396520

Yamamoto, T; Ono, K; Hitomi, S; Harano, N; Sago, T; Yoshida, M; Nunomaki, M; Shiiba, S; Watanabe, S; Nakanishi, O; Inenaga, K

2013-02-08

328

Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue.  

PubMed

The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies. Informed consent was obtained from patients presenting for extraction of normal wisdom teeth. Patients were anesthetized using nerve block injection, teeth were extracted and bisected, and pulp was removed and superfused in vitro. Basal and capsaicin-evoked peripheral release of immunoreactive calcitonin gene-related peptide (iCGRP) was analyzed by enzyme immunoassay. The presence of nociceptive markers within neurons of the dental pulp was characterized using confocal microscopy. Capsaicin increased the release of iCGRP from dental pulp biopsies in a concentration-dependent manner. Stimulated release was dependent on extracellular calcium, reversed by a TRPV1 receptor antagonist, and desensitized acutely (tachyphylaxis) and pharmacologically by pretreatment with capsaicin. Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition. These results indicate that the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity. PMID:19428185

Fehrenbacher, Jill C; Sun, Xiaoling X; Locke, Erin E; Henry, Michael A; Hargreaves, Kenneth M

2009-05-09

329

Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures.  

PubMed

The vanilloid receptor subtype 1 (VR1)/(TRPV1), binding capsaicin, is a non-selective cation channel that recently has been shown in human keratinocytes in vitro and in vivo. However, a description of VR1 localization in other cutaneous compartments in particular cutaneous nerve fibers is still lacking. We therefore investigated VR1 immunoreactivity as well as mRNA and protein expression in a series (n = 26) of normal (n = 7), diseased (n = 13) [prurigo nodularis (PN) (n = 10), generalized pruritus (n = 1), and mastocytosis (n = 2)], and capsaicin-treated human skin (n = 6). VR1 immunoreactivity could be observed in cutaneous sensory nerve fibers, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and the infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts, and the secretory portion of eccrine sweat glands. Upon reverse transcriptase-polymerase chain reaction and Western blot analysis, VR1 was detected in mast cells and keratinocytes from human skin. In pruritic skin of PN, VR1 expression was highly increased in epidermal keratinocytes and nerve fibers, which was normalized after capsaicin application. During capsaicin therapy, a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a major role for this receptor, e.g. in nociception and neurogenic inflammation. PMID:14987252

Ständer, Sonja; Moormann, Corinna; Schumacher, Mark; Buddenkotte, Jörg; Artuc, Metin; Shpacovitch, Victoria; Brzoska, Thomas; Lippert, Undine; Henz, Beate M; Luger, Thomas A; Metze, Dieter; Steinhoff, Martin

2004-03-01

330

Molecular target size of the vanilloid (capsaicin) receptor in pig dorsal root ganglia  

SciTech Connect

The size of the vanilloid receptor was examined by high-energy radiation inactivation analysis of the binding of ({sup 3}H)resiniferatoxin to pig dorsal root ganglion membranes; it was found to be 270 {plus minus} 25 kDa. This value most likely represents the size of a receptor complex rather than of an individual subunit. Other ligand-gated cation channel complexes have reported molecular weights in this range, e.g. 300 kDa for the acetylcholine receptor.

Szallasi, A.; Blumberg, P.M. (National Cancer Institute, Bethesda, MD (USA))

1991-01-01

331

Discovery of potent, orally available vanilloid receptor-1 antagonists. Structure-activity relationship of N-aryl cinnamides.  

PubMed

The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively). PMID:15634002

Doherty, Elizabeth M; Fotsch, Christopher; Bo, Yunxin; Chakrabarti, Partha P; Chen, Ning; Gavva, Narender; Han, Nianhe; Kelly, Michael G; Kincaid, John; Klionsky, Lana; Liu, Qingyian; Ognyanov, Vassil I; Tamir, Rami; Wang, Xianghong; Zhu, Jiawang; Norman, Mark H; Treanor, James J S

2005-01-13

332

Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbumin-sensitized guinea pig  

PubMed Central

BACKGROUND AND PURPOSE Airway sensory nerves play a key role in respiratory cough, dyspnoea, airway hyper-responsiveness (AHR), all fundamental features of airway diseases [asthma and chronic obstructive pulmonary disease (COPD) ]. Vagally mediated airway reflexes such as cough, bronchoconstriction and chest tightness originate from stimulation of airway sensory nerve endings. The transient receptor potential vanilloid 1 receptor (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological therapy of AHR in airway disease. EXPERIMENTAL APPROACH As guinea pig models can provide some of the essential features of asthma, including AHR, we have established the model with some classical pharmacological agents and examined the effect of the TRPV1 antagonists, SB-705498 and PF-04065463 on AHR to histamine evoked by ovalbumin (OA) in unanaesthetized sensitized guinea pigs restrained in a double chamber plethysmograph. Specific airway conductance (sGaw) derived from the airflow was calculated as a percentage of change from baseline. KEY RESULTS Cetirizine and salbutamol significantly inhibited OA-evoked bronchoconstriction [sGaw area under the curve (AUC): 70 and 78%, respectively]. Atropine, SB-705498 and PF-04065463 significantly inhibited OA-evoked AHR to histamine in unanaesthetized, OA-sensitized guinea pigs (sGaw AUC: 94%, 57% and 73%, respectively). Furthermore, this effect was not related to antagonism of histamine's activity. CONCLUSION AND IMPLICATIONS These data suggest that TRPV1 receptors located on airway sensory nerves are important in the development of AHR and that modulation of TRPV1-receptor activity represents a potential target for the pharmacological therapy of AHR in airway disease.

Delescluse, I; Mace, H; Adcock, JJ

2012-01-01

333

Inhibition of airway hyper-responsiveness by TRPV1 antagonists (SB-705498 and PF-04065463) in the unanaesthetized, ovalbumin-sensitized guinea pig.  

PubMed

BACKGROUND AND PURPOSE Airway sensory nerves play a key role in respiratory cough, dyspnoea, airway hyper-responsiveness (AHR), all fundamental features of airway diseases [asthma and chronic obstructive pulmonary disease (COPD)]. Vagally mediated airway reflexes such as cough, bronchoconstriction and chest tightness originate from stimulation of airway sensory nerve endings. The transient receptor potential vanilloid 1 receptor (TRPV1) is present on peripheral terminals of airway sensory nerves and modulation of its activity represents a potential target for the pharmacological therapy of AHR in airway disease. EXPERIMENTAL APPROACH As guinea pig models can provide some of the essential features of asthma, including AHR, we have established the model with some classical pharmacological agents and examined the effect of the TRPV1 antagonists, SB-705498 and PF-04065463 on AHR to histamine evoked by ovalbumin (OA) in unanaesthetized sensitized guinea pigs restrained in a double chamber plethysmograph. Specific airway conductance (sGaw) derived from the airflow was calculated as a percentage of change from baseline. KEY RESULTS Cetirizine and salbutamol significantly inhibited OA-evoked bronchoconstriction [sGaw area under the curve (AUC): 70 and 78%, respectively]. Atropine, SB-705498 and PF-04065463 significantly inhibited OA-evoked AHR to histamine in unanaesthetized, OA-sensitized guinea pigs (sGaw AUC: 94%, 57% and 73%, respectively). Furthermore, this effect was not related to antagonism of histamine's activity. CONCLUSION AND IMPLICATIONS These data suggest that TRPV1 receptors located on airway sensory nerves are important in the development of AHR and that modulation of TRPV1-receptor activity represents a potential target for the pharmacological therapy of AHR in airway disease. PMID:22320181

Delescluse, I; Mace, H; Adcock, J J

2012-07-01

334

TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis  

PubMed Central

Visceral afferents expressing transient receptor potential channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. In a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice/wk) of caerulein-induced acute pancreatitis (AP), we studied involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis, sprouting of pancreatic nerve fibers and increased TRPA1 and TRPV1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated prior to week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1 and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked development of CP and pain behaviors even when mice were challenged with seven more weeks of twice/wk caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest 1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, 2) there is transition from AP to CP, after which TRP channel antagonism is ineffective, and thus 3) that early intervention with TRP channel antagonists may effectively attenuate the transition to and development of CP.

Schwartz, Erica S.; La, Jun-Ho; Scheff, Nicole N.; Davis, Brian M.; Albers, Kathryn M.; Gebhart, G.F.

2013-01-01

335

Activation of TRPV1 and TRPA1 leads to muscle nociception and mechanical hyperalgesia  

Microsoft Academic Search

The involvement of TRPV1 and TRPA1 in mediating craniofacial muscle nociception and mechanical hyperalgesia was investigated in male Sprague–Dawley rats. First, we confirmed the expression of TRPV1 in masseter afferents in rat trigeminal ganglia (TG), and provided new data that TRPA1 is also expressed in primary afferents innervating masticatory muscles in double-labeling immunohistochemistry experiments. We then examined whether the activation

Jin Y. Ro; Jong-Seok Lee; Youping Zhang

2009-01-01

336

Thermal stimulation of primary sensory neurons in the rat hind paw: effect of morphine on ERK1/2 phosphorylation, TRPV1 and TRPA1 channel expression.  

PubMed

Temperature-sensitive transient receptor potential (TRP) channels or 'thermo-TRP' were stimulated on rat sensory afferents, and the effects on the phosphorylation of ERK1/2, on the regulation of TRPV1 and TRPA1, as well as the pharmacological modulation by the opioid analgesic morphine were investigated. The thermal stimuli were applied to the rat hind paw by immersion into either hot or cold water. Phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence-immunohistochemistry in the lumbar dorsal root ganglion (DRG) neurons. TRP channel mRNA expression was measured by RT-PCR in the innervating DRGs, and the protein content of TRPV1 and TRPA1 was determined by Western blot in the DRGs and in the sciatic nerve. The thermal stimuli led to a time-dependent increase in the number of DRG cells displaying cytoplasmic and nuclear staining for p-ERK1/2. Morphine partly prevented this increase in ERK1/2 phosphorylation, exerting its effect mainly on the nuclear staining. The mRNA expression for TRPV1 and TRPA1 in the DRG did not change within 24 h following the thermal stimuli. However, the protein content of both TRPV1 and TRPA1 was regulated by the thermal stimulation and by morphine. In the DRGs and in the sciatic nerve, heat or cold stimuli per se tended to decrease TRP protein levels, whereas with morphine pretreatment protein levels were raised. The present findings shed new light on the time-dependent reactions of primary sensory neurons towards irritant thermal stimuli to the skin and on their opioid modulation. PMID:23037317

Donnerer, Josef; Liebmann, Ingrid

2012-10-01

337

Capsaicin Responses in Heat-Sensitive and Heat-Insensitive A-Fiber Nociceptors  

Microsoft Academic Search

The recently cloned vanilloid receptor (VR1) is postulated to account for heat and capsaicin sensitivity in unmyelinated af- ferents. We sought to determine whether heat and capsaicin sensitivity also coexist in myelinated nociceptive afferents. Action potential (AP) activity was recorded from single A-fiber nociceptors that innervated the hairy skin in monkey. Before intradermal injection of capsaicin (10 mg\\/10 ml) into

Matthias Ringkamp; Yuan B. Peng; Gang Wu; Timothy V. Hartke; James N. Campbell; Richard A. Meyer

2001-01-01

338

Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons.  

PubMed

High concentrations of nicotine, as in the saliva of oral tobacco consumers or in smoking cessation aids, have been shown to sensitize/activate recombinant transient receptor potential vanilloid type 1 (rTRPV1) and mouse TRPA1 (mTRPA1) channels. By measuring stimulated calcitonin gene-related peptide (CGRP) release from the isolated mouse trachea, we established a bimodal concentration-response relationship with a threshold below 10 µM (-)-nicotine, a maximum at 100 µM, an apparent nadir between 0.5 and 10 mM, and a renewed increase at 20 mM. The first peak was unchanged in TRPV1/A1 double-null mutants as compared with wild-types and was abolished by specific nicotinic acetylcholine receptor (nAChR) inhibitors and by camphor, discovered to act as nicotinic antagonist. The nicotine response at 20 mM was strongly pHe-dependent, - five times greater at pH 9.0 than 7.4, indicating that intracellular permeation of the (uncharged) alkaloid was required to reach the TRPV1/A1 binding sites. The response was strongly reduced in both null mutants, and more so in double-null mutants. Upon measuring calcium transients in nodose/jugular and dorsal root ganglion neurons in response to 100 µM nicotine, 48% of the vagal (but only 14% of the somatic) sensory neurons were activated, the latter very weakly. However, nicotine 20 mM at pH 9.0 repeatedly activated almost every single cultured neuron, partly by releasing intracellular calcium and independent of TRPV1/A1 and nAChRs. In conclusion, in mouse tracheal sensory nerves nAChRs are 200-fold more sensitive to nicotine than TRPV1/A1; they are widely coexpressed with the capsaicin receptor among vagal sensory neurons and twice as abundant as TRPA1. Nicotine is the major stimulant in tobacco, and its sensory impact through nAChRs should not be disregarded. PMID:23926288

Kichko, Tatjana I; Lennerz, Jochen; Eberhardt, Mirjam; Babes, Ramona M; Neuhuber, Winfried; Kobal, Gerd; Reeh, Peter W

2013-08-07

339

Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates  

PubMed Central

Background Ablation of TRPV1-expressing nociceptive fibers with the potent capsaicin analog resiniferatoxin (RTX) results in long lasting pain relief. RTX is particularly adaptable to focal application, and the induced chemical axonopathy leads to analgesia with a duration that is influenced by dose, route of administration, and the rate of fiber regeneration. TRPV1 is expressed in a subpopulation of unmyelinated C- and lightly myelinated Adelta fibers that detect changes in skin temperature at low and high rates of noxious heating, respectively. Here we investigate fiber-type specific behaviors, their time course of recovery and molecular correlates of axon damage and nociception using infrared laser stimuli following an RTX-induced peripheral axonopathy. Results RTX was injected into rat hind paws (mid-plantar) to produce thermal hypoalgesia. An infrared diode laser was used to stimulate Adelta fibers in the paw with a small-diameter (1.6 mm), high-energy, 100 msec pulse, or C-fibers with a wide-diameter (5 mm), long-duration, low-energy pulse. We monitored behavioral responses to indicate loss and regeneration of fibers. At the site of injection, responses to C-fiber stimuli were significantly attenuated for two weeks after 5 or 50 ng RTX. Responses to Adelta stimuli were significantly attenuated for two weeks at the highest intensity stimulus, and for 5 weeks to a less intense Adelta stimulus. Stimulation on the toe, a site distal to the injection, showed significant attenuation of Adelta responses for 7- 8 weeks after 5 ng, or 9-10 weeks after 50 ng RTX. In contrast, responses to C-fiber stimuli exhibited basically normal responses at 5 weeks after RTX. During the period of fiber loss and recovery, molecular markers for nerve regeneration (ATF3 and galanin) are upregulated in the dorsal root ganglia (DRG) when behavior is maximally attenuated, but markers of nociceptive activity (c-Fos in spinal cord and MCP-1 in DRG), although induced immediately after RTX treatment, returned to normal. Conclusion Behavioral recovery following peripheral RTX treatment is linked to regeneration of TRPV1-expressing Adelta and C-fibers and sustained expression of molecular markers. Infrared laser stimulation is a potentially valuable tool for evaluating the behavioral role of Adelta fibers in pain and pain control.

2010-01-01

340

Treatment of trigeminal ganglion neurons in vitro with NGF, GDNF or BDNF: effects on neuronal survival, neurochemical properties and TRPV1-mediated neuropeptide secretion  

PubMed Central

Background Nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) all play important roles in the development of the peripheral sensory nervous system. Additionally, these growth factors are proposed to modulate the properties of the sensory system in the adult under pathological conditions brought about by nerve injury or inflammation. We have examined the effects of NGF, GDNF and BDNF on adult rat trigeminal ganglion (TG) neurons in culture to gain a better understanding of how these growth factors alter the cytochemical and functional phenotype of these neurons, with special attention to properties associated with nociception. Results Compared with no growth factor controls, GDNF, at 1 and 100 ng/ml, significantly increased by nearly 100% the number of neurons in culture at 5 days post-plating. A significant, positive, linear trend of increasing neuron number as a function of BDNF concentration was observed, also peaking at nearly 100%. NGF treatment was without effect. Chronic treatment with NGF and GDNF significantly and concentration-dependently increased 100 nM capsaicin (CAP)-evoked calcitonin gene-related peptide (CGRP) release, reaching approximately 300% at the highest concentration tested (100 ng/ml). Also, NGF and GDNF each augmented anandamide (AEA)- and arachidonyl-2-chloroethylamide (ACEA)-evoked CGRP release, while BDNF was without effect. Utilizing immunohistochemistry to account for the proportions of TRPV1- or CGRP-positive neurons under each growth factor treatment condition and then standardizing evoked CGRP release to these proportions, we observed that NGF was much more effective in enhancing CAP- and 50 mM K+-evoked CGRP release than was GDNF. Furthermore, NGF and GDNF each altered the concentration-response function for CAP- and AEA-evoked CGRP release, increasing the Emax without altering the EC50 for either compound. Conclusions Taken together, our results illustrate that NGF, GDNF and BDNF differentially alter TG sensory neuron survival, neurochemical properties and TRPV1-mediated neuropeptide release in culture. In particular, our findings suggest that GDNF and NGF differentially modulate TRPV1-mediated neuropeptide secretion sensitivity, with NGF having a much greater effect on a per neuron basis than GDNF. These findings are discussed in relation to possible therapeutic roles for growth factors or their modulators in pathological pain states, especially as these relate to the trigeminal system.

Price, Theodore J; Louria, Michael D; Candelario-Soto, Damaries; Dussor, Gregory O; Jeske, Nathanial A; Patwardhan, Amol M; Diogenes, Anibal; Trott, Amanda A; Hargreaves, Kenneth M; Flores, Christopher M

2005-01-01

341

The Transient Receptor Potential Vanilloid-1 Channel in Thermoregulation: A Thermosensor It Is Not  

PubMed Central

The development of antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel as pain therapeutics has revealed that these compounds cause hyperthermia in humans. This undesirable on-target side effect has triggered a surge of interest in the role of TRPV1 in thermoregulation and revived the hypothesis that TRPV1 channels serve as thermosensors. We review literature data on the distribution of TRPV1 channels in the body and on thermoregulatory responses to TRPV1 agonists and antagonists. We propose that two principal populations of TRPV1-expressing cells have connections with efferent thermoeffector pathways: 1) first-order sensory (polymodal), glutamatergic dorsal-root (and possibly nodose) ganglia neurons that innervate the abdominal viscera and 2) higher-order sensory, glutamatergic neurons presumably located in the median preoptic hypothalamic nucleus. We further hypothesize that all thermoregulatory responses to TRPV1 agonists and antagonists and thermoregulatory manifestations of TRPV1 desensitization stem from primary actions on these two neuronal populations. Agonists act primarily centrally on population 2; antagonists act primarily peripherally on population 1. We analyze what roles TRPV1 might play in thermoregulation and conclude that this channel does not serve as a thermosensor, at least not under physiological conditions. In the hypothalamus, TRPV1 channels are inactive at common brain temperatures. In the abdomen, TRPV1 channels are tonically activated, but not by temperature. However, tonic activation of visceral TRPV1 by nonthermal factors suppresses autonomic cold-defense effectors and, consequently, body temperature. Blockade of this activation by TRPV1 antagonists disinhibits thermoeffectors and causes hyperthermia. Strategies for creating hyperthermia-free TRPV1 antagonists are outlined. The potential physiological and pathological significance of TRPV1-mediated thermoregulatory effects is discussed.

Almeida, Maria C.; Garami, Andras; Steiner, Alexandre A.; Norman, Mark H.; Morrison, Shaun F.; Nakamura, Kazuhiro; Burmeister, Jeffrey J.; Nucci, Tatiane B.

2009-01-01

342

Heteromeric heat-sensitive transient receptor potential channels exhibit distinct temperature and chemical response.  

PubMed

TRPV1 and TRPV3 are two heat-sensitive ion channels activated at distinct temperature ranges perceived by human as hot and warm, respectively. Compounds eliciting human sensations of heat or warmth can also potently activate these channels. In rodents, TRPV3 is expressed predominantly in skin keratinocytes, whereas in humans TRPV1 and TRPV3 are co-expressed in sensory neurons of dorsal root ganglia and trigeminal ganglion and are known to form heteromeric channels with distinct single channel conductances as well as sensitivities to TRPV1 activator capsaicin and inhibitor capsazepine. However, how heteromeric TRPV1/TRPV3 channels respond to heat and other stimuli remains unknown. In this study, we examined the behavior of heteromeric TRPV1/TRPV3 channels activated by heat, capsaicin, and voltage. Our results demonstrate that the heteromeric channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1 and TRPV3 subunits. Our results suggest that heteromeric TRPV1/TRPV3 channels are unique heat sensors that may contribute to the fine-tuning of sensitivity to sensory inputs. PMID:22184123

Cheng, Wei; Yang, Fan; Liu, Shuang; Colton, Craig K; Wang, Chunbo; Cui, Yuanyuan; Cao, Xu; Zhu, Michael X; Sun, Changsen; Wang, KeWei; Zheng, Jie

2011-12-19

343

Heteromeric Heat-sensitive Transient Receptor Potential Channels Exhibit Distinct Temperature and Chemical Response*  

PubMed Central

TRPV1 and TRPV3 are two heat-sensitive ion channels activated at distinct temperature ranges perceived by human as hot and warm, respectively. Compounds eliciting human sensations of heat or warmth can also potently activate these channels. In rodents, TRPV3 is expressed predominantly in skin keratinocytes, whereas in humans TRPV1 and TRPV3 are co-expressed in sensory neurons of dorsal root ganglia and trigeminal ganglion and are known to form heteromeric channels with distinct single channel conductances as well as sensitivities to TRPV1 activator capsaicin and inhibitor capsazepine. However, how heteromeric TRPV1/TRPV3 channels respond to heat and other stimuli remains unknown. In this study, we examined the behavior of heteromeric TRPV1/TRPV3 channels activated by heat, capsaicin, and voltage. Our results demonstrate that the heteromeric channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1 and TRPV3 subunits. Our results suggest that heteromeric TRPV1/TRPV3 channels are unique heat sensors that may contribute to the fine-tuning of sensitivity to sensory inputs.

Cheng, Wei; Yang, Fan; Liu, Shuang; Colton, Craig K.; Wang, Chunbo; Cui, Yuanyuan; Cao, Xu; Zhu, Michael X.; Sun, Changsen; Wang, KeWei; Zheng, Jie

2012-01-01

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