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1

Monoacylglycerols Activate Capsaicin Receptor, TRPV1  

Microsoft Academic Search

Transient receptor potential vanilloid subtype 1 (TRPV1) is known as capsaicin (CAP) receptor and activated by CAP. Activation\\u000a of TRPV1 by CAP increases energy expenditure and thermogenesis in rodents or human. Therefore, TRPV1 may be target for energy\\u000a expenditure enhancement and thermogenesis. To search for novel TRPV1 agonist, we screened 19 types of foods by using TRPV1-expressing\\u000a HEK293 cells. TRPV1

Yusaku Iwasaki; Orine Saito; Manabu Tanabe; Kimiko Inayoshi; Kenji Kobata; Shuichi Uno; Akihito Morita; Tatsuo Watanabe

2008-01-01

2

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

3

Rapid disassembly of dynamic microtubules upon activation of the capsaicin receptor TRPV1.  

PubMed

The transmission of pain signalling involves the cytoskeleton, but mechanistically this is poorly understood. We recently demonstrated that the capsaicin receptor TRPV1, a non-selective cation channel expressed by nociceptors that is capable of detecting multiple pain-producing stimuli, directly interacts with the tubulin cytoskeleton. We hypothesized that the tubulin cytoskeleton is a downstream effector of TRPV1 activation. Here we show that activation of TRPV1 results in the rapid disassembly of microtubules, but not of the actin or neurofilament cytoskeletons. TRPV1 activation mainly affects dynamic microtubules that contain tyrosinated tubulins, whereas stable microtubules are apparently unaffected. The C-terminal fragment of TRPV1 exerts a stabilizing effect on microtubules when over-expressed in F11 cells. These findings suggest that TRPV1 activation may contribute to cytoskeleton remodelling and so influence nociception. PMID:16336230

Goswami, C; Dreger, M; Otto, H; Schwappach, B; Hucho, F

2006-01-01

4

Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling.  

PubMed

Transient receptor potential (TRP) channels detect diverse sensory stimuli, including alterations in osmolarity. However, a molecular detector of noxious hypertonic stimuli has not yet been identified. We show here that acute pain-related behavior evoked by elevated ionic strength is abolished in TRP vanilloid subtype 1 (TRPV1)-null mice and inhibited by iodoresiniferatoxin, a potent TRPV1 antagonist. Electrophysiological recordings demonstrate a novel form of ion channel modulation by which extracellular Na+, Mg2+, and Ca2+ ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg2+ (from 1 to 5 mM) or Na+ (+50 mM) increased ligand-activated currents up to fourfold, and 10 mM Mg2+ reduced the EC50 for activation by capsaicin from 890 to 450 nM. Moreover, concentrations of divalent cations >10 mM directly gate the receptor. These effects occur via electrostatic interactions with two glutamates (E600 and E648) formerly identified as proton-binding residues. Furthermore, phospholipase C-mediated signaling enhances the effects of cations, and physiological concentrations of cations contribute to the bradykinin-evoked activation of TRPV1 and the sensitization of the receptor to heat. Thus, the modulation of TRPV1 by cationic strength may contribute to inflammatory pain signaling. PMID:15917451

Ahern, Gerard P; Brooks, Ian M; Miyares, Rosa Linda; Wang, Xiang-bin

2005-05-25

5

ThermoTRP Channels in Nociceptors: Taking a Lead from Capsaicin Receptor TRPV1  

PubMed Central

Nociceptors with peripheral and central projections express temperature sensitive transient receptor potential (TRP) ion channels, also called thermoTRP’s. Chemosensitivity of thermoTRP’s to certain natural compounds eliciting pain or exhibiting thermal properties has proven to be a good tool in characterizing these receptors. Capsaicin, a pungent chemical in hot peppers, has assisted in the cloning of the first thermoTRP, TRPV1. This discovery initiated the search for other receptors encoding the response to a wide range of temperatures encountered by the body. Of these, TRPV1 and TRPV2 encode unique modalities of thermal pain when exposed to noxious heat. The ability of TRPA1 to encode noxious cold is presently being debated. The role of TRPV1 in peripheral inflammatory pain and central sensitization during chronic pain is well known. In addition to endogenous agonists, a wide variety of chemical agonists and antagonists have been discovered to activate and inhibit TRPV1. Efforts are underway to determine conditions under which agonist-mediated desensitization of TRPV1 or inhibition by antagonists can produce analgesia. Also, identification of specific second messenger molecules that regulate phosphorylation of TRPV1 has been the focus of intense research, to exploit a broader approach to pain treatment. The search for a role of TRPV2 in pain remains dormant due to the lack of suitable experimental models. However, progress into TRPA1’s role in pain has received much attention recently. Another thermoTRP, TRPM8, encoding for the cool sensation and also expressed in nociceptors, has recently been shown to reduce pain via a central mechanism, thus opening a novel strategy for achieving analgesia. The role of other thermoTRP’s (TRPV3 and TRPV4) encoding for detection of warm temperatures and expressed in nociceptors cannot be excluded. This review will discuss current knowledge on the role of nociceptor thermoTRPs in pain and therapy and describes the activator and inhibitor molecules known to interact with them and modulate their activity.

Mandadi, Sravan; Roufogalis, Basil D.

2008-01-01

6

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

7

A Bivalent Tarantula Toxin Activates the Capsaicin Receptor, TRPV1, by Targeting the Outer Pore Domain  

PubMed Central

SUMMARY Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency, illustrating a new paradigm in toxin structure and evolution. The ‘double-knot’ toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation.

Bohlen, Christopher J.; Priel, Avi; Zhou, Sharleen; King, David; Siemens, Jan; Julius, David

2010-01-01

8

A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain.  

PubMed

Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency. The "double-knot" toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation. PMID:20510930

Bohlen, Christopher J; Priel, Avi; Zhou, Sharleen; King, David; Siemens, Jan; Julius, David

2010-05-28

9

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel  

PubMed Central

Capsaicin elicits burning pain via the activation of the vanilloid receptor (TRPV1). Intriguingly, several reports showed that capsaicin also inhibits Na+ currents but the mechanisms remain unclear. To explore this non-TRPV1 action we applied capsaicin to HEK293 cells stably expressing inactivation-deficient rat skeletal muscle Na+ mutant channels (rNav1.4-WCW). Capsaicin elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents. The 50% inhibitory concentration (IC50) of capsaicin for open Na+ channels at +30 mV was measured 6.8 ± 0.6 ?M (n = 5), a value that is 10–30 times lower than those for resting (218 ?M) and inactivated (74 ?M) wild-type Na+ channels. On-rate and off-rate constants for capsaicin open-channel block at +30 mV were estimated to be 6.37 ?M?1 s?1 and 34.4 s?1, respectively, with a calculated dissociation constant (KD) of 5.4 ?M. Capsaicin at 30 ?M produced ~70% additional use-dependent block of remaining rNav1.4-WCW Na+ currents during repetitive pulses at 1 Hz. Site-directed mutagenesis showed that the local anesthetic receptor was not responsible for the capsaicin block of the inactivation-deficient Na+ channel. Interestingly, capsaicin elicited little time-dependent block of batrachotoxin-modified rNav1.4-WCW Na+ currents, indicating that batrachotoxin prevents capsaicin binding. Finally, neuronal open Na+ channels endogenously expressed in GH3 cells were as sensitive to capsaicin block as rNav1.4 counterparts. We conclude that capsaicin preferentially blocks persistent late Na+ currents, probably via a receptor that overlaps the batrachotoxin receptor but not the local anesthetic receptor. Drugs that target such a non-TRPV1 receptor could be beneficial for patients with neuropathic pain.

Wang, Sho-Ya; Mitchell, Jane; Wang, Ging Kuo

2007-01-01

10

TRPV1b overexpression negatively regulates TRPV1 responsiveness to capsaicin, heat and low pH in HEK293 cells.  

PubMed

Transient receptor potential channel type V (TRPV) 1 is a non-selective cation channel that can be activated by capsaicin, endogenous vanilloids, heat and protons. The human TRPV1 splice variant, TRPV1b, lacking exon 7, was cloned from human dorsal root ganglia (DRG) RNA. The expression profile and relative abundance of TRPV1b and TRPV1 in 35 different human tissues were determined by quantitative RT-PCR using isoform-specific probes. TRPV1b was most abundant in fetal brain, adult cerebellum and DRG. Functional studies using electrophysiological techniques showed that recombinant TRPV1b was not activated by capsaicin (1 microM), protons (pH 5.0) or heat (50 degrees C). However, recombinant TRPV1b did form multimeric complexes and was detected on the plasma membrane of cells, demonstrating that the lack of channel function was not due to defects in complex formation or cell surface expression. These results demonstrate that exon 7, which encodes the third ankyrin domain and 44 amino acids thereafter, is required for normal channel function of human TRPV1. Moreover, when co-expressed with TRPV1, TRPV1b formed complexes with TRPV1, and inhibited TRPV1 channel function in response to capsaicin, acidic pH, heat and endogenous vanilloids, dose-dependently. Taken together, these data support the hypothesis that TRPV1b is a naturally existing inhibitory modulator of TRPV1. PMID:17018028

Vos, Melissa H; Neelands, Torben R; McDonald, Heath A; Choi, Won; Kroeger, Paul E; Puttfarcken, Pamela S; Faltynek, Connie R; Moreland, Robert B; Han, Ping

2006-11-01

11

TRPV1 receptors and nasal trigeminal chemesthesis.  

PubMed

The trigeminal nerve responds to a wide variety of irritants. Trigeminal nerve fibers express several receptors that respond to chemicals, including TRPV1 (vanilloid) receptors, acid-sensing ion channels, P2X (purinergic) receptors, and nicotinic acetylcholine receptors. In order to assess whether TRPV1 plays a role in responses to a broad array of substances, TRPV1 (along with green fluorescent protein) was expressed in human embyonic kidney cells (HEK) 293t cells which were then stimulated with diverse trigeminal irritants. Calcium imaging was used to measure responses to capsaicin, amyl acetate, cyclohexanone, acetic acid, toluene, benzaldehyde, (-)-nicotine, (R)-(+)-limonene, (R)-(-)-carvone, and (S)-(+)-carvone. Three irritants (acetic acid and the 2 carvones) stimulated nontransfected controls. Two irritants (capsaicin and cyclohexanone) stimulated only transfected cells. The response could be eliminated with capsazepine, a TRPV1 blocker. The 5 remaining irritants were nonstimulatory in both nontransfected and transfected cells. Because all the compounds tested on HEK cells elicited neural responses from the ethmoid branch of the trigeminal nerve in rats, the 5 nonstimulatory compounds must do so by a non-TRPV1 receptor. These results suggest that TRPV1 serves as a receptor for both cyclohexanone and capsaicin in trigeminal nerve endings. PMID:16908491

Silver, Wayne L; Clapp, Tod R; Stone, Leslie M; Kinnamon, Sue C

2006-11-01

12

Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism.  

PubMed

The assessment of the biological activity of capsaicin, the compound responsible for the spicy flavor of chili pepper, produced controversial results, showing either carcinogenicity or cancer prevention. The innate immune system plays a pivotal role in cancer pathology and prevention; yet, the effect of capsaicin on natural killer (NK) cells, which function in cancer surveillance, is unclear. This study found that capsaicin inhibited NK cell-mediated cytotoxicity and cytokine production (interferon-? and tumor necrosis factor-?). Capsaicin impaired the cytotoxicity of NK cells, thereby inhibiting lysis of standard target cells and gastric cancer cells by modulating calcium mobilization in NK cells. Capsaicin also induced apoptosis in gastric cancer cells, but that effect required higher concentrations and longer exposure times than those required to trigger NK cell dysfunction. Furthermore, capsaicin inhibited the cytotoxicity of isolated NK cells and of an NK cell line, suggesting a direct effect on NK cells. Antagonists of transient receptor potential vanilloid subfamily member 1 (TRPV1), a cognate capsaicin receptor, or deficiency in TRPV1 expression failed to prevent the defects induced by capsaicin in NK cells expressing functional TRPV1. Thus, the mechanism of action of capsaicin on NK cells is largely independent of TRPV1. Taken together, capsaicin may have chemotherapeutic potential but may impair NK cell function, which plays a central role in tumor surveillance. PMID:24743513

Kim, Hun Sik; Kwon, Hyung-Joon; Kim, Gye Eun; Cho, Mi-Hyang; Yoon, Seung-Yong; Davies, Alexander J; Oh, Seog Bae; Lee, Heuiran; Cho, Young Keol; Joo, Chul Hyun; Kwon, Seog Woon; Kim, Sun Chang; Kim, Yoo Kyum

2014-07-01

13

Activation of TRPV1 by Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension  

PubMed Central

SUMMARY Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation on the regulation of vascular function and blood pressure. Here we report that chronic TRPV1 activation by dietary capsaicin increases the phosphorylation of protein kinase A (PKA) and eNOS and thus production of nitric oxide (NO) in endothelial cells, which is calcium dependent. TRPV1 activation by capsaicin enhances endothelium-dependent relaxation in wild-type mice, an effect absent in TRPV1-deficient mice. Long-term stimulation of TRPV1 can activate PKA, which contributes to increased eNOS phosphorylation, improves vasorelaxation, and lowers blood pressure in genetically hypertensive rats. We conclude that TRPV1 activation by dietary capsaicin improves endothelial function. TRPV1-mediated increase in NO production may represent a promising target for therapeutic intervention of hypertension.

Yang, Dachun; Luo, Zhidan; Ma, Shuangtao; Wong, Wing Tak; Ma, Liqun; Zhong, Jian; He, Hongbo; Zhao, Zhigang; Cao, Tingbing; Yan, Zhencheng; Liu, Daoyan; Arendshorst, William J.; Huang, Yu; Tepel, Martin; Zhu, Zhiming

2014-01-01

14

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

PubMed Central

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 and anandamide induced Ca2+ influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca2+ influx, was increased ?3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca2+ ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency. That a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a previously undescribed mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation.

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

2005-01-01

15

Design and synthesis of conformationally restricted capsaicin analogues based in the 1, 3, 4-thiadiazole heterocycle reveal a novel family of transient receptor potential vanilloid 1 (TRPV1) antagonists.  

PubMed

4-hydroxy-3-methoxybenzaldehyde was used as starting material to obtain a number of 1, 3, 4-thiadiazole alkylamide derivatives. The pharmacological properties of these conformationally restricted capsaicin analogues were evaluated on HEK-293T cells transiently expressing TRPV1 receptor. By means of a highthroughput calcium imaging assay we find that 1, 3, 4-thiadiazoles (compounds 8-15) act as potent antagonists of the capsaicin receptor, inhibiting both, the capsaicin- and temperature-dependent activation. Docking studies suggested a different binding orientation on the vanilloid binding site when compared with capsaicin analogues, such as 5-iodononivamide. Overall, our studies suggest that 1, 3, 4-thiadiazoles interact with capsaicin's binding region of the receptor, although using a different set of interactions within the vanilloid binding pocket. PMID:23796768

Rebolledo, Carolyne Lespay; Sotelo-Hitschfeld, Pamela; Brauchi, Sebastián; Olavarría, Miguel Zárraga

2013-08-01

16

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

PubMed Central

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-Isc). 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-Isc by capsaicin. Neither resiniferatoxin nor N-oleoyldopamine, two selective agonists of TRPV1, blocked the FSK-Isc. Conversely capsaicin, resiniferatoxin, and N-oleoyldopamine raised intracellular calcium ([Ca2+]i) in T84 cells and AMG-9810 blocked the rise in [Ca2+]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.

Tang, Xu; Weber, Christopher R.; Shen, Le; Turner, Jerrold R.; Matthews, Jeffrey B.

2013-01-01

17

New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy.  

PubMed

Painful diabetic neuropathy is a disease of the peripheral sensory neuron with impaired opioid responsiveness. Since ?-opioid receptor (MOR) activation can inhibit the transient receptor potential vanilloid 1 (TRPV1) activity in peripherally sensory neurons, this study investigated the mechanisms of impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity in painful diabetic neuropathy. Intravenous injection of streptozotocin (STZ, 45 mg/kg) in Wistar rats led to a degeneration of insulin producing pancreatic ?-cells, elevated blood glucose, and mechanical hypersensitivity (allodynia). In these animals, local morphine's inhibitory effects on capsaicin-induced nocifensive behavior as well as on capsaicin-induced TRPV1 current in dorsal root ganglion cells were significantly impaired. These changes were associated with a loss in MOR but not TRPV1 in peripheral sensory neurons. Intrathecal delivery of nerve growth factor in diabetic animals normalized sensory neuron MOR and subsequently rescued morphine's inhibitory effects on capsaicin-induced TRPV1 activity in vivo and in vitro. These findings identify a loss in functional MOR on sensory neurons as a contributing factor for the impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity during advanced STZ-induced diabetes. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (e.g. arthritis, cancer, neuropathy) and may give novel therapeutic incentives. PMID:24863039

Shaqura, Mohammed; Khalefa, Baled I; Shakibaei, Mehdi; Zöllner, Christian; Al-Khrasani, Mahmoud; Fürst, Susanna; Schäfer, Michael; Mousa, Shaaban A

2014-10-01

18

Neonatal capsaicin treatment in rats affects TRPV1-related noxious heat sensation and circadian body temperature rhythm.  

PubMed

The transient receptor potential vanilloid 1 (TRPV1) is a cation channel that serves as a polymodal detector of noxious stimuli such as capsaicin. Therefore, capsaicin treatment has been used to investigate the physiological function of TRPV1. Here, we report physiological changes induced by treating neonatal rats with capsaicin. Capsaicin (50mg/kg) (cap-treated) or vehicle (vehicle-treated) was systemically administered to newborn SD rat pups within 48 h after birth. TRPV1 expression, intake volume of capsaicin water, and noxious heat sensation were measured 6 weeks after capsaicin treatment. Circadian body temperature and locomotion were recorded by biotelemetry. Expression of Per1, Per2, Bmal1 and Hsf1 (clock genes) was also investigated. Neonatal capsaicin treatment not only decreased TRPV1 expression but also induced desensitization to noxious heat stimuli. Circadian body temperature of cap-treated rats increased significantly compared with that of vehicle-treated rats. Additionally, the amplitude of the circadian body temperature was reversed in cap-treated rats. Expression of the hypothalamic Hsf1 and liver Per2 clock genes followed a similar trend. Therefore, we suggest that these findings will be useful in studying various physiological mechanisms related to TRPV1. PMID:24746025

Jeong, Keun-Yeong; Seong, Jinsil

2014-06-15

19

The ? opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase A pathway  

Microsoft Academic Search

BACKGROUND: The vanilloid receptor 1 (TRPV1) is critical in the development of inflammatory hyperalgesia. Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA) pathway to potentiate TRPV1-mediated capsaicin responses. Such regulation may have significance in inflammatory pain. However, few functional receptor interactions that inhibit PKA-mediated potentiation

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

2006-01-01

20

N-octanoyl-dopamine is an agonist at the capsaicin receptor TRPV1 and mitigates ischemia-induced [corrected] acute kidney injury in rat.  

PubMed

Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNF? stimulated proximal tubular epithelial cells, inhibition of NF?B and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization. PMID:22916273

Tsagogiorgas, Charalambos; Wedel, Johannes; Hottenrott, Maximilia; Schneider, Michael O; Binzen, Uta; Greffrath, Wolfgang; Treede, Rolf-Detlef; Theisinger, Bastian; Theisinger, Sonja; Waldherr, Rüdiger; Krämer, Bernhard K; Thiel, Manfred; Schnuelle, Peter; Yard, Benito A; Hoeger, Simone

2012-01-01

21

N-octanoyl-Dopamine Is an Agonist at the Capsaicin Receptor TRPV1 and Mitigates Is Chemia-Induced Acute Kidney Injury in Rat  

PubMed Central

Since stimulation of transient receptor potential channels of the vanilloid receptor subtype 1 (TRPV1) mitigates acute kidney injury (AKI) and endogenous N-acyl dopamine derivatives are able to activate TRPV1, we tested if synthetic N-octanoyl-dopamine (NOD) activates TRPV1 and if it improves AKI. These properties of NOD and its intrinsic anti-inflammatory character were compared with those of dopamine (DA). TRPV1 activation and anti-inflammatory properties of NOD and DA were tested using primary cell cultures in vitro. The influence of NOD and DA on AKI was tested in a prospective, randomized, controlled animal study with 42 inbred male Lewis rats (LEW, RT1), treated intravenously with equimolar concentrations of DA or NOD one hour before the onset of warm ischemia and immediately before clamp release. NOD, but not DA, activates TRPV1 channels in isolated dorsal root ganglion neurons (DRG) that innervate several tissues including kidney. In TNF? stimulated proximal tubular epithelial cells, inhibition of NF?B and subsequent inhibition of VCAM1 expression by NOD was significantly stronger than by DA. NOD improved renal function compared to DA and saline controls. Histology revealed protective effects of NOD on tubular epithelium at day 5 and a reduced number of monocytes in renal tissue of DA and NOD treated rats. Our data demonstrate that NOD but not DA activates TRPV1 and that NOD has superior anti-inflammatory properties in vitro. Although NOD mitigates deterioration in renal function after AKI, further studies are required to assess to what extend this is causally related to TRPV1 activation and/or desensitization.

Tsagogiorgas, Charalambos; Wedel, Johannes; Hottenrott, Maximilia; Schneider, Michael O.; Binzen, Uta; Greffrath, Wolfgang; Treede, Rolf-Detlef; Theisinger, Bastian; Theisinger, Sonja; Waldherr, Rudiger; Kramer, Bernhard K.; Thiel, Manfred; Schnuelle, Peter; Yard, Benito A.; Hoeger, Simone

2012-01-01

22

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

23

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

24

Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1  

PubMed Central

BACKGROUND AND PURPOSE The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca2+) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1?/? mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca2+ in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat.

Czikora, A; Lizanecz, E; Bako, P; Rutkai, I; Ruzsnavszky, F; Magyar, J; Porszasz, R; Kark, T; Facsko, A; Papp, Z; Edes, I; Toth, A

2012-01-01

25

Presynaptic TRPV1 vanilloid receptor function is age- but not CB1 cannabinoid receptor-dependent in the rodent forebrain.  

PubMed

Neocortical and striatal TRPV1 (vanilloid or capsaicin) receptors (TRPV1Rs) are excitatory ligand-gated ion channels, and are implicated in psychiatric disorders. However, the purported presynaptic neuromodulator role of TRPV1Rs in glutamatergic, serotonergic or dopaminergic terminals of the rodent forebrain remains little understood. With the help of patch-clamp electrophysiology and neurochemical approaches, we mapped the age-dependence of presynaptic TRPV1R function, and furthermore, we aimed at exploring whether the presence of CB1 cannabinoid receptors (CB1Rs) influences the function of the TRPV1Rs, as both receptor types share endogenous ligands. We found that the major factor which affects presynaptic TRPV1R function is age: by post-natal day 13, the amplitude of capsaicin-induced release of dopamine and glutamate is halved in the rat striatum, and two weeks later, capsaicin already loses its effect. However, TRPV1R receptor function is not enhanced by chemical or genetic ablation of the CB1Rs in dopaminergic, glutamatergic and serotonergic terminals of the mouse brain. Altogether, our data indicate a possible neurodevelopmental role for presynaptic TRPV1Rs in the rodent brain, but we found no cross-talk between TRPV1Rs and CB1Rs in the same nerve terminal. PMID:23831917

Köles, László; Garçăo, Pedro; Zádori, Zoltán S; Ferreira, Samira G; Pinheiro, Bárbara S; da Silva-Santos, Carla S; Ledent, Catherine; Köfalvi, Attila

2013-08-01

26

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

2013-03-01

27

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

28

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

29

?-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

30

?-Arrestin-2 desensitizes the transient receptor potential vanilloid 1 (TRPV1) channel.  

PubMed

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. PMID:22952227

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

2012-10-26

31

Localization of TRPV1 and contractile effect of capsaicin in mouse large intestine: high abundance and sensitivity in rectum and distal colon.  

PubMed

We investigated immunohistochemical differences in the distribution of TRPV1 channels and the contractile effects of capsaicin on smooth muscle in the mouse rectum and distal, transverse, and proximal colon. In the immunohistochemical study, TRPV1 immunoreactivity was found in the mucosa, submucosal, and muscle layers and myenteric plexus. Large numbers of TRPV1-immunoreactive axons were observed in the rectum and distal colon. In contrast, TRPV1-positive axons were sparsely distributed in the transverse and proximal colon. The density of TRPV1-immunoreactive axons in the rectum and distal colon was much higher than those in the transverse and proximal colon. Axons double labeled with TRPV1 and protein gene product (PGP) 9.5 were detected in the myenteric plexus, but PGP 9.5-immunoreactive cell bodies did not colocalize with TRPV1. In motor function studies, capsaicin induced a fast transient contraction, followed by a large long-lasting contraction in the rectum and distal colon, whereas in the transverse and proximal colon only the transient contraction was observed. The capsaicin-induced transient contraction from the proximal colon to the rectum was moderately inhibited by an NK1 or NK2 receptor antagonist. The capsaicin-induced long-lasting contraction in the rectum and distal colon was markedly inhibited by an NK2 antagonist, but not by an NK1 antagonist. The present results suggest that TRPV1 channels located on the rectum and distal colon play a major role in the motor function in the large intestine. PMID:19497956

Matsumoto, Kenjiro; Kurosawa, Emi; Terui, Hiroyuki; Hosoya, Takuji; Tashima, Kimihito; Murayama, Toshihiko; Priestley, John V; Horie, Syunji

2009-08-01

32

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

2009-04-01

33

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

34

Eriodictyol: a flavonoid antagonist of the TRPV1 receptor with antioxidant activity.  

PubMed

The transient potential vanilloid 1 receptor (TRPV1) is a calcium-permeable channel responsible for the transduction and modulation of acute and chronic pain signaling. As such, this receptor is a potential target for the treatment of a number of pain disorders. However, AMG517, a TRPV1 antagonist, presents several clinical limitations that include the induction of severe hyperthermia. The aim of this study was to investigate the possible interaction of the flavonoid eriodictyol with the TRPV1 receptor and to determine its putative antinociceptive and hyperthermic effects. Eriodictyol was able to displace [(3)H]-resiniferatoxin binding (IC(50)=47; 21-119nM) and to inhibit calcium influx mediated by capsaicin (IC(50)=44; 16-125nM), suggesting that eriodictyol acts as a TRPV1 antagonist. Moreover, eriodictyol induced antinociception in the intraplantar capsaicin test, with maximal inhibition of 49±10 and 64±4% for oral (ID(50)=2.3; 1.1-5.7mg/kg) and intrathecal (ID(50)=2.2; 1.7-2.9nmol/site) administration, respectively. Eriodictyol did not induce any change in body temperature or locomotor activity. Orally administered eriodictyol (4.5mg/kg) prevented the nociception induced by intrathecal injections of capsaicin, as well as the non-protein thiol loss and 3-nitrotyrosine (3-NT) formation induced by capsaicin in spinal cord. Eriodictyol also reduced the thermal hyperalgesia and mechanical allodynia elicited by complete Freund's adjuvant (CFA) paw injection. In conclusion, eriodictyol acts as an antagonist of the TRPV1 receptor and as an antioxidant; it induces antinociception without some of the side effects and limitations such as hyperthermia that are expected for TRPV1 antagonists. PMID:21087598

Rossato, Mateus Fortes; Trevisan, Gabriela; Walker, Cristiani Isabel Banderó; Klafke, Jonatas Zeni; de Oliveira, Ana Paula; Villarinho, Jardel Gomes; Zanon, Ricardo Basso; Royes, Luiz Fernando Freire; Athayde, Margareth Linde; Gomez, Marcus Vinicius; Ferreira, Juliano

2011-02-15

35

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

36

Capsaicin Blocks the Hyperpolarization-Activated Inward Currents via TRPV1 in the Rat Dorsal Root Ganglion Neurons  

PubMed Central

Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, prolonged exposures of capsaicin will cause desensitization to nociceptive stimuli. Hyperpolarization-activated cation currents (Ih) contribute to the maintenance of the resting membrane potential and excitability of neurons. In the cultured dorsal root ganglion (DRG) neurons, we investigated mechanisms underlying capsaicin-mediated modulation of Ih using patch clamp recordings. Capsaicin (1 µM) inhibited Ih only in the capsaicin-sensitive neurons. The capsaicin-induced inhibition of Ih was prevented by preexposing the TRPV1 antagonist, capsazepine (CPZ). Capsaicin-induced inhibition of Ih was dose dependent (IC50= 0.68 µM) and partially abolished by intracellular BAPTA and cyclosporin A, specific calcineurin inhibitor. In summary, the inhibitory effects of capsaicin on Ih are mediated by activation of TRPV1 and Ca2+-triggered cellular responses. Analgesic effects of capsaicin have been thought to be related to desensitization of nociceptive neurons due to depletion of pain-related substances. In addition, capsaicin-induced inhibition of Ih is likely to be important in understanding the analgesic mechanism of capsaicin.

2012-01-01

37

Anxiogenic-like effect induced by TRPV1 receptor activation within the dorsal periaqueductal gray matter in mice.  

PubMed

Pharmacological manipulation of TRPV1 (Transient Receptor Potential Vanilloid type-1) receptors has been emerging as a novel target in the investigation of anxiety states. Here, we attempt to show the role played by the TRPV1 receptors within the dorsal periaqueductal gray matter (dPAG), a midbrain structure strongly involved in the modulation of anxiety. Anxiety was assessed by recording spatiotemporal [percent open arm entries (%OE) and percent open arm time (%OT)] and ethological [e.g., head dipping (HD), stretched-attend postures (SAP)] measures in mice exposed to the elevated plus-maze (EPM). Mice received an intra-dPAG injection of the TRPV1 agonist capsaicin (0, 0.01, 0.1 or 1.0nmol/0.2?L; Experiment 1) or antagonist capsazepine (0, 10, 30 or 60nmol/0.2?L; Experiment 2), or combined injections of capsazepine (30nmol) and capsaicin (1.0nmol) (Experiment 3), and were exposed to the EPM to record spatiotemporal and ethological measures. While capsaicin produced an anxiogenic-like effect (it reduced %OE and %OT and frequency of SAP and HD in the open arms), capsazepine did not change any behavior in the EPM. However, when injected before capsaicin (1.0nmol), intra-dPAG capsazepine (30nmol-a dose devoid of intrinsic effects) antagonized completely the anxiogenic-like effect of the TRPV1 agonist. These results suggest that the anxiogenic-like effect produced by capsaicin is primarily due to TRPV1 activation within the dPAG in mice, but that dPAG TRPV1 receptors do not exert a tonic control over defensive behavior in mice exposed to the EPM. PMID:23707246

Mascarenhas, Diego Cardozo; Gomes, Karina Santos; Nunes-de-Souza, Ricardo Luiz

2013-08-01

38

Real-Time Translocation and Function of PKC?II Isoform in Response to Nociceptive Signaling via the TRPV1 Pain Receptor  

PubMed Central

Serine/threonine protein kinase C ?II isoform (PKC?II) or the pain receptor transient receptor potential vanilloid 1 (TRPV1) have been separately implicated in mediating heat hyperalgesia during inflammation or diabetic neuropathy. However, detailed information on the role of PKC ?II in nociceptive signaling mediated by TRPV1 is lacking. This study presents evidence for activation and translocation of the PKC ?II isoform as a signaling event in nociception mediated by activation of TRPV1 by capsaicin. We show that capsaicin induces translocation of cytosolic PKC?II isoform fused with enhanced green fluorescence protein (PKC?II-EGFP) in dorsal root ganglion (DRG) neurons. We also show capsaicin-induced translocation in Chinese Hamster Ovarian (CHO) cells co-transfected with TRPV1 and PKC?II-EGFP, but not in CHO cells expressing PKC?II-EGFP alone. By contrast, the PKC activator phorbol-12-myristate-13-acetate (PMA) induced translocation of PKC?II-EGFP which was sustained and independent of calcium or TRPV1. In addition PMA-induced sensitization of TRPV1 to capsaicin response in DRG neurons was attenuated by PKC?II blocker CGP 53353. Capsaicin response via TRPV1 in the DRG neurons was confirmed by TRPV1 antagonist AMG 9810. These results suggested a novel and potential signaling link between PKC?II and TRPV1. These cell culture models provide a platform for investigating mechanisms of painful neuropathies mediated by nociceptors expressing the pain sensing gene TRPV1, and its regulation by the PKC isoform PKC?II.

Mandadi, Sravan; Armati, Patricia J.; Roufogalis, Basil D.

2011-01-01

39

Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+) permeable non-selective cation channel activated by physical and chemical stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have determined the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concentrations of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (P(o)) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at negative potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at negative and positive potentials. The areas of distribution of the longer open time constants are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp experiments reveal that low concentrations of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concentrations of capsaicin required for the same extent of depolarization generated a significantly greater number of action potentials. These properties of RTX may play a role in its clinical usefulness. PMID:16037081

Raisinghani, Manish; Pabbidi, Reddy M; Premkumar, Louis S

2005-09-15

40

Caged vanilloid ligands for activation of TRPV1 receptors by 1- and 2-photon excitation†  

PubMed Central

Nociceptive neurons in the peripheral nervous system detect noxious stimuli and report the information to the central nervous system. Most nociceptive neurons express the vanilloid receptor, TRPV1, a non-selective cation channel gated by vanilloid ligands such as capsaicin, the pungent essence of chili peppers. Here, we report the synthesis and biological application of two caged vanilloids—biologically inert precursors that, when photolyzed, release bioactive vanilloid ligands. The two caged vanilloids, Nb-VNA and Nv-VNA, are photoreleased with quantum efficiency of 0.13 and 0.041, respectively. Under flash photolysis conditions, photorelease of Nb-VNA and Nv-VNA is 95% complete in ?40 ?s and ?125 ?s, respectively. Through 1-photon excitation with ultraviolet light (360 nm), or 2-photon excitation with red light (720 nm), the caged vanilloids can be photoreleased in situ to activate TRPV1 receptors on nociceptive neurons. The consequent increase in intracellular free Ca2+ concentration ([Ca2+]i) can be visualized by laser-scanning confocal imaging of neurons loaded with the fluorescent Ca2+ indicator, fluo-3. Stimulation results from TRPV1 receptor activation, because the response is blocked by capsazepine, a selective TRPV1 antagonist. In Ca2+-free extracellular medium, photoreleased vanilloid can still elevate [Ca2+]i, which suggests that TRPV1 receptors also reside on endomembranes in neurons and can mediate Ca2+ release from intracellular stores. Notably, whole-cell voltage clamp measurements showed that flash photorelease of vanilloid can activate TRPV1 channels in < 4 msec at 22°C. In combination with 1- or 2-photon excitation, caged vanilloids are a powerful tool for probing morphologically distinct structures of nociceptive sensory neurons with high spatial and temporal precision.

Zhao, Jun; Gover, Tony D.; Muralidharan, Sukumaran; Auston, Darryl A.; Weinreich, Daniel; Kao, Joseph P. Y.

2008-01-01

41

Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via ?-arrestin-2-mediated cross-talk.  

PubMed

The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that ?-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of ?-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in ?-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates ?-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven ?-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions. PMID:24695785

Rowan, Matthew P; Bierbower, Sonya M; Eskander, Michael A; Szteyn, Kalina; Por, Elaine D; Gomez, Ruben; Veldhuis, Nicholas; Bunnett, Nigel W; Jeske, Nathaniel A

2014-01-01

42

Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed  

PubMed Central

In the isolated rat mesenteric bed, the 1 min perfusion with 100 nm anandamide, a concentration that did not evoke vasorelaxation, elicited an acute release of 165.1 ± 9.2 pmol nitric oxide (NO) that was paralleled by a 2-fold increase in cGMP tissue levels. The rise in NO released was mimicked by either (R)-(+)-methanandamide or the vanilloid receptor agonists resiniferatoxin and (E)-capsaicin but not by its inactive cis-isomer (Z)-capsaicin. The NO release elicited by either anandamide or capsaicin was reduced by the TRPV1 receptor antagonists 5?-iodoresiniferatoxin, SB 366791 and capsazepine as well as by the cannabinoid CB1 receptor antagonists SR 141716A or AM251. The outflow of NO elicited by anandamide and capsaicin was also reduced by endothelium removal or NO synthase inhibition, suggesting the specific participation of endothelial TRPV1 receptors, rather than the novel endothelial TRPV4 receptors. Consistently, RT-PCR showed the expression of the mRNA coding for the rat TRPV1 receptor in the endothelial cell layer, in addition to its expression in sensory nerves. The participation of sensory nerves on the release of NO was precluded on the basis that neonatal denervation of the myenteric plexus sensory nerves did not modify the pattern of NO release induced by anandamide and capsaicin. We propose that low concentrations of anandamide, devoid of vasorelaxing effects, elicit an acute release of NO mediated predominantly by the activation of endothelial TRPV1 receptors whose physiological significance remains elusive.

Poblete, Ines M; Orliac, Maria Luz; Briones, Rene; Adler-Graschinsky, Edda; Huidobro-Toro, J Pablo

2005-01-01

43

Promiscuous activation of transient receptor potential vanilloid 1 (TRPV1) channels by negatively charged intracellular lipids: the key role of endogenous phosphoinositides in maintaining channel activity.  

PubMed

The regulation of the heat- and capsaicin-activated transient receptor potential vanilloid 1 (TRPV1) channels by phosphoinositides is controversial. Data in cellular systems support the dependence of TRPV1 activity on phosphoinositides. The purified TRPV1, however, was recently shown to be fully functional in artificial liposomes in the absence of phosphoinositides. Here, we show that several other negatively charged phospholipids, including phosphatidylglycerol, can also support TRPV1 activity in excised patches at high concentrations. When we incorporated TRPV1 into planar lipid bilayers consisting of neutral lipids, capsaicin-induced activity depended on phosphatidylinositol 4,5-bisphosphate. We also found that TRPV1 activity in excised patches ran down and that MgATP reactivated the channel. Inhibition of phosphatidylinositol 4-kinases or enzymatic removal of phosphatidylinositol abolished this effect of MgATP, suggesting that it activated TRPV1 by generating endogenous phosphoinositides. We conclude that endogenous phosphoinositides are positive cofactors for TRPV1 activity. Our data highlight the importance of specificity in lipid regulation of ion channels and may reconcile discordant data obtained in various experimental settings. PMID:24158445

Lukacs, Viktor; Rives, Jan-Michael; Sun, Xiaohui; Zakharian, Eleonora; Rohacs, Tibor

2013-12-01

44

Alteration in TRPV1 and Muscarinic (M3) Receptor Expression and Function in Idiopathic Overactive Bladder Urothelial Cells (Running title: Changes in TRPV1/M3 expression and function in human OAB urothelial cells)  

PubMed Central

Aim To examine function of both cholinergic (muscarinic) and TRPV1 receptors in human bladder urothelial (HBUC) from non-neurogenic overactive bladder (OAB) patients as compared to control subjects. Methods Primary HBUC cultures were derived from cystoscopic biopsies from OAB and control subjects. Muscarinic and TRPV1 function was assessed by acetylcholine (5 µM) or capsaicin (0.5 µM) evoked ATP release, measured by luciferase-assay. Overall expression of TRPV1 and muscarinic M3 receptors in bladder urothelial cells was accomplished using western immunoblotting. Results Our findings revealed that the response to acetylcholine in OAB HBUC cultures (which was blocked by the nonselective muscarinic antagonist, atropine methylnitrate or AMN) was not significantly different than from controls. The acetylcholine M3 receptor was slightly decreased as compared to control. In contrast, OAB HBUC cultures exhibited a capsaicin-hypersensitivity and augmented release of ATP (3.2 fold higher), which was blocked by the antagonist capsazepine. The increase in capsaicin-sensitivity correlated with increased urothelial TRPV1 expression. Conclusion Though characterized in a small number of subjects, augmented release of urothelial-derived transmitters such as ATP could ‘amplify’ signaling between and within urothelial cells and nearby afferent nerves.

Birder, Lori A.; Wolf-Johnston, Amanda S.; Sun, Yan; Chai, Toby C.

2012-01-01

45

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

46

Trpv1.  

PubMed

TRPV1 is a well-characterised channel expressed by a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non-neuronal sites in the mammalian body. Functionally, TRPV1 acts as a sensor for noxious heat (greater than ~42 °C). It can also be activated by some endogenous lipid-derived molecules, acidic solutions (pH < 6.5) and some pungent chemicals and food ingredients such as capsaicin, as well as by toxins such as resiniferatoxin and vanillotoxins. Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which (e.g. AKAP79/150) are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50-100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed. Studies with TRPV1 agonists and antagonists and Trpv1 (-/-) mice have suggested a role for TRPV1 in pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder. TRPV1 antagonists have advanced to clinical trials where findings of drug-induced hyperthermia and loss of heat sensitivity have raised questions about the viability of this therapeutic approach. PMID:24756708

Bevan, Stuart; Quallo, Talisia; Andersson, David A

2014-01-01

47

TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia.  

PubMed

Modulation of nociceptive synaptic transmission in the spinal cord is implicated in the development and maintenance of several pathological pain states. The chemokine CCL2 (C-C motif ligand 2) was shown to be an important factor in the development of neuropathic pain after peripheral nerve injury. In our experiments we have studied the effect of CCL2 application and TRPV1 (transient receptor potential vanilloid 1) receptor activation on nociceptive signaling and the modulation of synaptic transmission. Intrathecal drug application in behavioral experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) from superficial dorsal horn neurons in acute rat spinal cord slices were used. The intrathecal application of CCL2 induced thermal hyperalgesia and mechanical allodynia, while pretreatment with the TRPV1 receptor antagonist SB366791 diminished the thermal but not the mechanical hypersensitivity. Patch-clamp experiments showed an increase of sEPSC and mEPSC (124.5 ± 12.8% and 161.2 ± 17.3%, respectively) frequency in dorsal horn neurons after acute CCL2 application. This CCL2-induced increase was prevented by SB366791 pretreatment (89.4 ± 6.0%, 107.5 ± 14.2%). CCL2 application increased the amplitude of eEPSCs (188.1 ± 32.1%); this increase was significantly lower in experiments with SB366791 pretreatment (120.8 ± 17.2%). Our results demonstrate that the activation of spinal TRPV1 receptors plays an important role in the modulation of nociceptive signaling induced by CCL2 application. The mechanisms of cooperation between the CCL2 activated receptors and TRPV1 receptors on the central branches of primary afferent fibers may be especially important during different pathological pain states and need to be further investigated. PMID:24495396

Spicarova, Diana; Adamek, Pavel; Kalynovska, Nataliia; Mrozkova, Petra; Palecek, Jiri

2014-06-01

48

Construction of a stable cell line uniformly expressing the rat TRPV1 receptor.  

PubMed

We constructed and analyzed a new cell line called HT5-1, which stably expresses an enhanced green fluorescent protein-tagged version of the rat vanilloid receptor 1 (VR1/TRPV1). The fluorescent receptor allowed easy measurement of receptor expression and expression level-based purification of cells via fluorescence-activated cell sorting. The HT5-1 cell line was compared to cells transiently transfected with the fluorescent receptor, to cells expressing the native rat vanilloid receptor, and to isolated capsaicin-sensitive rat trigeminal sensory neurons. Fura-2 microfluorimetry measurements of the calcium influx upon capsaicin induction showed that, by contrast to transiently transfected cells, HT5-1 cells respond uniformly to the stimulation, due to the similar level of receptor expression in individual cells. HT5-1 cells showed similar behaviour to isolated trigeminal root ganglion neurons, including marked tachyphylaxis upon repeated capsaicin induction, and a lack of calcium ion release from intracellular storage sites. PMID:16217559

Sándor, Zoltán; Varga, Angelika; Horváth, Péter; Nagy, Barbara; Szolcsányi, János

2005-01-01

49

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

50

Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel.  

PubMed

The capsaicin receptor, transient receptor potential vanilloid type 1 ion channel (TRPV1), has been identified as a polymodal transducer molecule on a sub-set of primary sensory neurons which responds to various stimuli including noxious heat (> -42 degrees C), protons and vanilloids such as capsaicin, the hot ingredient of chilli peppers. Subsequently, TRPV1 has been found indispensable for the development of burning pain and reflex hyperactivity associated with inflammation of peripheral tissues and viscera, respectively. Therefore, TRPV1 is regarded as a major target for the development of novel agents for the control of pain and visceral hyperreflexia in inflammatory conditions. Initial efforts to introduce agents acting on TRPV1 into clinics have been hampered by unexpected side-effects due to wider than expected expression in various tissues, as well as by the complex pharmacology, of TRPV1. However, it is believed that better understanding of the pharmacological properties of TRPV1 and specific targeting of tissues may eventually lead to the development of clinically useful agents. In order to assist better understanding of TRPV1 pharmacology, here we are giving a comprehensive account on the activation and inactivation mechanisms and the structure-function relationship of TRPV1. PMID:24941664

Nagy, Istvan; Friston, Dominic; Valente, Jojo Sousa; Torres Perez, Jose Vicente; Andreou, Anna P

2014-01-01

51

Transient receptor potential (TRP) A1 activated currents in TRPV1 and cholecystokinin-sensitive cranial visceral afferent neurons.  

PubMed

Culinary use of the pungent spices has potential health benefits including a reduction in food intake. Pungent spices often contain ingredients that activate members of the transient receptor potential (TRP) family A1 and evoke pain from capsaicin-sensitive somatosensory neurons. TRPA1 channel have also been identified on cranial visceral afferent neurons but their distribution and functional contributions are poorly understood. Visceral vagal neurons transduce mechanical and chemical signals from peripheral organs to the nucleus tractus solitarii. Many capsaicin-sensitive vagal afferents participate in peripheral satiety signaling that includes cholecystokinin (CCK) sensitive neurons. To assess signaling, the TRPA1 selective agonist allyl isothiocyanate (AITC) was tested together with CCK and capsaicin (200nM), a TRPV1 specific agonist. In isolated nodose neurons, AITC (0.05-0.2mM) evoked concentration-dependent inward currents in 38% of the tested neurons. The TRPA1 specific antagonist HC-030031 (10?M) blocked AITC responses. TRPA1 responses were mixed across neurons that were capsaicin-sensitive and -insensitive. However CCK evoked inward currents only on capsaicin-sensitive neurons and 28% of the CCK-sensitive neurons expressed TRPA1. Our results indicate that TRPA1 is co-expressed with TRPV1 in CCK-sensitive nodose neurons. The findings indicate a potential mechanism by which spices can act within cranial visceral afferent pathways mediating satiety and contribute to the reduction of the food intake associated with spiced diets. PMID:21316356

Choi, Myung-Jin; Jin, Zhenhua; Park, Yong Seek; Rhee, Young Kyoung; Jin, Young-Ho

2011-04-01

52

Inter-dependent regulation of afferent renal nerve activity and renal function: Role of TRPV1, NK1 and CGRP receptors  

PubMed Central

Our previous studies have shown that the activation of the transient receptor potential vanilloid type 1 (TRPV1) expressed in the renal pelvis leads to an increase in ipsilateral afferent renal nerve activity (ARNA) and contralateral renal excretory function, but the molecular mechanisms of TRPV1 action are largely unknown. This study tests the hypothesis that activation of receptors of neurokinin 1 (NK1) or calcitonin gene-related peptide (CGRP) by endogenously released substance P (SP) or CGRP following TRPV1 activation, respectively, governs TRPV1-induced increases in ARNA and renal excretory function. Capsaicin (CAP, 0.04, 0.4, 4nM), a selective TRPV1 agonist, administrated into the renal pelvis dose-dependently increased ARNA. CAP (4nM)-induced increases in ipsilateral ARNA or contralateral urine flow rate (Uflow) and urinary sodium excretion (UNa) were abolished by capsazepine (CAPZ), a selective TRPV1 antagonist, RP67580, or L703,606, selective NK1 antagonists, but not by CGRP8-37, a selective CGRP receptor antagonist. Both SP (7.4nM) and CGRP (0.13?M) increased ARNA, Uflow, or UNa, and increases in these parameters induced by CGRP but not SP were abolished by CAPZ. CAP at 4nM perfused into the renal pelvis caused the release of SP and CGRP, which was blocked by CAPZ but not by RP67580, L703,606, or CGRP8-37. Immunofluorescence results showed that NK1 receptors were expressed in sensory neurons in dorsal root ganglion (DRG) and sensory nerve fibers innervating the renal pelvis. Taken together, our data indicate that NK1 activation induced by SP release upon TRPV1 activation governs TRPV1 function and a TRPV1-dependent mechanism is operant in CGRP action.

Xie, Chaoqin; Sachs, Jeffrey R.; Wang, Donna H.

2009-01-01

53

Antinociceptive effect of antisense oligonucleotides against the vanilloid receptor VR1\\/TRPV1  

Microsoft Academic Search

To examine the role of the vanilloid receptor TRPV1 in neuropathic pain, we assessed the effects of the receptor antagonist thioxo-BCTC and antisense oligonucleotides against the TRPV1 mRNA in a rat model of spinal nerve ligation. In order to identify accessible sites on the mRNA of TRPV1, the RNase H assay was used, leading to the successful identification of binding

Thomas Christoph; Clemens Gillen; Joanna Mika; Arnold Grünweller; Martin K.-H. Schäfer; Klaus Schiene; Robert Frank; Ruth Jostock; Gregor Bahrenberg; Eberhard Weihe; Volker A. Erdmann; Jens Kurreck

2007-01-01

54

Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1).  

PubMed

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 (EC(50)) 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. PMID:18579526

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

2008-08-29

55

Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors  

PubMed Central

Background and purpose: N-arachidonoyl-serotonin (AA-5-HT) is an inhibitor of fatty acid amide hydrolase (FAAH)-catalysed hydrolysis of the endocannabinoid/ endovanilloid compound, anandamide (AEA). We investigated if AA-5-HT antagonizes the transient receptor potential vanilloid-1 (TRPV1) channel and, as FAAH and TRPV1 are targets for analgesic compounds, if it exerts analgesia in rodent models of hyperalgesia. Experimental approach: AA-5-HT was tested in vitro, on HEK-293 cells overexpressing the human or the rat recombinant TRPV1 receptor, and in vivo, in rats and mice treated with formalin and in rats with chronic constriction injury of the sciatic nerve. The levels of the endocannabinoids, AEA and 2-arachidonoylglycerol, in supraspinal (periaqueductal grey, rostral ventromedial medulla), spinal or peripheral (skin) tissues were measured. Key results: AA-5-HT behaved as an antagonist at both rat and human TRPV1 receptors (IC50=37-40 nM against 100 nM capsaicin). It exerted strong analgesic activity in all pain models used here. This activity was partly due to FAAH inhibition, elevation of AEA tissue levels and indirect activation of cannabinoid CB1 receptors, as it was reversed by AM251, a CB1 antagonist. AA-5-HT also appeared to act either via activation/desensitization of TRPV1, following elevation of AEA, or as a direct TRPV1 antagonist, as suggested by the fact that its effects were either reversed by capsazepine and 5?-iodo-resiniferatoxin, two TRPV1 antagonists, or mimicked by these compounds administered alone. Conclusions and implications: Possibly due to its dual activity as a FAAH inhibitor and TRPV1 antagonist, AA-5-HT was highly effective against both acute and chronic peripheral pain.

Maione, S; De Petrocellis, L; de Novellis, V; Moriello, A Schiano; Petrosino, S; Palazzo, E; Rossi, F Sca; Woodward, D F; Di Marzo, V

2007-01-01

56

The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1).  

PubMed

Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation. PMID:23613529

Morales-Lázaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

2013-07-01

57

The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)  

PubMed Central

Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.

Morales-Lazaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

2013-01-01

58

Peripheral Glutamate Receptors Are Required for Hyperalgesia Induced by Capsaicin  

PubMed Central

Transient receptor potential vanilloid1 (TRPV1) and glutamate receptors (GluRs) are located in small diameter primary afferent neurons (nociceptors), and it was speculated that glutamate released in the peripheral tissue in response to activation of TRPV1 might activate nociceptors retrogradely. But, it was not clear which types of GluRs are functioning in the nociceptive sensory transmission. In the present study, we examined the c-Fos expression in spinal cord dorsal horn following injection of drugs associated with glutamate receptors with/without capsaicin into the hindpaw. The subcutaneous injection of capsaicin or glutamate remarkably evoked c-Fos expression in ipsilateral sides of spinal cord dorsal horn. This capsaicin evoked increase of c-Fos expression was significantly prevented by concomitant administration of MK801, CNQX, and CPCCOEt. On the other hand, there were not any significant changes in coinjection of capsaicin and MCCG or MSOP. These results reveal that the activation of iGluRs and group I mGluR in peripheral afferent nerves play an important role in mechanisms whereby capsaicin evokes/maintains nociceptive responses.

Jin, You-Hong; Takemura, Motohide; Furuyama, Akira; Yonehara, Norifumi

2012-01-01

59

Peripheral glutamate receptors are required for hyperalgesia induced by capsaicin.  

PubMed

Transient receptor potential vanilloid1 (TRPV1) and glutamate receptors (GluRs) are located in small diameter primary afferent neurons (nociceptors), and it was speculated that glutamate released in the peripheral tissue in response to activation of TRPV1 might activate nociceptors retrogradely. But, it was not clear which types of GluRs are functioning in the nociceptive sensory transmission. In the present study, we examined the c-Fos expression in spinal cord dorsal horn following injection of drugs associated with glutamate receptors with/without capsaicin into the hindpaw. The subcutaneous injection of capsaicin or glutamate remarkably evoked c-Fos expression in ipsilateral sides of spinal cord dorsal horn. This capsaicin evoked increase of c-Fos expression was significantly prevented by concomitant administration of MK801, CNQX, and CPCCOEt. On the other hand, there were not any significant changes in coinjection of capsaicin and MCCG or MSOP. These results reveal that the activation of iGluRs and group I mGluR in peripheral afferent nerves play an important role in mechanisms whereby capsaicin evokes/maintains nociceptive responses. PMID:22110945

Jin, You-Hong; Takemura, Motohide; Furuyama, Akira; Yonehara, Norifumi

2012-01-01

60

THE TRPV1 RECEPTOR: TARGET OF TOXICANTS AND THERAPEUTICS  

EPA Science Inventory

Understanding the structural and functional complexities of the TRPV1 is essential to the therapeutic modulation of inflammation and pain. Because of its central role in initiating inflammatory processes and integrating painful stimuli, there is an understandable interest...

61

A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats.  

PubMed

Although most commonly associated with actions at cannabinoid CB1 receptors on the extracellular surface of the plasma membrane, the endocannabinoid anandamide (AEA) is also transported into the cell, by the putative anandamide membrane transporter (AMT), and activates the vanilloid receptor 1 (TRPV1) at an intracellular site. AEA is then inactivated by fatty acid amide hydrolase (FAAH). As systemic administration of TRPV1 ligands reduces locomotor activity in normal rodents, we hypothesised that activation of TRPV1 by endocannabinoids could play a role in the control of voluntary movement and that such actions could be regulated by AMT and FAAH. Motor activity was assessed in normal, in reserpine-treated, and in reserpine-treated rats treated with L-DOPA. In normal rats, the TRPV1 agonist capsaicin (1 mg/kg) or the FAAH inhibitor URB597 (10 mg/kg) caused a significant reduction in movement in both the horizontal (locomotion) and vertical (rearing) planes (-45% and -53% respectively with capsaicin; -33% and -37% for URB597). Capsaicin-induced hypolocomotion was attenuated by the TRPV1 antagonist, capsazepine. There was no effect of capsaicin, URB597 or the AMT inhibitor OMDM-2 on motor activity in reserpine-treated rats. L-DOPA treatment of reserpine-treated rats elicited high levels of motor activity in both the horizontal and vertical planes. Horizontal activity was attenuated by capsaicin (1 mg/kg, -60%), but not by URB597 (10 mg/kg) or OMDM-2 (5 mg/kg). Vertical activity was attenuated by capsaicin (1 mg/kg, -61%) and by URB597 (10 mg/kg, -54%), but not by OMDM-2. These data suggest that activation of the TRPV1 system can suppress spontaneous locomotion in normal animals and modulates several L-DOPA-induced behaviours in reserpine-treated rats. PMID:16806299

Lee, Joohyung; Di Marzo, Vincenzo; Brotchie, Jonathan M

2006-09-01

62

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

63

Molecular cloning and functional characterization of Xenopus tropicalis frog transient receptor potential vanilloid 1 reveal its functional evolution for heat, acid, and capsaicin sensitivities in terrestrial vertebrates.  

PubMed

The functional difference of thermosensitive transient receptor potential (TRP) channels in the evolutionary context has attracted attention, but thus far little information is available on the TRP vanilloid 1 (TRPV1) function of amphibians, which diverged earliest from terrestrial vertebrate lineages. In this study we cloned Xenopus tropicalis frog TRPV1 (xtTRPV1), and functional characterization was performed using HeLa cells heterologously expressing xtTRPV1 (xtTRPV1-HeLa) and dorsal root ganglion neurons isolated from X. tropicalis (xtDRG neurons) by measuring changes in the intracellular calcium concentration ([Ca(2+)](i)). The channel activity was also observed in xtTRPV1-expressing Xenopus oocytes. Furthermore, we tested capsaicin- and heat-induced nocifensive behaviors of the frog X. tropicalis in vivo. At the amino acid level, xtTRPV1 displays ?60% sequence identity to other terrestrial vertebrate TRPV1 orthologues. Capsaicin induced [Ca(2+)](i) increases in xtTRPV1-HeLa and xtDRG neurons and evoked nocifensive behavior in X. tropicalis. However, its sensitivity was extremely low compared with mammalian orthologues. Low extracellular pH and heat activated xtTRPV1-HeLa and xtDRG neurons. Heat also evoked nocifensive behavior. In oocytes expressing xtTRPV1, inward currents were elicited by heat and low extracellular pH. Mutagenesis analysis revealed that two amino acids (tyrosine 523 and alanine 561) were responsible for the low sensitivity to capsaicin. Taken together, our results indicate that xtTRPV1 functions as a polymodal receptor similar to its mammalian orthologues. The present study demonstrates that TRPV1 functions as a heat- and acid-sensitive channel in the ancestor of terrestrial vertebrates. Because it is possible to examine vanilloid and heat sensitivities in vitro and in vivo, X. tropicalis could be the ideal experimental lower vertebrate animal for the study of TRPV1 function. PMID:22130664

Ohkita, Masashi; Saito, Shigeru; Imagawa, Toshiaki; Takahashi, Kenji; Tominaga, Makoto; Ohta, Toshio

2012-01-20

64

C-fibers, but not the transient potential receptor vanilloid 1 (TRPV1), play a role in experimental allergic airway inflammation.  

PubMed

The activation of C-fibers in the airways induces coughing, mucus production and bronchoconstriction, which are also symptoms of airway diseases. In this study, we evaluated the role of the C-fibers and the TRPV1 (transient receptor potential vanilloid 1) receptor in an experimental mouse model of allergic airway inflammation. To study the role of C-fibers, we either degenerated the C-fibers persistently (capsaicin administration in neonate mice) or transiently (capsaicin administration in adult mice). No alteration was observed in eosinophil recruitment to the bronchoalveolar lavage fluid in animals treated with capsaicin in the neonatal period. However, in adult animals, capsaicin treatment after the first ovalbumin challenge (in the establishment of the inflammatory process) decreased the eosinophil numbers. This effect was more pronounced in adult animals treated with capsaicin before beginning the ovalbumin immunization (in the development of the inflammatory process). In addition, interleukin (IL)-5 and chemokine ligand 11 (CCL11) levels in the bronchoalveolar lavage fluid, as well as P-selectin expression and p65 nuclear factor ?B (NF-?B) activation in the lung were also decreased. No alterations were observed in the IL-10 and IL-13 levels. Next we determined the effect of TRPV1 receptor blockade on allergic airway inflammation. SB366791 administrated in mice by intraperitoneal (500?g/kg) or intranasal (0.1, 1 or 10nmol/site) route failed to decrease eosinophil recruitment to the bronchoalveolar lavage fluid or alter any other metrics cited above. Thus, the present results confirm and extend previous data supporting the involvement of C-fibers, but not the TRPV1 receptor, in allergic airway inflammation. PMID:21539840

Rogerio, Alexandre P; Andrade, Edinéia L; Calixto, Joăo B

2011-07-15

65

Streptozotocin-Induced Early Thermal Hyperalgesia is independent of Glycemic State of Rats: Role of Transient Receptor Potential Vanilloid 1(TRPV1) and Inflammatory mediators  

PubMed Central

Background Streptozotocin (STZ) is used as a common tool to induce diabetes and to study diabetes-induced complications including diabetic peripheral neuropathy (DPN). Previously, we have reported that STZ induces a direct effect on neurons through expression and function of the Transient receptor potential vanilloid 1 (TRPV1) channel in sensory neurons resulting in thermal hyperalgesia, even in non-diabetic STZ-treated mice. In the present study, we investigated the role of expression and function of TRPV1 in the central sensory nerve terminals in the spinal cord in STZ-induced hyperalgesia in rats. Results We found that a proportion of STZ-treated rats were normoglycemic but still exhibited thermal hyperalgesia and mechanical allodynia. Immunohistochemical data show that STZ treatment, irrespective of glycemic state of the animal, caused microglial activation and increased expression of TRPV1 in spinal dorsal horn. Further, there was a significant increase in the levels of pro-inflammatory mediators (IL-1?, IL-6 and TNF-?) in spinal cord tissue, irrespective of the glycemic state. Capsaicin-stimulated release of calcitonin gene related peptide (CGRP) was significantly higher in the spinal cord of STZ-treated animals. Intrathecal administration of resiniferatoxin (RTX), a potent TRPV1 agonist, significantly attenuated STZ-induced thermal hyperalgesia, but not mechanical allodynia. RTX treatment also prevented the increase in TRPV1-mediated neuropeptide release in the spinal cord tissue. Conclusions From these results, it is concluded that TRPV1 is an integral component of initiating and maintaining inflammatory thermal hyperalgesia, which can be alleviated by intrathecal administration of RTX. Further, the results suggest that enhanced expression and inflammation-induced sensitization of TRPV1 at the spinal cord may play a role in central sensitization in STZ-induced neuropathy.

2011-01-01

66

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

PubMed Central

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.

JI, WENJIN; CUI, CAN; ZHANG, ZHIWEI; LIANG, JIEXIAN

2013-01-01

67

Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel.  

PubMed

Furanocoumarin imperatorin is the major active component of Angelica dahurica root extracts, widely used in traditional medicine to treat headache, toothache, and orbital eye pain. In this study, we investigated the mechanisms that may underlie the pain-relieving effects of the compound. We found that imperatorin significantly inhibited formalin- and capsaicin-induced nocifensive responses but did not alter baseline thermal withdrawal thresholds in the rat. We established that imperatorin is a weak agonist of TRPV1, a channel implicated in detecting several noxious stimuli, exhibiting a 50% effective concentration (EC50) of 12.6 ± 3.2 ?M. A specific TRPV1 antagonist, JNJ-17203212 (0.5 ?M), potently inhibited imperatorin-induced TRPV1 activation. Site-directed mutagenesis studies revealed that imperatorin most likely acted via a site adjacent to or overlapping with the TRPV1 capsaicin-binding site. TRPV1 recovery from desensitization was delayed in the presence of imperatorin. Conversely, imperatorin sensitized TRPV1 to acid activation but did not affect the current amplitude and/or the activation-inactivation properties of Na(v)1.7, a channel important for transmission of nociceptive information. Thus, our data indicate that furanocoumarins represent a novel group of TRPV1 modulators that may become important lead compounds in the drug discovery process aimed at developing new treatments for pain management. PMID:24569998

Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G; Riley, Ashley M; Cummins, Theodore R; Fehrenbacher, Jill C; Obukhov, Alexander G

2014-04-01

68

Identification and characterization of a Ca2+ -sensitive interaction of the vanilloid receptor TRPV1 with tubulin.  

PubMed

The vanilloid receptor TRPV1 plays a well-established functional role in the detection of a range of chemical and thermal noxious stimuli, such as those associated with tissue inflammation and the resulting pain. TRPV1 activation results in membrane depolarization, but may also trigger intracellular Ca2+ -signalling events. In a proteomic screen for proteins associated with the C-terminal sequence of TRPV1, we identified beta-tubulin as a specific TRPV1-interacting protein. We demonstrate that the TRPV1 C-terminal tail is capable of binding tubulin dimers, as well as of binding polymerized microtubules. The interaction is Ca2+ -sensitive, and affects microtubule properties, such as microtubule sensitivity towards low temperatures and nocodazole. Our data thus provide compelling evidence for the interaction of TRPV1 with the cytoskeleton. The Ca2+ -sensitivity of this interaction suggests that the microtubule cytoskeleton at the cell membrane may be a downstream effector of TRPV1 activation. PMID:15569253

Goswami, C; Dreger, M; Jahnel, R; Bogen, O; Gillen, C; Hucho, F

2004-12-01

69

B-Type Natriuretic Peptide-Induced Delayed Modulation of TRPV1 and P2X3 Receptors of Mouse Trigeminal Sensory Neurons  

PubMed Central

Important pain transducers of noxious stimuli are small- and medium-diameter sensory neurons that express transient receptor vanilloid-1 (TRPV1) channels and/or adenosine triphosphate (ATP)-gated P2X3 receptors whose activity is upregulated by endogenous neuropeptides in acute and chronic pain models. Little is known about the role of endogenous modulators in restraining the expression and function of TRPV1 and P2X3 receptors. In dorsal root ganglia, evidence supports the involvement of the natriuretic peptide system in the modulation of nociceptive transmission especially via the B-type natriuretic peptide (BNP) that activates the natriuretic peptide receptor-A (NPR-A) to downregulate sensory neuron excitability. Since the role of BNP in trigeminal ganglia (TG) is unclear, we investigated the expression of BNP in mouse TG in situ or in primary cultures and its effect on P2X3 and TRPV1 receptors of patch-clamped cultured neurons. Against scant expression of BNP, almost all neurons expressed NPR-A at membrane level. While BNP rapidly increased cGMP production and Akt kinase phosphorylation, there was no early change in passive neuronal properties or responses to capsaicin, ?,?-meATP or GABA. Nonetheless, 24 h application of BNP depressed TRPV1 mediated currents (an effect blocked by the NPR-A antagonist anantin) without changing responses to ?,?-meATP or GABA. Anantin alone decreased basal cGMP production and enhanced control ?,?-meATP-evoked responses, implying constitutive regulation of P2X3 receptors by ambient BNP. These data suggest a slow modulatory action by BNP on TRPV1 and P2X3 receptors outlining the role of this peptide as a negative regulator of trigeminal sensory neuron excitability to nociceptive stimuli.

Ntamati, Niels; Nistri, Andrea

2013-01-01

70

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

2013-09-01

71

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

72

Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway.  

PubMed

Capsaicin, the pungent ingredient of chili peppers, displays potent anti-neoplastic activity in a wide array of human cancer cells. The present manuscript examines the signaling pathways underlying the apoptotic activity of capsaicin in human small cell lung cancer (SCLC) in vitro and in vivo. Studies in neuronal cells show that capsaicin exerts its biological activity via the transient receptor potential vanilloid (TRPV) superfamily of cation-channel receptors. The TRPV family is comprised of six members (TRPV1-6). Capsaicin is a known agonist of the TRPV1 receptor. We observed that capsaicin-induced apoptosis in human SCLC cells was mediated via the TRPV receptor family; however it was independent of TRPV1. Surprisingly, the apoptotic activity of capsaicin required the TRPV6 receptor. Depletion of TRPV6 receptor by siRNA methodology abolished the apoptotic activity of capsaicin in SCLC cells. Immunostaining and ELISA showed that TRPV6 receptor was robustly expressed on human SCLC tissues (from patients) and SCLC cell lines but almost absent in normal lung tissues. This correlates with our results that capsaicin induced very little apoptosis in normal lung epithelial cells. The pro-apoptotic activity of capsaicin was mediated by the intracellular calcium and calpain pathway. The treatment of human SCLC cells with capsaicin increased the activity of calpain 1 and 2 by threefold relative to untreated SCLC cells. Such calpain activation, in response to capsaicin, was downstream of the TRPV6 receptor. Taken together, our data provide insights into the mechanism underlying the apoptotic activity of capsaicin in human SCLCs. PMID:24878626

Lau, Jamie K; Brown, Kathleen C; Dom, Aaron M; Witte, Theodore R; Thornhill, Brent A; Crabtree, Clayton M; Perry, Haley E; Brown, J Michael; Ball, John G; Creel, Rebecca G; Damron, C Luke; Rollyson, William D; Stevenson, Cathryn D; Hardman, W Elaine; Valentovic, Monica A; Carpenter, A Betts; Dasgupta, Piyali

2014-08-01

73

The biophysical and molecular basis of TRPV1 proton gating  

PubMed Central

The capsaicin receptor TRPV1, a member of the transient receptor potential family of non-selective cation channels is a polymodal nociceptor. Noxious thermal stimuli, protons, and the alkaloid irritant capsaicin open the channel. The mechanisms of heat and capsaicin activation have been linked to voltage-dependent gating in TRPV1. However, until now it was unclear whether proton activation or potentiation or both are linked to a similar voltage-dependent mechanism and which molecular determinants underlie the proton gating. Using the whole-cell patch-clamp technique, we show that protons activate and potentiate TRPV1 by shifting the voltage dependence of the activation curves towards more physiological membrane potentials. We further identified a key residue within the pore region of TRPV1, F660, to be critical for voltage-dependent proton activation and potentiation. We conclude that proton activation and potentiation of TRPV1 are both voltage dependent and that amino acid 660 is essential for proton-mediated gating of TRPV1.

Aneiros, Eduardo; Cao, Lishuang; Papakosta, Marianthi; Stevens, Edward B; Phillips, Stephen; Grimm, Christian

2011-01-01

74

Sumatriptan Inhibits TRPV1 Channels in Trigeminal Neurons  

PubMed Central

Objective To understand a possible role for transient potential receptor vanilloid 1 (TRPV1) ion channels in sumatriptan relief of pain mediated by trigeminal nociceptors. Background TRPV1 channels are expressed in small nociceptive sensory neurons. In dorsal root ganglia (DRG), TRPV1-containing nociceptors mediate certain types of inflammatory pain. Neurogenic inflammation of cerebral dura and blood vessels in the trigeminal nociceptive system is thought to be important in migraine pain, but the ion channels important in transducing migraine pain are not known. Sumatriptan is an agent effective in treatment of migraine and cluster headache. We hypothesized that sumatriptan might modulate activity of TRPV1 channels found in the trigeminal nociceptive system. Methods We used immunohistochemistry to detect the presence of TRPV1 channel protein, whole cell recording in acutely dissociated trigeminal ganglia (TG) to detect functionality of TRPV1 channels, and whole cell recording in trigeminal nucleus caudalis (TNC) to detect effects on release of neurotransmitters from trigeminal neurons onto second order sensory neurons. Effects specifically on TG neurons that project to cerebral dura were assessed by labeling dural nociceptors with DiI. Results Immunohistochemistry demonstrated that TRPV1 channels are present in cerebral dura, trigeminal ganglion, and in the trigeminal nucleus caudalis. Capsaicin, a TRPV1 agonist, produced depolarization and repetitive action potential firing in current clamp recordings and large inward currents in voltage clamp recordings from acutely dissociated TG neurons, demonstrating that TRPV1 channels are functional in trigeminal neurons. Capsaicin increased spontaneous excitatory postsynaptic currents (sEPSCs) in neurons of layer II in TNC slices, showing that these channels have a physiological effect on central synaptic transmission. Sumatriptan (10 ?M), a selective anti-migraine drug inhibited TRPV1-mediated inward currents in TG. and capsaicin-elicited sEPSCs in TNC slices. The same effects of capsaicin and sumatriptan were found in acutely dissociated DiI-labeled TG neurons innervating cerebral dura. Conclusion Our results build on previous work indicating that TRPV1 channels in trigeminal nociceptors play a role in craniofacial pain. Our findings that TRPV1 is inhibited by the specific antimigraine drug sumatriptan, and that TRPV1 channels are functional in neurons projecting to cerebral dura suggests a specific role for these channels in migraine or cluster headache.

Evans, M. Steven; Cheng, Xiangying; Jeffry, Joseph A.; Disney, Kimberly E.; Premkumar, Louis S.

2011-01-01

75

Transient Receptor Potential Vanilloid 1 Activation by Dietary Capsaicin Promotes Urinary Sodium Excretion by Inhibiting Epithelial Sodium Channel ? Subunit-Mediated Sodium Reabsorption.  

PubMed

High salt (HS) intake contributes to the development of hypertension. Epithelial sodium channels play crucial roles in regulating renal sodium reabsorption and blood pressure. The renal transient receptor potential vanilloid 1 (TRPV1) cation channel can be activated by its agonist capsaicin. However, it is unknown whether dietary factors can act on urinary sodium excretion and renal epithelial sodium channel (ENaC) function. Here, we report that TRPV1 activation by dietary capsaicin increased urinary sodium excretion through reducing sodium reabsorption in wild-type (WT) mice on a HS diet but not in TRPV1(-/-) mice. The effect of capsaicin on urinary sodium excretion was involved in inhibiting ?ENaC and its related with-no-lysine kinase 1/serum- and glucocorticoid-inducible protein kinase 1 pathway in renal cortical collecting ducts of WT mice. Dietary capsaicin further reduced the increased ?ENaC activity in WT mice attributed to the HS diet. In contrast, this capsaicin effect was absent in TRPV1(-/-) mice. Immunoprecipitation study indicated ?ENaC specifically coexpressed and functionally interact with TRPV1 in renal cortical collecting ducts of WT mice. Additionally, ENaC activity and expression were suppressed by capsaicin-mediated TRPV1 activation in cultured M1-cortical collecting duct cells. Long-term dietary capsaicin prevented the development of high blood pressure in WT mice on a HS diet. It concludes that TRPV1 activation in the cortical collecting ducts by capsaicin increases urinary sodium excretion and avoids HS diet-induced hypertension through antagonizing ?ENaC-mediated urinary sodium reabsorption. Dietary capsaicin may represent a promising lifestyle intervention in populations exposed to a high dietary salt intake. PMID:24890824

Li, Li; Wang, Fei; Wei, Xing; Liang, Yi; Cui, Yuanting; Gao, Feng; Zhong, Jian; Pu, Yunfei; Zhao, Yu; Yan, Zhencheng; Arendshorst, William J; Nilius, Bernd; Chen, Jing; Liu, Daoyan; Zhu, Zhiming

2014-08-01

76

Phospholipase C mediated modulation of TRPV1 channels  

PubMed Central

The Transient Receptor Potential Vanilloid type 1 (TRPV1) channels are involved in both thermosensation and nociception. They are activated by heat, protons and capsaicin, and modulated by a plethora of other agents. This review will focus on the consequences of phospholipase C (PLC) activation, with special emphasis on the effects of phosphatidylinositol 4,5-bisphosphate (PIP2) on these channels. Two opposing effects of PIP2 have been reported on TRPV1. PIP2 has been proposed to inhibit TRPV1, and relief from this inhibition was suggested to be involved in sensitization of these channels by pro-inflammatory agents. In excised patches, however, PIP2 was shown to activate TRPV1. Calcium flowing through TRPV1 activates PLC and the resulting depletion of PIP2 was proposed to play a role in capsaicin-induced desensitization of these channels. We will describe the data indicating involvement of PLC and PIP2 in sensitization and desensitization of TRPV1, and will also discuss other pathways potentially contributing to these two phenomena. We attempt to resolve the seemingly contradictory data by proposing that PIP2 can both activate and inhibit TRPV1 depending on the experimental conditions, more specifically on the level of stimulation of these channels. Finally, we also discuss data in the literature indicating that other TRP channels, TRPA1 and some members of the TRPC subfamily, may also be under a similar dual control by PIP2.

Thyagarajan, Baskaran; Lukacs, Viktor

2008-01-01

77

CONSTRUCTION OF A STABLE CELL LINE UNIFORMLY EXPRESSING THE RAT TRPV1 RECEPTOR  

Microsoft Academic Search

We constructed and analyzed a new cell line called HT5-1, which stably expresses an enhanced green fluorescent protein-tagged version of the rat vanilloid receptor 1 (VR1\\/TRPV1). The fluorescent receptor allowed easy measurement of receptor expression and expression level-based purification of cells via fluorescence-activated cell sorting. The HT5-1 cell line was compared to cells transiently transfected with the fluorescent receptor, to

ZOLTÁN SÁNDOR; ANGELIKA VARGA; PÉTER HORVÁTH; BARBARA NAGY; JÁNOS SZOLCSÁNYI

2005-01-01

78

Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity  

Microsoft Academic Search

Acid-sensing ion channels (ASICs) are neuronal H+-gated cation channels, and the transient receptor potential vanilloid 1 channel (TRPV1) is a multimodal cation channel activated\\u000a by low pH, noxious heat, capsaicin, and voltage. ASICs and TRPV1 are present in sensory neurons. It has been shown that raising\\u000a the temperature increases TRPV1 and decreases ASIC H+-gated current amplitudes. To understand the underlying

Maxime G. Blanchard; Stephan Kellenberger

2011-01-01

79

Transient Receptor Potential Cation Channel V1 (TRPV1) Is Degraded by Starvation- and Glucocorticoid-Mediated Autophagy  

PubMed Central

A mammalian cell renovates itself by autophagy, a process through which cellular components are recycled to produce energy and maintain homeostasis. Recently, the abundance of gap junction proteins was shown to be regulated by autophagy during starvation conditions, suggesting that transmembrane proteins are also regulated by autophagy. Transient receptor potential vanilloid type 1 (TRPV1), an ion channel localized to the plasma membrane and endoplasmic reticulum (ER), is a sensory transducer that is activated by a wide variety of exogenous and endogenous physical and chemical stimuli. Intriguingly, the abundance of cellular TRPV1 can change dynamically under pathological conditions. However, the mechanisms by which the protein levels of TRPV1 are regulated have not yet been explored. Therefore, we investigated the mechanisms of TRPV1 recycling using HeLa cells constitutively expressing TRPV1. Endogenous TRPV1 was degraded in starvation conditions; this degradation was blocked by chloroquine (CLQ), 3MA, or downregulation of Atg7. Interestingly, a glucocorticoid (cortisol) was capable of inducing autophagy in HeLa cells. Cortisol increased cellular conversion of LC3-I to LC-3II, leading autophagy and resulting in TRPV1 degradation, which was similarly inhibited by treatment with CLQ, 3MA, or downregulation of Atg7. Furthermore, cortisol treatment induced the colocalization of GFP-LC3 with endogenous TRPV1. Cumulatively, these observations provide evidence that degradation of TRPV1 is mediated by autophagy, and that this pathway can be enhanced by cortisol.

Ahn, Seyoung; Park, Jungyun; An, Inkyung; Jung, Sung Jun; Hwang, Jungwook

2014-01-01

80

Fibronectin Stimulates TRPV1 Translocation in Primary Sensory Neurons  

PubMed Central

Summary Extracellular matrix (ECM) molecules are highly variable in their composition and receptor recognition. Their ubiquitous expression profile has been linked to roles in cell growth, differentiation, and survival. Recent work has identified certain ECM molecules that serve as dynamic signal modulators, versus the more-recognized role of chronic modulation of signal transduction. In this study, we investigated the role that fibronectin plays in the dynamic modulation of TRPV1 translocation to the plasma membrane in trigeminal ganglia (TG) sensory neurons. Confocal immunofluorescence analyses identify co-expression of the TRPV1 receptor with integrin subunits that bind fibronectin. TG neurons cultured upon or treated with fibronectin experienced a leftward shift in the EC50 of capsaicin-stimulated neuropeptide release. This fibronectin-induced increase in TRPV1 sensitivity to activation is coupled by an increase in plasma membrane expression of TRPV1, as well as an increase in tyrosine phosphorylation of TRPV1 in TG neurons. Furthermore, TG neurons cultured on fibronectin demonstrated an increase in capsaicin-mediated Ca+2 accumulation relative to neurons cultured on poly-D-lysine. Data presented from these studies indicate that fibronectin stimulates tyrosine-phosphorylation-dependent translocation of the TRPV1 receptor to the plasma membrane, identifying fibronectin as a critical component of the ECM capable of sensory neuron sensitization.

Jeske, Nathaniel A.; Patwardhan, Amol M.; Henry, Michael A.; Milam, Stephen B.

2009-01-01

81

TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated vascular smooth muscle cells.  

PubMed

Vascular smooth muscle cells (VSMCs) are an important origin of foam cells besides macrophages. The mechanisms underlying VSMC foam cell formation are relatively little known. Activation of transient receptor potential vanilloid subfamily 1 (TRPV1) and autophagy have a potential role in regulating foam cell formation. Our study demonstrated that autophagy protected against foam cell formation in oxidized low-density lipoprotein (oxLDL)-treated VSMCs; activation of TRPV1 by capsaicin rescued the autophagy impaired by oxLDL and activated autophagy-lysosome pathway in VSMCs; activation of TRPV1 by capsaicin impeded foam cell formation of VSMCs through autophagy induction; activation of TRPV1 by capsaicin induced autophagy through AMP-activated protein kinase (AMPK) signaling pathway. This study provides evidence that autophagy plays an important role in VSMC foam cell formation and highlights TRPV1 as a promising therapeutic target in atherosclerosis. PMID:24743737

Li, B-H; Yin, Y-W; Liu, Y; Pi, Y; Guo, L; Cao, X-J; Gao, C-Y; Zhang, L-L; Li, J-C

2014-01-01

82

A "cute" desensitization of TRPV1.  

PubMed

Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process. PMID:20932251

Touska, Filip; Marsakova, Lenka; Teisinger, Jan; Vlachova, Viktorie

2011-01-01

83

Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect???  

PubMed Central

Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.

Birrell, Mark A.; Bonvini, Sara J.; Dubuis, Eric; Maher, Sarah A.; Wortley, Michael A.; Grace, Megan S.; Raemdonck, Kristof; Adcock, John J.; Belvisi, Maria G.

2014-01-01

84

Serotonin Increases the Functional Activity of Capsaicin-Sensitive Rat Trigeminal Nociceptors via Peripheral Serotonin Receptors  

PubMed Central

Peripheral serotonin (5HT) has been implicated in migraine and temporomandibular pain disorders in humans and animal models and yet the mechanism(s) by which 5HT evokes pain remains unclear. Trigeminal pain can be triggered by activation of the transient receptor potential V1 channel (TRPV1), expressed by a subset of nociceptive trigeminal ganglia (TG) neurons and gated by capsaicin, noxious heat, and other noxious stimuli. As 5HT is released in the periphery during inflammation and evokes thermal hyperalgesia and TRPV1 is essential for thermal hyperalgesia, we hypothesized that 5HT increases the activity of capsaicin-sensitive trigeminal neurons and that this increase can be attenuated by pharmacologically targeting peripheral 5HT receptors. TG cultures were pretreated with 5HT (10 nM–100 µM), sumatriptan (5HT1B/1D agonist), ketanserin (5HT2A antagonist), granisetron (5HT3 antagonist) or vehicle prior to capsaicin (30 nM – 50 nM). Single-cell accumulation of intracellular calcium was recorded or CGRP release was measured following each treatment. In addition, using in situ hybridization and immunohistochemistry, we detected the co-localization of 5HT1B, 5HT1D, 5HT2A and 5HT3A, but not 5HT2C, mRNA with TRPV1 in TG cells. 5HT pretreatment evoked a significant increase in calcium accumulation in capsaicin-sensitive trigeminal neurons and enhanced capsaicin-evoked CGRP release, but had no significant effect when given alone. Sumatriptan, ketanserin and granisetron treatment attenuated calcium accumulation and 5HT enhancement of capsaicin-evoked CGRP release. Together these results indicate that 5HT increases the activity of capsaicin-sensitive peripheral nociceptors, which can be attenuated by pharmacologically targeting peripheral 5HT receptors, thereby providing a mechanistic basis for peripheral craniofacial pain therapy.

Loyd, Dayna R.; Weiss, Gabriela; Henry, Michael A.; Hargreaves, Kenneth M.

2011-01-01

85

Topographical organization of TRPV1-immunoreactive epithelium and CGRP-immunoreactive nerve terminals in rodent tongue  

PubMed Central

Transient receptor potential vanilloid subfamily member 1 (TRPV1) is activated by capsaicin, acid, and heat and mediates pain through peripheral nerves. In the tongue, TRPV1 expression has been reported also in the epithelium. This indicates a possibility that sensation is first received by the epithelium. However, how nerves receive sensations from the epithelium remains unclear. To clarify the anatomical basis of this interaction, we performed immunohistochemical studies in the rodent tongue to detect TRPV1 and calcitonin gene-related peptide (CGRP), a neural marker. Strong expression of TRPV1 in the epithelium was observed and was restricted to the apex of the tongue. Double immunohistochemical staining revealed that CGRP-expressing nerve terminals were in close apposition to the strongly TRPV1-expressing epithelium of fungiform papilla in the apex of rodent tongues. These results suggest that the TRPV1-expressing epithelium monitors the oral environment and acquired information may then be conducted to the adjacent CGRP-expressing terminals.

Kawashima, M.; Imura, K.; Sato, I.

2012-01-01

86

Sensitization by Pulmonary Reactive Oxygen Species of Rat Vagal Lung C-Fibers: The Roles of the TRPV1, TRPA1, and P2X Receptors  

PubMed Central

Sensitization of vagal lung C-fibers (VLCFs) induced by mediators contributes to the pathogenesis of airway hypersensitivity, which is characterized by exaggerated sensory and reflex responses to stimulants. Reactive oxygen species (ROS) are mediators produced during airway inflammation. However, the role of ROS in VLCF-mediated airway hypersensitivity has remained elusive. Here, we report that inhalation of aerosolized 0.05% H2O2 for 90 s potentiated apneic responses to intravenous capsaicin (a TRPV1 receptor agonist), ?,?-methylene-ATP (a P2X receptor agonist), and phenylbiguanide (a 5-HT3 receptor agonist) in anesthetized rats. The apneic responses to these three stimulants were abolished by vagatomy or by perivagal capsaicin treatment, a procedure that blocks the neural conduction of VLCFs. The potentiating effect of H2O2 on the apneic responses to these VLCF stimulants was prevented by catalase (an enzyme that degrades H2O2) and by dimethylthiourea (a hydroxyl radical scavenger). The potentiating effect of H2O2 on the apneic responses to capsaicin was attenuated by HC-030031 (a TRPA1 receptor antagonist) and by iso-pyridoxalphosphate-6-azophenyl-2?,5?-disulphonate (a P2X receptor antagonist). The potentiating effect of H2O2 on the apneic responses to ?,?-methylene-ATP was reduced by capsazepine (a TRPV1 receptor antagonist), and by HC-030031. The potentiating effect of H2O2 on the apneic responses to phenylbiguanide was totally abolished when all three antagonists were combined. Consistently, our electrophysiological studies revealed that airway delivery of aerosolized 0.05% H2O2 for 90 s potentiated the VLCF responses to intravenous capsaicin, ?,?-methylene-ATP, and phenylbiguanide. The potentiating effect of H2O2 on the VLCF responses to phenylbiguanide was totally prevented when all antagonists were combined. Inhalation of 0.05% H2O2 indeed increased the level of ROS in the lungs. These results suggest that 1) increased lung ROS sensitizes VLCFs, which leads to exaggerated reflex responses in rats and 2) the TRPV1, TRPA1, and P2X receptors are all involved in the development of this airway hypersensitivity.

Ruan, Ting; Lin, Yu-Jung; Hsu, Tien-Huan; Lu, Shing-Hwa; Jow, Guey-Mei; Kou, Yu Ru

2014-01-01

87

TRPV1 structures in distinct conformations reveal mechanisms of activation  

PubMed Central

TRP channels are polymodal signal detectors that respond to a wide range of physical and chemical stimuli. Elucidating how these channels integrate and convert physiological signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiological conditions. Here we exploit pharmacological probes (a peptide toxin and small vanilloid agonists) to determine structures of two activated states of the capsaicin receptor, TRPV1. A domain (S1-S4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiologic modulation exhibited by TRPV1 and other TRP channels.

Cao, Erhu; Liao, Maofu; Cheng, Yifan; Julius, David

2014-01-01

88

Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil  

Microsoft Academic Search

Artemin, a member of the glial cell line-derived neurotrophic factor (GDNF) family, supports a subpopulation of trigeminal sensory neurons through activation of the Ret\\/GFR?3 receptor tyrosine kinase complex. In a previous study we showed that artemin is increased in inflamed skin of wildtype mice and that transgenic overexpression of artemin in skin increases TRPV1 and TRPA1 expression in dorsal root

Christopher M. Elitt; Sacha A. Malin; H. Richard Koerber; Brian M. Davis; Kathryn M. Albers

2008-01-01

89

Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and TRPV1) Co-Expressing Cells  

PubMed Central

Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1.

Sadofsky, Laura R.; Sreekrishna, Koti T.; Lin, Yakang; Schinaman, Renee; Gorka, Kate; Mantri, Yogita; Haught, John Christian; Huggins, Thomas G.; Isfort, Robert J.; Bascom, Charles C.; Morice, Alyn H.

2014-01-01

90

Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and TRPV1) Co-Expressing Cells.  

PubMed

Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1. PMID:24921186

Sadofsky, Laura R; Sreekrishna, Koti T; Lin, Yakang; Schinaman, Renee; Gorka, Kate; Mantri, Yogita; Haught, John Christian; Huggins, Thomas G; Isfort, Robert J; Bascom, Charles C; Morice, Alyn H

2014-01-01

91

TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling.  

PubMed

The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity. PMID:24855942

Riera, Céline E; Huising, Mark O; Follett, Patricia; Leblanc, Mathias; Halloran, Jonathan; Van Andel, Roger; de Magalhaes Filho, Carlos Daniel; Merkwirth, Carsten; Dillin, Andrew

2014-05-22

92

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.  

PubMed

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 lowered heat pain thresholds while warm detection thresholds were unchanged, suggesting an effect purely on nociceptor nerve fibres. The amplitude of contact heat-evoked potentials (CHEP) and evoked pain ratings were negatively correlated after capsaicin, whereas CHEP had been correlated positively without capsaicin in a previous volunteer study. Menthol caused cold hypersensitivity and cinnamaldehyde caused heat hypersensitivity, but neither had an effect on evoked potentials. The CHEP after application of capsaicin show features observed in some patients with painful neuropathy, and could provide a model for development of novel analgesics, particularly TRPV1 antagonists. PMID:21550252

Roberts, K; Shenoy, R; Anand, P

2011-07-01

93

TRPV1: A Potential Drug Target for Treating Various Diseases.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically. PMID:24861977

Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P; Ramkumar, Vickram

2014-01-01

94

TRPV1: A Potential Drug Target for Treating Various Diseases  

PubMed Central

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically.

Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

2014-01-01

95

Capsaicin-based therapies for pain control.  

PubMed

The TRPV1 receptor is known to play a role in nociceptive transmission in multiple organ systems, usually in response to the pain of inflammation. TRPV1 antagonism has so far shown limited benefit in antinociception. Capsaicin, a TRPV1 agonist, has been shown to induce a refractory period in the nerve terminal expressing TRPV1 and even, in sufficient dosing, to create long-term nerve terminal defunctionalization. This has led to research into topical capsaicin as a treatment for multiple painful conditions. The majority of work has focused on musculoskeletal pain and neuropathic pain and has revealed that although low-dose topical capsaicin has limited effectiveness as an analgesic, high-dose capsaicin, when tolerated, has the potential for long-term analgesia in certain types of neuropathic pain. PMID:24941667

Smith, Howard; Brooks, John R

2014-01-01

96

Altered pharmacology of native rodent spinal cord TRPV1 after phosphorylation  

PubMed Central

Background and Purpose Evidence suggests that phosphorylation of TRPV1 is an important component underlying its aberrant activation in pathological pain states. To date, the detailed pharmacology of diverse TRPV1 receptor agonists and antagonists has yet to be reported for native TRPV1 under phosphorylating conditions. Our goal was to optimize a relatively high-throughput methodology to allow pharmacological characterization of the native TRPV1 receptor using a spinal cord neuropeptide release assay under naive and phosphorylating states. Experimental Approach Herein, we describe characterization of rodent TRPV1 by measurement of CGRP release from acutely isolated lumbar (L1-L6) spinal cord using a 96-well technique that combines use of native, adult tissue with quantitation of CGRP release by elisa. Key Results We have studied a diverse panel of TRPV1 agonists and antagonists under basal and phosphorylating conditions. We show that TRPV1-mediated CGRP release is evoked, in a temperature-dependent manner, by a PKC activator, phorbol 12,13-dibutyrate (PDBu); and that treatment with PDBu increases the potency and efficacy of known TRPV1 chemical agonists, in an agonist-specific manner. We also show that the pharmacological profile of diverse TRPV1 antagonists is dependent on whether the stimulus is PDBu or capsaicin. Of note, HPPB was identified as an antagonist of capsaicin-evoked, but a potentiator of PDBu-evoked, CGRP release. Conclusions and Implications Our findings indicate that both TRPV1 agonist and antagonist profiles can be differentially altered by PKC activation. These findings may offer new insights for targeting TRPV1 in pain states.

Mogg, AJ; Mill, CEJ; Folly, EA; Beattie, RE; Blanco, MJ; Beck, JP; Broad, LM

2013-01-01

97

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

98

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

99

Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons.  

PubMed

Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca(2+)-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides. We found that in sensory neurons PLC? activation by bradykinin led to a moderate decrease in phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), but no sustained change in the levels of its precursor PI(4)P. Preventing this selective decrease in PI(4,5)P2 inhibited TRPV1 sensitization, while selectively decreasing PI(4,5)P2 independently of PLC potentiated the sensitizing effect of protein kinase C (PKC) on the channel, thereby inducing increased TRPV1 responsiveness. Maximal pharmacological TRPV1 stimulation led to a robust decrease of both PI(4,5)P2 and its precursor PI(4)P in sensory neurons. Attenuating the decrease of either lipid significantly reduced desensitization, and simultaneous reduction of PI(4,5)P2 and PI(4)P independently of PLC inhibited TRPV1. We found that, on the mRNA level, the dominant highly Ca(2+)-sensitive PLC isoform in dorsal root ganglia is PLC?4. Capsaicin-induced desensitization of TRPV1 currents was significantly reduced, whereas capsaicin-induced nerve impulses in the skin-nerve preparation increased in mice lacking this isoform. We propose a comprehensive model in which differential changes in phosphoinositide levels mediated by distinct PLC isoforms result in opposing changes in TRPV1 activity. PMID:23843517

Lukacs, Viktor; Yudin, Yevgen; Hammond, Gerald R; Sharma, Esseim; Fukami, Kiyoko; Rohacs, Tibor

2013-07-10

100

Nobilamides A-H, long-acting transient receptor potential vanilloid-1 (TRPV1) antagonists from mollusk-associated bacteria.  

PubMed

New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogues for treatment of pain. PMID:21524089

Lin, Zhenjian; Reilly, Christopher A; Antemano, Rowena; Hughen, Ronald W; Marett, Lenny; Concepcion, Gisela P; Haygood, Margo G; Olivera, Baldomero M; Light, Alan; Schmidt, Eric W

2011-06-01

101

Nobilamides A-H, Long-Acting Transient Receptor Potential Vanilloid-1 (TRPV1) Antagonists from Mollusk-Associated Bacteria  

PubMed Central

New compounds nobilamides A-H and related known compounds A-3302-A and A-3302-B were isolated based upon their suppression of capsaicin-induced calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, nobilamide B and A-3302-A, were shown to be long-acting antagonists of mouse and human TRPV1 channels, abolishing activity for >1 h after removal of drug presumably via a covalent attachment. Other derivatives also inhibited the TRPV1 channel, albeit with low potency, affording a structure-activity profile to support the proposed mechanism of action. While the activities were modest, we propose a new mechanism of action and a new site of binding for these inhibitors that may spur development of related analogs for treatment of pain.

Lin, Zhenjian; Reilly, Christopher A.; Antemano, Rowena; Hughen, Ronald W.; Marett, Lenny; Concepcion, Gisela P.; Haygood, Margo G.; Olivera, Baldomero M.; Light, Alan; Schmidt, Eric W.

2011-01-01

102

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

103

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), 130.7 mg/g and 20.3 mg/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 100 mg/kg, i.p.) with an ED50=2 mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100 mg/kg, i.p.), a non-steroidal anti-inflammatory drug, with an ED50=11.56 mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2 mg/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=44 mg/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

2013-09-01

104

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

105

Role for the TRPV1 Channel in Insulin Secretion from Pancreatic Beta Cells.  

PubMed

Transient receptor potential channels have been put forward as regulators of insulin secretion. A role for the TRPV1 ion channel in insulin secretion has been suggested in pancreatic beta cell lines. We explored whether TRPV1 is functionally expressed in RINm5F and primary beta cells from neonate and adult rats. We examined if capsaicin could activate cationic non-selective currents. Our results show that TRPV1 channels are not functional in insulin-secreting cells, since capsaicin did not produce current activation, not even under culture conditions known to induce the expression of other ion channels in these cells. Although TRPV1 channels seem to be irrelevant for the physiology of isolated beta cells, they may play a role in glucose homeostasis acting through the nerve fibers that regulate islet function. At the physiological level, we observed that Trpv1 (-/-) mice presented lower fasting insulin levels than their wild-type littermates, however, we did not find differences between these experimental groups nor in the glucose tolerance test or in the insulin secretion. However, we did find that the Trpv1 (-/-) mice exhibited a higher insulin sensitivity compared to their wild-type counterparts. Our results demonstrate that TRPV1 does not contribute to glucose-induced insulin secretion in beta cells as was previously thought, but it is possible that it may control insulin sensitivity. PMID:24676478

Diaz-Garcia, Carlos Manlio; Morales-Lázaro, Sara L; Sánchez-Soto, Carmen; Velasco, Myrian; Rosenbaum, Tamara; Hiriart, Marcia

2014-06-01

106

Modulation of single-channel properties of TRPV1 by phosphorylation  

PubMed Central

Activation of TRPV1, the heat and capsaicin receptor, is known to be promoted by phosphorylation, but the molecular details are unclear. In the present study we recorded from single TRPV1 ion channels using the cell-attached patch clamp technique. The influence of capsaicin concentration on the time constants of open and closed states demonstrates the existence of at least four closed and three open states, and shows that channel opening can occur from partially liganded states. Activation of protein kinase C (PKC) promotes channel opening in some channels but not others, consistent with some channels being inaccessible to the kinase. The changes in open and closed state time constants following activation of PKC are equivalent to an increased affinity of capsaicin binding, but other arguments suggest that channel opening must be potentiated by downstream changes in channel activation rather than by a direct action of phosphorylation on the capsaicin binding site. Mutation of functionally important PKC phosphorylation sites on TRPV1, or application of staurosporine, a broad-spectrum kinase inhibitor, completely inhibited the effect of PKC in enhancing channel open time. Staurosporine also inhibited channel activity in the absence of overt PKC activation, showing that TRPV1 is partially phosphorylated at rest. This study elucidates the mechanism by which phosphorylation by PKC potentiates the activation of single TRPV1 ion channels.

Studer, Milena; McNaughton, Peter A

2010-01-01

107

TRPV1 receptors on unmyelinated C-fibres mediate colitis-induced sensitization of pelvic afferent nerve fibres in rats  

PubMed Central

Patients with inflammatory bowel disease often suffer from gastrointestinal motility and sensitivity disorders. The aim of the current study was to investigate the role of transient receptor potential of the vanilloid type 1 (TRPV1) receptors in the pathophysiology of colitis-induced pelvic afferent nerve sensitization. Trinitrobenzene sulphate (TNBS) colitis (7.5 mg, 30% ethanol) was induced in Wistar rats 72 h prior to the experiment. Single-fibre recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root. Fibres responding to colorectal distension (CRD) were identified in controls and rats with TNBS colitis. The effect of the TRPV1 antagonist N-(4-tertiarybutylphenyl)-4-(3-chlorophyridin-2-yl)tetrahydropyrazine-1(2H)carboxamide (BCTC; 0.25–5 mg kg?1) or its vehicle (hydroxypropyl-?-cyclodextrin) was tested on the afferent response to repetitive distensions (60 mmHg). Immunocytochemical staining of TRPV1 and NF200, a marker for A-fibre neurons, was performed in the dorsal root ganglia L6–S1. TNBS colitis significantly increased the response to colorectal distension of pelvic afferent C-fibres. BCTC did not significantly affect the C-fibre response in controls, but normalized the sensitized response in rats with colitis. TNBS colitis increased the spontaneous activity of C-fibres, an effect which was insensitive to administration of BCTC. TNBS colitis had no effect on A?-fibres, nor was their activity modulated by BCTC. TNBS colitis caused an immunocytochemical up-regulation of TRPV1 receptors in the cell bodies of pelvic afferent NF200 negative neurons. TRPV1 signalling mediates the colitis-induced sensitization of pelvic afferent C-fibres to CRD, while A?-fibres are neither sensitized by colitis nor affected by TRPV1 inhibition.

De Schepper, H U; De Winter, B Y; Van Nassauw, L; Timmermans, J-P; Herman, A G; Pelckmans, P A; De Man, J G

2008-01-01

108

Capsaicin receptor as target of calcitonin gene-related peptide in the gut.  

PubMed

Calcitonin gene-related peptide (CGRP), a 37 aminoacid-residue peptide, is a marker of afferent fibers in the upper gastrointestinal tract, being almost completely depleted following treatment with the selective neurotoxin capsaicin that targets these fibers via transient receptor potential vanilloid type-1 (TRPV-1). It is widely distributed in the peripheral nervous system of mammals where it is present as alpha isoform, while intrinsic neurons of the enteric nervous systems express predominantly CGRP-beta. Many gastrointestinal functions involve CGRP-containing afferent fibers of the enteric nervous system such as defense against irritants, intestinal nociception, modulation of gastrointestinal motility and secretion, and healing of gastric ulcers. The main effects on stomach homeostasis rely on local vasodilator actions during increased acid-back diffusion. In humans, release of CGRP through the activation of TRPV-1 has been shown to protect from gastric damage induced by several stimuli and to be involved in gastritis. In both dyspepsia and irritable bowel syndrome the repeated stimulation of TRPV-1 induced an improvement in epigastric pain of these patients. The TRPV-1/CGRP pathway might be a novel target for therapeutics in gastric mucosal injury and visceral sensitivity. PMID:24941672

Evangelista, Stefano

2014-01-01

109

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

110

Corticosterone Mediates Reciprocal Changes in CB1 and TRPV1 Receptors in Primary Sensory Neurons in the Chronically Stressed Rat  

PubMed Central

Background & Aims Chronic stress is associated with visceral hyperalgesia in functional gastrointestinal disorders. We investigated whether corticosterone plays a role in chronic psychological stress-induced visceral hyperalgesia. Methods Male rats were subjected to 1-hour water avoidance (WA) stress or subcutaneous corticosterone injection daily for 10 consecutive days in the presence or absence of corticoid receptor antagonist RU-486 and cannabinoid receptor agonist WIN55,212-2. The visceromotor response (VMR) to colorectal distension (CRD) was measured. Receptor protein levels were measured and whole-cell patch-clamp recordings employed to assess TRPV1 currents in L6-S2 DRG neurons. Mass spectrometry was used to measure endocannabinoid anandamide content. Results Chronic WA stress was associated with visceral hyperalgesia in response to CRD, increased stool output and reciprocal changes in CB1 (decreased) and TRPV1 (increased) receptor expression and function. Treatment of WA stressed rats with RU-486 prevented these changes. Control rats treated with serial injections of corticosterone in situ demonstrated a significant increase in serum corticosterone associated with visceral hyperalgesia, enhanced anandamide content, increased TRPV1 and decreased CB1 receptor protein levels which were prevented by co-treatment with RU-486. Exposure of isolated control L6-S2 DRGs in vitro to corticosterone reproduced the changes in CB1 and TRPV1 receptors observed in situ which was prevented by co-treatment with RU-486 or WIN55,212-2. Conclusions These results support a novel role for corticosterone to modulate CB1 and TRPV1 receptor pathways in L6-S2 DRGs in the chronic WA stressed rat which contributes to visceral hyperalgesia observed in this model.

Hong, Shuangsong; Zheng, Gen; Wu, Xiaoyin; Snider, Natasha T.; Owyang, Chung; Wiley, John W.

2010-01-01

111

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

2012-01-01

112

Morphine Reduces Expression of TRPV1 Receptors in the Amygdala but not in the Hippocampus of Male Rats.  

PubMed

Background: Chronic use of opioids usually results in physical dependence. The underlying mechanisms for this dependence are still being evaluated. Transient receptor potential vanilloid type 1 (TRPV1) are important receptors of pain perception. Their role during opioid dependence has not been studied well. The aim of this study was to evaluate the effect of morphine-dependence on the expression of TRPV1 receptors in the amygdala and CA1 region of the hippocampus. Methods: This study used four groups of rats. Two groups of rats (morphine and morphine+naloxone) received morphine based on the following protocol: 10 mg/kg (twice daily, 3 days) followed by 20, 30, 40 and 50 mg/kg (twice daily), respectively, for 4 consecutive days. Another group received vehicle (1 ml/kg) instead of morphine given using the same schedule. The morphine+naloxone group of rats additionally received naloxone (5 mg/kg) at the end of the protocol. The control group rats received no injections or intervention. The amygdala and CA1 regions of the morphine, saline-treated and intact animals were isolated and prepared for real-time PCR analysis. Results: Administration of naloxone induced withdrawal signs in morphine-treated animals. The results showed a significant decrease in TRPV1 gene expression in the amygdala (P<0.05) but not the CA1 region of morphine dependent rats. Conclusion: TRPV1 receptors may be involved in morphine-induced dependence. PMID:24850983

Hakimizadeh, Elham; Kazemi Arababadi, Mohammad; Shamsizadeh, Ali; Allahtavakoli, Mohammad; Rezvani, Mohammad Ebrahim; Roohbakhsh, Ali

2014-05-01

113

Morphine Reduces Expression of TRPV1 Receptors in the Amygdala but not in the Hippocampus of Male Rats  

PubMed Central

Background: Chronic use of opioids usually results in physical dependence. The underlying mechanisms for this dependence are still being evaluated. Transient receptor potential vanilloid type 1 (TRPV1) are important receptors of pain perception. Their role during opioid dependence has not been studied well. The aim of this study was to evaluate the effect of morphine-dependence on the expression of TRPV1 receptors in the amygdala and CA1 region of the hippocampus. Methods: This study used four groups of rats. Two groups of rats (morphine and morphine+naloxone) received morphine based on the following protocol: 10 mg/kg (twice daily, 3 days) followed by 20, 30, 40 and 50 mg/kg (twice daily), respectively, for 4 consecutive days. Another group received vehicle (1 ml/kg) instead of morphine given using the same schedule. The morphine+naloxone group of rats additionally received naloxone (5 mg/kg) at the end of the protocol. The control group rats received no injections or intervention. The amygdala and CA1 regions of the morphine, saline-treated and intact animals were isolated and prepared for real-time PCR analysis. Results: Administration of naloxone induced withdrawal signs in morphine-treated animals. The results showed a significant decrease in TRPV1 gene expression in the amygdala (P<0.05) but not the CA1 region of morphine dependent rats. Conclusion: TRPV1 receptors may be involved in morphine-induced dependence.

Hakimizadeh, Elham; Kazemi Arababadi, Mohammad; Shamsizadeh, Ali; Allahtavakoli, Mohammad; Rezvani, Mohammad Ebrahim; Roohbakhsh, Ali

2014-01-01

114

TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in the peripheral and central nervous systems. The membrane surface expression of TRPV1 is known to occur in neuronal cell bodies and sensory neuron axons. TRPV1 receptors are also expressed in the hippocampus, the main epileptogenic region in the brain. Although, previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been attempted. Here, we evaluate the role of TRPV1 channels in the modulation of epileptiform activity as well as the anti-convulsant properties of capsazepine (CZP), an established TRPV1 competitive antagonist, using in vitro and in vivo models. To this end, we used 4-aminopyridine (4-AP) to trigger seizure-like activity. We found that CZP suppressed 4-AP induced epileptiform activity in vitro (10-100?M) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100?M) and triggered bursting activity in vivo (100?M dialysis perfusion), which was abolished by the TRPV1 antagonist CZP. To further investigate the mechanisms of TRPV1 modulation, we studied the effect of capsaicin and CZP on evoked potentials. Capsaicin (1-100?M) and CZP (10-100?M) increased and decreased, respectively, the amplitude of extracellular field evoked potentials in a concentration-dependent manner. Additional in vitro studies showed that the effect of the TRPV1 blocker on evoked potentials was similar whether the response was orthodromic or antidromic, suggesting that the effect involves interference with membrane depolarization on cell bodies and axons. The fact that CZP could act directly on axons was confirmed by decreased amplitude of the compound action potential and by an increased delay of both the antidromic potentials and the axonal response. Histological studies using transgenic mice also show that, in addition to the known neural expression, TRPV1 channels are widely expressed in alvear oligodendrocytes in the hippocampus. Taken together, these results indicate that activation of TRPV1 channels leads to enhanced excitability, while their inhibition can effectively suppress ongoing electrographic seizures. These results support a role for TRPV1 channels in the suppression of convulsive activity, indicating that antagonism of TRPV1 channels particularly in axons may possibly be a novel target for effective acute suppression of seizures. PMID:24145133

Gonzalez-Reyes, Luis E; Ladas, Thomas P; Chiang, Chia-Chu; Durand, Dominique M

2013-12-01

115

Discrimination of intracellular calcium store subcompartments using TRPV1 (transient receptor potential channel, vanilloid subfamily member 1) release channel activity.  

PubMed Central

The store-operated calcium-release-activated calcium current, I (CRAC), is a major mechanism for calcium entry into non-excitable cells. I (CRAC) refills calcium stores and permits sustained calcium signalling. The relationship between inositol 1,4,5-trisphosphate receptor (InsP(3)R)-containing stores and I (CRAC) is not understood. A model of global InsP(3)R store depletion coupling with I (CRAC) activation may be simplistic, since intracellular stores are heterogeneous in their release and refilling activities. Here we use a ligand-gated calcium channel, TRPV1 (transient receptor potential channel, vanilloid subfamily member 1), as a new tool to probe store heterogeneity and define intracellular calcium compartments in a mast cell line. TRPV1 has activity as an intracellular release channel but does not mediate global calcium store depletion and does not invade a store coupled with I (CRAC). Intracellular TRPV1 localizes to a subset of the InsP(3)R-containing stores. TRPV1 sensitivity functionally subdivides the InsP(3)-sensitive store, as does heterogeneity in the sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase isoforms responsible for store refilling. These results provide unequivocal evidence that a specific 'CRAC store' exists within the InsP(3)-releasable calcium stores and describe a novel methodology for manipulation of intracellular free calcium.

Turner, Helen; Fleig, Andrea; Stokes, Alexander; Kinet, Jean-Pierre; Penner, Reinhold

2003-01-01

116

Mechanisms involved in abdominal nociception induced by either TRPV1 or TRPA1 stimulation of rat peritoneum.  

PubMed

Abdominal pain is a frequent symptom of peritoneal cavity irritation, but little is known about the role of the receptors for irritant substances, transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), in this painful condition. Thus, we investigated the abdominal nociception caused by peritoneal stimulation with TRPV1 (capsaicin) and TRPA1 (allyl isothiocyanate, AITC) agonists and their mechanisms in rats. The intraperitoneal (i.p.) injection of either capsaicin or AITC (0.03-10 mg/kg) induced short-term (up to 20 min) and dose-dependent abdominal nociception, and also produced c-fos expression in spinal afferents of the dorsal horn. TRPV1 antagonism prevented (94 ± 4% inhibition) nociception induced by capsaicin but not by AITC. In contrast, the TRPA1 antagonism almost abolished AITC-induced nociception (95 ± 2% inhibition) without altering the capsaicin response. Moreover, nociception induced by either capsaicin or AITC was reduced by the desensitisation of TRPV1-positive sensory fibres with resiniferatoxin (73 ± 18 and 76 ± 15% inhibitions, respectively) and by the NK1 receptor antagonist aprepitant (56 ± 5 and 53 ± 8% inhibitions, respectively). Likewise, the i.p. injections of capsaicin or AITC increased the content of substance P in the peritoneal fluid. Nevertheless, neither the mast cell membrane stabiliser cromoglycate, nor the H1 antagonist promethazine, nor depletion of peritoneal macrophages affected abdominal nociception induced either by capsaicin or AITC. Accordingly, neither capsaicin nor AITC increased the histamine content in the peritoneal fluid or provoked peritoneal mast cell degranulation in vitro. Collectively, our findings suggest that TRPV1 and TRPA1 stimulation in the peritoneum produces abdominal nociception that is mediated by sensory fibres activation. PMID:23911956

Trevisan, Gabriela; Rossato, Mateus F; Hoffmeister, Carin; Oliveira, Sara M; Silva, Cássia R; Matheus, Filipe C; Mello, Gláucia C; Antunes, Edson; Prediger, Rui D S; Ferreira, Juliano

2013-08-15

117

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

118

Sulphur-containing compounds of durian activate the thermogenesis-inducing receptors TRPA1 and TRPV1.  

PubMed

Durian (Durio zibethinus Murr.) is classified as a body-warming food in Indian herbalism, and its hyperthermic effect is empirically known in Southeast Asia. To investigate the mechanism underlying this effect, we focused on the thermogenesis-inducing receptors, TRPA1 and TRPV1. Durian contains sulphides similar to the TRPA1 and TRPV1 agonists of garlic. Accordingly, we hypothesized that the thermogenic effect of durian is driven by sulphide-induced TRP channel activation. To investigate our hypothesis, we measured the TRPA1 and TRPV1 activity of the sulphur-containing components of durian and quantified their content in durian pulp. These sulphur-containing components had a stronger effect on TRPA1 than TRPV1. Furthermore, sulphide content in the durian pulp was sufficient to evoke TRP channel activation and the main agonist was diethyl disulphide. From these results, we consider that the body-warming effect of durian is elicited by TRPA1 activation with its sulphides, as can be seen in spices. PMID:24679773

Terada, Yuko; Hosono, Takashi; Seki, Taiichiro; Ariga, Toyohiko; Ito, Sohei; Narukawa, Masataka; Watanabe, Tatsuo

2014-08-15

119

TRPV1: Contribution to Retinal Ganglion Cell Apoptosis and Increased Intracellular Ca2+ with Exposure to Hydrostatic Pressure  

PubMed Central

Purpose Elevated hydrostatic pressure induces retinal ganglion cell (RGC) apoptosis in culture. The authors investigated whether the transient receptor potential vanilloid 1 (TRPV1) channel, which contributes to pressure sensing and Ca2+-dependent cell death in other systems, also contributes to pressure-induced RGC death and whether this contribution involves Ca2+. Methods trpv1 mRNA expression in RGCs was probed with the use of PCR and TRPV1 protein localization through immunocytochemistry. Subunit-specific antagonism (iodo-resiniferatoxin) and agonism (capsaicin) were used to probe how TRPV1 activation affects the survival of isolated RGCs at ambient and elevated hydrostatic pressure (+70 mm Hg). Finally, for RGCs under pressure, the authors tested whether EGTA chelation of Ca2+ improves survival and whether, with the Ca2+ dye Fluo-4 AM, TRPV1 contributes to increased intracellular Ca2+. Results RGCs express trpv1 mRNA, with robust TRPV1 protein localization to the cell body and axon. For isolated RGCs under pressure, TRPV1 antagonism increased cell density and reduced apoptosis to ambient levels (P ? 0.05), whereas for RGCs at ambient pressure, TRPV1 agonism reduced density and increased apoptosis to levels for elevated pressure (P ? 0.01). Chelation of extracellular Ca2+ reduced RGC apoptosis at elevated pressure by nearly twofold (P ? 0.01). Exposure to elevated hydrostatic pressure induced a fourfold increase in RGC intracellular Ca2+ that was reduced by half with TRPV1 antagonism. Finally, in the DBA/2 mouse model of glaucoma, levels of TRPV1 in RGCs increased with elevated IOP. Conclusions RGC apoptosis induced by elevated hydrostatic pressure arises substantially through TRPV1, likely through the influx of extracellular Ca2+.

Sappington, Rebecca M.; Sidorova, Tatiana; Long, Daniel J.; Calkins, David J.

2013-01-01

120

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

121

An inhibitor of TRPV1 channels isolated from funnel Web spider venom.  

PubMed

Capsaicin receptor channels (TRPV1) are nonselective cation channels that integrate multiple noxious stimuli in sensory neurons. In an effort to identify new inhibitors of these channels we screened a venom library for activity against TRPV1 channels and found robust inhibitory activity in venom from Agelenopsis aperta, a north American funnel web spider. Fractionation of the venom using reversed-phase HPLC resulted in the purification of two acylpolyamine toxins, AG489 and AG505, which inhibit TRPV1 channels from the extracellular side of the membrane. The activity of AG489 was characterized further, and the toxin was found to inhibit TRPV1 channels with a K(i) of 0.3 microM at -40 mV. Inhibition of TRPV1 channels by AG489 is strongly voltage-dependent, with relief of inhibition at positive voltages, consistent with the toxin inhibiting the channel through a pore-blocking mechanism. We used scanning mutagenesis throughout the TM5-TM6 linker, a region thought to form the outer pore of TRPV1 channels, to identify pore mutations that alter toxin affinity. Four mutants dramatically decrease toxin affinity and several mutants increase toxin affinity, consistent with the notion that the TM5-TM6 linker forms the outer vestibule of TRPV1 channels and that AG489 is a pore blocker. PMID:16300403

Kitaguchi, Tetsuya; Swartz, Kenton J

2005-11-29

122

First “hybrid” ligands of vanilloid TRPV1 and cannabinoid CB 2 receptors and non-polyunsaturated fatty acid-derived CB 2-selective ligands  

Microsoft Academic Search

12-Phenylacetyl-ricinoleoyl-vanillamide (phenylacetylrinvanil, PhAR, IDN5890), is an ultra-potent agonist of human vanilloid TRPV1 receptors also endowed with moderate affinity for human cannabinoid CB2 receptors. To improve its CB2 affinity and temper its potency at TRPV1, the modification of the polar headgroup and the lipophilic 12-acylgroup of PhAR was pursued. Replacement of the vanillyl headgroup of PhAR with various aromatic or alkyl

Giovanni Appendino; Maria Grazia Cascio; Sara Bacchiega; Aniello Schiano Moriello; Alberto Minassi; Adčle Thomas; Ruth Ross; Roger Pertwee; Luciano De Petrocellis; Vincenzo Di Marzo

2006-01-01

123

Activation and desensitization of TRPV1 channels in sensory neurons by the PPAR? agonist palmitoylethanolamide  

PubMed Central

Background and Purpose Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain-inducing stimuli such as capsaicin (CAP) or bradykinin (BK) to influence intracellular calcium concentrations ([Ca2+]i) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPAR? and of TRPV1 channels in PEA-induced effects was also studied. Experimental Approach [Ca2+]i was evaluated by single-cell microfluorimetry in differentiated F11 cells. Activation of TRPV1 channels was assessed by imaging and patch-clamp techniques in CHO cells transiently-transfected with rat TRPV1 cDNA. Key Results In F11 cells, PEA (1–30 ?M) dose-dependently increased [Ca2+]i. The TRPV1 antagonists capsazepine (1 ?M) and SB-366791 (1 ?M), as well as the PPAR? antagonist GW-6471 (10 ?M), inhibited PEA-induced [Ca2+]i increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPAR?. When compared with CAP, PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub-effective PEA concentrations, closer to those found in vivo, counteracted CAP- and BK-induced [Ca2+]i transients, as well as CAP-induced TRPV1 activation. Conclusions and Implications Activation of PPAR? and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced [Ca2+]i transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences.

Ambrosino, Paolo; Soldovieri, Maria Virginia; Russo, Claudio; Taglialatela, Maurizio

2013-01-01

124

HCl-induced and ATP-dependent upregulation of TRPV1 receptor expression and cytokine production by human esophageal epithelial cells  

PubMed Central

The pathogenesis of gastroesophageal reflux disease (GERD) remains elusive, but recent evidence suggests that early secretion of inflammatory cytokines and chemokines by the mucosa leads to influx of immune cells followed by tissue damage. We previously showed that exposure of esophageal mucosa to HCl causes ATP release, resulting in activation of acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (lyso-PAF AT), the enzyme responsible for the production of platelet-activating factor (PAF). In addition, HCl causes release of IL-8 from the esophageal mucosa. We demonstrate that esophageal epithelial cells secrete proinflammatory mediators in response to HCl and that this response is mediated by ATP. Monolayers of the human esophageal epithelial cell line HET-1A were exposed to acidified cell culture medium (pH 5) for 12 min, a total of seven times over 48 h, to simulate the recurrent acid exposure clinically occurring in GERD. HCl upregulated mRNA and protein expression for the acid-sensing transient receptor potential cation channel, subfamily vanilloid member 1 (TRPV1), lyso-PAF AT, IL-8, eotaxin-1, -2, and -3, macrophage inflammatory protein-1?, and monocyte chemoattractant protein-1. The chemokine profile secreted by HET-1A cells in response to repeated HCl exposure parallels similar findings in erosive esophagitis patients. In HET-1A cells, the TRPV1 agonist capsaicin reproduced these findings for mRNA of the inflammatory mediators lyso-PAF AT, IL-8, and eotaxin-1. These effects were blocked by the TRPV1 antagonists iodoresiniferatoxin and JNJ-17203212. These effects were imitated by direct application of ATP and blocked by the nonselective ATP antagonist suramin. We conclude that HCl/TRPV-induced ATP release upregulated secretion of various chemoattractants by esophageal epithelial cells. These chemoattractants are selective for leukocyte subsets involved in acute inflammatory responses and allergic inflammation. The data support the validity of HET-1A cells as a model of the response of the human esophageal mucosa in GERD.

Ma, Jie; Altomare, Annamaria; Guarino, Michele; Cicala, Michele; Rieder, Florian; Fiocchi, Claudio; Li, Dan; Cao, Weibiao; Behar, Jose; Biancani, Piero

2012-01-01

125

TRPV1: a stress response protein in the central nervous system  

PubMed Central

The transient receptor potential (TRP) family comprises a diverse group of cation channels that regulate a variety of intracellular signaling pathways. The TRPV1 (vanilloid 1) channel is best known for its role in nociception and sensory transmission. First studied in the dorsal root ganglia as the receptor for capsaicin, TRPV1 is now recognized to have a broader distribution and function within the central nervous system (CNS). Because it can be activated by a range of potentially noxious stimuli, TRPV1’s polymodal nature and ability to interact with other receptor pathways make it a candidate for a stress response protein. As a result, TRPV1 is emerging as a key mediator of CNS function through modulation of both glial and neuronal activity. Growing evidence has suggested that TRPV1 can mediate a variety of pathways from glial reactivity and cytokine release to synaptic transmission and plasticity. This review highlights the increasing importance of TRPV1 as a regulator of CNS function in response to stress.

Ho, Karen W; Ward, Nicholas J; Calkins, David J

2012-01-01

126

TRPV1-antagonist AMG9810 promotes mouse skin tumorigenesis through EGFR/Akt signaling  

PubMed Central

In addition to capsaicin, a transient receptor potential channel vanilloid subfamily 1 (TRPV1) agonist, two kinds of antagonists against this receptor are used as therapeutic drugs for pain relief. Indeed, a number of small molecule TRPV1 antagonists are currently undergoing Phase I/II clinical trials to determine their effect on relieving chronic inflammatory pain and migraine headache pain. However, we previously reported that the absence of TRPV1 in mice results in a striking increase in skin carcinogenesis, suggesting that chronic blockade of TRPV1 might increase the risk of tumor development. In this study, we found that a typical TRPV1 antagonist, AMG9810, promotes mouse skin tumor development. The topical application of AMG9810 resulted in a significant increase in the expression level of the epidermal growth factor receptor (EGFR) and its downstream Akt/mammalian target of rapamycin (mTOR)-signaling pathway. This increase was not only observed in AMG9810-treated tumor tissue but was also found in skin tissue treated with AMG9810. In telomerase-immortalized primary human keratinocytes, AMG9810 promoted proliferation that was mediated through the EGFR/Akt/mTOR-signaling pathway. In summary, our data suggest that the TRPV1 antagonist, AMG9810, promotes mouse skin tumorigenesis mediated through EGFR/Akt/mTOR signaling. Thus, the application of this compound for pain relief might increase the risk of skin cancer.

Li, Shengqing; Bode, Ann M.; Zhu, Feng; Liu, Kangdong; Zhang, Jishuai; Kim, Myoung Ok; Reddy, Kanamata; Zykova, Tatyana; Ma, Wei-ya; Carper, Andria L.; Langfald, Alyssa K.; Dong, Zigang

2011-01-01

127

A- Kinase Anchoring Protein 150 Controls Protein Kinase C-mediated Phosphorylation and Sensitization of TRPV1  

PubMed Central

Post-translational modifications on various receptor proteins have significant effects on receptor activation. For the Transient Receptor Potential family V type 1 (TRPV1) receptor, phosphorylation of certain serine/threonine amino acid residues sensitizes the receptor to activation by capsaicin and heat. Although Protein Kinase C (PKC) phosphorylates TRPV1 on certain serine/threonine residues, it is not completely understood how PKC functionally associates with TRPV1. Recent studies have reported that the A-kinase Anchoring Protein 150 (AKAP150) mediates PKA phosphorylation of TRPV1 in several nociceptive models. Here, we demonstrate that AKAP150 also mediates PKC-directed phosphorylation and sensitization of TRPV1. In cultured rat trigeminal ganglia, immunocytochemical analyses demonstrate co-localization of AKAP150 and PKC isoforms ?, ?, ?, and ? in TRPV1-positive neurons. Additional biochemical evidence supports immunocytochemical results, indicating that AKAP150 preferentially associates with certain PKC isoforms in rat trigeminal ganglia neurons. Employing siRNA-mediated knock-down of AKAP150 expression, we demonstrate that PKC-mediated phosphorylation of TRPV1 and sensitization to a capsaicin response is dependent upon functional expression of the AKAP150 scaffolding protein. Furthermore, PKC-induced sensitization to a thermal stimulus is abrogated in AKAP150 knock-out animals relative to wild-type. Collectively, results from these studies indicate that the AKAP150 scaffolding protein functionally modulates PKC-mediated phosphorylation and sensitization of the TRPV1 receptor in rat sensory neurons, suggesting the scaffolding protein to be an integral regulator of peripheral inflammatory hyperalgesia.

Jeske, Nathaniel A.; Patwardhan, Amol M.; Ruparel, Nikita B.; Akopian, Armen N; Shapiro, Mark S.; Henry, Michael A.

2009-01-01

128

Developmental Toxicity Study of Pure trans-Capsaicin in Rats and Rabbits  

Microsoft Academic Search

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

Sanjay Chanda; Valerie Sharper; Alan Hoberman; Keith Bley

2006-01-01

129

Effects of single swim stress on changes in TRPV1-mediated plasticity in the amygdala.  

PubMed

By examining the involvement of transient receptor potential vanilloid type 1 (TRPV1) in the stress modulation of learning and memory processes in mice, we evaluated the effects of endovanilloid N-oleoyldopamine (OLDA) on the long-term potentiation (LTP) of the lateral nucleus of the amygdala (LA). After high-frequency stimulation of external capsule fibers we found that LA-LTP is reduced in OLDA-treated slices derived from adult C57BL/6 control mice. The specificity of the TRPV1 receptor activation by OLDA was confirmed by blocking the OLDA-induced inhibitory effect on LA-LTP with the specific TRPV1 receptor antagonist AMG 9810. The specificity of OLDA was further supported by using TRPV1 deficient mice, where the effect of OLDA on LA-LTP was missing. Following exposure to a forced swim test (FST) OLDA enhanced LA-LTP in control but not TRPV1-deficient mice. The results also show that a short period of acute stress significantly impairs LA-LTP. Since we have recently shown the involvement of cannabinoid CB1 receptors in the mediation of capsaicin-induced inhibitory effects on LA-LTP ([23] Zschenderlein et al., 2011), it is reasonable to assume that the OLDA-induced enhancement of LA-LTP after the forced swim test can be attributed to the up-regulation of TRPV1 and the action of ligands such as anandamide on TRPV1. As a result, stimulation of TRPV1 receptors rescues LTP in slices derived from swim-stressed mice. PMID:22982038

Kulisch, Christoph; Albrecht, Doris

2013-01-01

130

Activation of transient receptor potential A1 by a non-pungent capsaicin-like compound, capsiate  

PubMed Central

BACKGROUND AND PURPOSE Capsiate is produced by ‘CH-19 Sweet’ (Capsicum annuun L.), a non-pungent cultivar of red pepper. Like capsaicin, capsiate is thought to enhance energy metabolism by activating the sympathetic nervous system and suppressing inflammation, but the underlying mechanisms for this are uncertain. We previously reported that capsiate could activate transient receptor potential vanilloid 1 (TRPV1), a capsaicin receptor. The purpose of the present study is to investigate whether capsinoids activate other TRP channels. EXPERIMENTAL APPROACH Using Ca2+ imaging and whole-cell patch-clamp methods, we analysed the response of TRP channels to three kinds of capsinoids, capsiate, dihydrocapsiate and nordihydrocapsiate, in HEK293T cells expressing TRP channels or in primary cultures of mouse dorsal root ganglion neurons. KEY RESULTS We found that in both cell types TRP ankyrin 1 (TRPA1) had a slightly weaker response to capsinoids compared with TRPV1, with the capsiate EC50 for TRPA1 activation being more than that for TRPV1 activation, and that the capsinoid-evoked action was blocked by a specific TRPA1 antagonist. TRPA1 was activated by capsinoids, but not by their degradation products. Amino acids known to participate in TRPA1 activation following cysteine covalent modification or zinc treatment were not involved in the activation of TRPA1 by capsinoid. CONCLUSIONS AND IMPLICATIONS Taken together, these results indicate that capsinoids activate TRPA1 by an as yet unknown mechanism, and TRPA1 could be involved in physiological phenomena associated with capsinoid treatment.

Shintaku, Kenji; Uchida, Kunitoshi; Suzuki, Yoshiro; Zhou, Yiming; Fushiki, Tohru; Watanabe, Tatsuo; Yazawa, Susumu; Tominaga, Makoto

2012-01-01

131

Signaling in TRPV1-induced platelet activating factor (PAF) in human esophageal epithelial cells  

PubMed Central

Transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) receptors were identified in human esophageal squamous epithelial cell line HET-1A by RT-PCR and by Western blot. In fura-2 AM-loaded cells, the TRPV1 agonist capsaicin caused a fourfold cytosolic calcium increase, supporting a role of TRPV1 as a capsaicin-activated cation channel. Capsaicin increased production of platelet activating factor (PAF), an important inflammatory mediator that acts as a chemoattractant and activator of immune cells. The increase was reduced by the p38 MAP kinase (p38) inhibitor SB203580, by the cytosolic phospholipase A2 (cPLA2) inhibitor AACOCF3, and by the lyso-PAF acetyltransferase inhibitor sanguinarin, indicating that capsaicin-induced PAF production may be mediated by activation of cPLA2, p38, and lyso-PAF acetyltransferase. To establish a sequential signaling pathway, we examined the phosphorylation of p38 and cPLA2 by Western blot. Capsaicin induced phosphorylation of p38 and cPLA2. Capsaicin-induced p38 phosphorylation was not affected by AACOCF3. Conversely, capsaicin-induced cPLA2 phosphorylation was blocked by SB203580, indicating that capsaicin-induced PAF production depends on sequential activation of p38 and cPLA2. To investigate how p38 phosphorylation may result from TRPV1-mediated calcium influx, we examined a possible role of calmodulin kinase (CaM-K). p38 phosphorylation was stimulated by the calcium ionophore A23187 and by capsaicin, and the response to both agonists was reduced by a CaM inhibitor and by CaM-KII inhibitors, indicating that calcium induced activation of CaM and CaM-KII results in P38 phosphorylation. Acetyl-CoA transferase activity increased in response to capsaicin and was inhibited by SB203580, indicating that p38 phosphorylation in turn causes activation of acetyl-CoA transferase to produce PAF. Thus epithelial cells produce PAF in response to TRPV1-mediated calcium elevation.

Ma, Jie; Harnett, Karen M.; Behar, Jose; Biancani, Piero

2010-01-01

132

Consequences of activating the calcium-permeable ion channel TRPV1 in breast cancer cells with regulated TRPV1 expression.  

PubMed

Increased expression of specific calcium channels in some cancers and the role of calcium signaling in proliferation and invasion have led to studies assessing calcium channel inhibitors as potential therapies for some cancers. The use of channel activators to promote death of cancer cells has been suggested, but the risk of activators promoting cancer cell proliferation and the importance of the degree of channel over-expression is unclear. We developed an MCF-7 breast cancer cell line with inducible TRPV1 overexpression and assessed the role of TRPV1 levels on cell death mediated by the TRPV1 activator capsaicin and the potential for submaximal activation to promote proliferation. The TRPV1 level was a determinant of cell death induced by capsaicin. A concentration response curve with varying TRPV1 expression levels identified the minimum level of TRPV1 required for capsaicin induced cell death. At no level of TRPV1 over-expression or capsaicin concentration did TRPV1 activation enhance proliferation. Cell death induced by capsaicin was necrotic and associated with up-regulation of c-Fos and RIP3. These studies suggest that activators of specific calcium channels may be an effective way to induce necrosis and that this approach may not always be associated with enhancement of cancer cell proliferation. PMID:24889371

Wu, Tina T L; Peters, Amelia A; Tan, Ping T; Roberts-Thomson, Sarah J; Monteith, Gregory R

2014-08-01

133

CCAAT/ enhancer-binding protein ? activation by capsaicin contributes to the regulation of CYP1A1 expression, mediated by the aryl hydrocarbon receptor  

PubMed Central

BACKGROUND AND PURPOSE Capsaicin, a constituent of peppers, has been linked to the suppression of tumorigenesis and carcinogenesis. The influence of capsaicin on cytochrome P450 (CYP) 1A1, which is involved in metabolism of carcinogens, and the underlying mechanisms remain unclear. Here, we examined the effect of capsaicin on CYP1A1 expression in mouse hepatoma cells. EXPERIMENTAL APPROACH Murine hepatoma Hepa-1c1c7 cells were incubated with capsaicin and/or 3-methylcholanthrene (3-MC). Effects of capsaicin on CYP1A1 levels were determined by analysing mRNA expression, transcription activity and protein expression. Regulation of CYP1A1 was investigated by determining transcriptional factor expression, activation and binding activity with cotreatment with target signal antagonists. KEY RESULTS Capsaicin alone slightly induced CYP1A1 activity, mRNA expression, protein level and promoter activity. Treatment with transient receptor potential vanilloid type-1 receptor (TRPV1) or aryl hydrocarbon receptor (AhR) antagonist decreased induction of CYP1A1 expression by capsaicin. Additionally, capsaicin significantly inhibited 3-MC-induced CYP1A1 mRNA and protein level and xenobiotic response element–luciferase activity. Capsaicin also inhibited 3-MC-induced AhR transactivation and nuclear localization of AhRs. Moreover, capsaicin increased Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) and CCAAT/ enhancer-binding protein ? (C/EBP?) activation, downstream of TRPV1 receptors. Capsaicin-induced C/EBP? activation inhibited induction of CYP1A1 mRNA and protein by 3-MC. CONCLUSIONS AND IMPLICATIONS Capsaicin alone weakly induced CYP1A1 expression, and 3-MC-induced CYP1A1 levels were suppressed by capsaicin. Activation of C/EBP? and inhibition of 3-MC-induced AhR transactivation by capsaicin contributed to the suppression of CYP1A1 expression. Capsaicin has a potential chemopreventive effect through inhibiting induction of CYP1A1 by poly aryl hydrocarbons.

Han, Eun Hee; Hwang, Yong Pil; Kim, Hyung Gyun; Choi, Jai Ho; Park, Bong Hwan; Song, Gye Yong; Lee, Gye Won; Jeong, Tae Cheon; Jeong, Hye Gwang

2011-01-01

134

A novel TRPV1 receptor antagonist JNJ-17203212 attenuates colonic hypersensitivity in rats.  

PubMed

This study examined the efficacy of a novel TRPV1 antagonist, JNJ-17203212, in two experimental rat models that exhibit a hypersensitive visceral motor response (VMR) to colorectal distension (CRD). In the first model, intraluminal administration of acetic acid (1% solution) into the distal colon produced an acute colonic hypersensitivity. In the second model, intraluminal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) into the distal colon produced a chronic, post-inflammatory colonic hypersensitivity 30 days post-TNBS administration. Throughout this study, colonic sensitivity was assessed via quantification of VMR to CRD in rats following a single, oral administration of JNJ-17203212 (3, 10 or 30 mg/kg) or vehicle. Intraluminal administration of acetic acid and TNBS resulted in increased VMR to CRD when compared to controls. In both groups, VMR to CRD was significantly reduced by administration of JNJ-17203212 at 30 mg/kg. The results of this study show that the selective TRPV1 antagonist, JNJ-17203212, reduces sensitivity to luminal distension in both an acute, noninflammatory and a chronic, post-inflammatory rodent model of colonic hypersensitivity. These data indicate that TRPV1 is involved in the pathogenesis of visceral hypersensitivity and that JNJ-17203212 may be a potential therapeutic agent for functional bowel disorders characterized by abdominal hypersensitivity, such as irritable bowel syndrome. PMID:21132125

Wiskur, B J; Tyler, K; Campbell-Dittmeyer, K; Chaplan, S R; Wickenden, A D; Greenwood-Van Meerveld, B

2010-10-01

135

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

136

Agonist-dependent potentiation of vanilloid receptor transient receptor potential vanilloid type 1 function by stilbene derivatives.  

PubMed

Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel activated by capsaicin, low pH, and noxious heat and plays a key role in nociception. Understanding mechanisms for functional modulation of TRPV1 has important implications. One characteristic of TRPV1 is that channel activity induced by either capsaicin or other activators can be sensitized or modulated by factors involving different cell signaling mechanisms. In this study, we describe a novel mechanism for the modulation of TRPV1 function: TRPV1 function is modulated by 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) and its analogs. We found that, in rat dorsal root ganglion neurons, although DIDS did not induce the activation of TRPV1 per se but drastically increased the TRPV1 currents induced by either capsaicin or low pH. DIDS also blocked the tachyphylaxis of the low pH-induced TRPV1 currents. 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), a DIDS analog, failed to enhance the capsaicin-evoked TRPV1 current but increased the low pH-evoked TRPV1 currents, with an effect comparable with that of DIDS. SITS also blocked the low pH-induced tachyphylaxis. DIDS also potentiated the currents of TRPV1 channels expressed in human embryonic kidney 293 cells, with an effect of left-shifting the concentration-response curve of the capsaicin-induced TRPV1 currents. This study demonstrates that DIDS and SITS, traditionally used chloride channel blockers, can modify TRPV1 channel function in an agonist-dependent manner. The results provide new input for understanding TRPV1 modulation and developing new modulators of TRPV1 function. PMID:22328719

Zhang, Xuan; Du, Xiao-Na; Zhang, Guo-Hong; Jia, Zhan-Feng; Chen, Xing-Juan; Huang, Dong-Yang; Liu, Bo-Yi; Zhang, Hai-Lin

2012-05-01

137

Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold  

PubMed Central

Transient receptor potential vanilloid type 1 (TRPV1) channel responds to a wide spectrum of physical and chemical stimuli. In doing so, it serves as a polymodal cellular sensor for temperature change and pain. Many chemicals are known to strongly potentiate TRPV1 activation, though how this is achieved remains unclear. In this study we investigated the molecular mechanism underlying the gating effects of divalent cations Mg2+ and Ba2+. Using a combination of fluorescence imaging and patch-clamp analysis, we found that these cations potentiate TRPV1 gating by most likely promoting the heat activation process. Mg2+ substantially lowers the activation threshold temperature; as a result, a significant fraction of channels are heat-activated at room temperature. Although Mg2+ also potentiates capsaicin- and voltage-dependent activation, these processes were found either to be not required (in the case of capsaicin) or insufficient (in the case of voltage) to mediate the activating effect. In support of a selective effect on heat activation, Mg2+ and Ba2+ cause a Ca2+-independent desensitization that specifically prevents heat-induced channel activation but does not prevent capsaicin-induced activation. These results can be satisfactorily explained within an allosteric gating framework in which divalent cations strongly promote the heat-dependent conformational change or its coupling to channel activation, which is further coupled to the voltage- and capsaicin-dependent processes.

Cao, Xu; Ma, Linlin; Yang, Fan

2014-01-01

138

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

139

A Randomised Trial Evaluating the Effects of the TRPV1 Antagonist SB705498 on Pruritus Induced by Histamine, and Cowhage Challenge in Healthy Volunteers  

PubMed Central

Background Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies. Objectives To select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents. Methods A clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch. Results Following capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine) was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins) between the 3% dose of SB705498 and placebo for the cowhage challenge was ?0.64, whilst the histamine challenge showed on average a ?4.65 point change. Conclusions The 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch. Trial Registration ClinicalTrials.gov NCT01673529

Gibson, Rachel A.; Robertson, Jon; Mistry, Harshna; McCallum, Stewart; Fernando, Disala; Wyres, Melody; Yosipovitch, Gil

2014-01-01

140

Activation of the TRPV1 channel attenuates N-methyl-d-aspartic acid-induced neuronal injury in the rat retina.  

PubMed

Capsaicin, a transient receptor potential vanilloid type1 (TRPV1) agonist, has been reported to protect against ischemia-reperfusion injury in various organs, including the brain, heart, and kidney, whereas activation of TRPV1 was also reported to contribute to neurodegeneration, including pressure-induced retinal ganglion cell death in vitro. We histologically investigated the effects of capsaicin and SA13353, TRPV1 agonists, on retinal injury induced by intravitreal N-methyl-d-aspartic acid (NMDA; 200nmol/eye) in rats in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal NMDA injection. Capsaicin (5.0nmol/eye) was intravitreally admianeously with NMDA injection. SA13353 (10mg/kg) was intraperitoneally administered 15min before NMDA injection. Morphometric evaluation at 7 days after NMDA injection showed that intravitreal NMDA injection resulted in ganglion cell loss. Capsaicin and SA13353 almost completely prevented this damage. Treatment with capsazepine (TRPV1 antagonist, 0.5nmol/eye), CGRP (8-37) (calcitonin gene-related peptide (CGRP) receptor antagonist, 0.5pmol/eye), or RP67580 (tachykinin NK1 receptor antagonist, 0.5nmol/eye) almost completely negated the protective effect of capsaicin in the NMDA-injected rats. Seven days after intravitreal NMDA injection, the cell number of retinal ganglion cell was significantly smaller than in the eye that had received capsaicin in B6.Cg-TgN(Thy1-CFP)23Jrs/J transgenic mice that express the enhanced cyan fluorescent protein in retinal ganglion cells in the retina. These results suggested that activation of TRPV1 protects retinal neurons from the injury induced by intravitreal NMDA in rats in vivo. Activation of CGRP and tachykinin NK1 receptors is possibly involved in underlying protective mechanisms. PMID:24704373

Sakamoto, Kenji; Kuroki, Taiyo; Okuno, Yui; Sekiya, Haruna; Watanabe, Akihiro; Sagawa, Tomonori; Ito, Hiroko; Mizuta, Aya; Mori, Asami; Nakahara, Tsutomu; Ishii, Kunio

2014-06-15

141

LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons.  

PubMed

Recent studies have demonstrated that the lipopolysaccharide (LPS) receptor (TLR4) is expressed in TRPV1 containing trigeminal sensory neurons. In this study, we evaluated whether LPS activates trigeminal neurons, and sensitizes TRPV1 responses via TLR4. To test this novel hypothesis, we first demonstrated that LPS binds to receptors in trigeminal neurons using competitive binding. Second, we demonstrated that LPS evoked a concentration-dependent increase in intracellular calcium accumulation (Ca(2+))(i) and inward currents. Third, LPS significantly sensitized TRPV1 to capsaicin measured by (Ca(2+))(i), release of calcitonin gene-related peptide, and inward currents. Importantly, a selective TLR4 antagonist blocked these effects. Analysis of these data, collectively, demonstrates that LPS is capable of directly activating trigeminal neurons, and sensitizing TRPV1 via a TLR4-mediated mechanism. These findings are consistent with the hypothesis that trigeminal neurons are capable of detecting pathogenic bacterial components leading to sensitization of TRPV1, possibly contributing to the inflammatory pain often observed in bacterial infections. PMID:21393555

Diogenes, A; Ferraz, C C R; Akopian, A N; Henry, M A; Hargreaves, K M

2011-06-01

142

Monoacylglycerols activate TRPV1--a link between phospholipase C and TRPV1.  

PubMed

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous "entourage" compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain. PMID:24312564

Zygmunt, Peter M; Ermund, Anna; Movahed, Pouya; Andersson, David A; Simonsen, Charlotte; Jönsson, Bo A G; Blomgren, Anders; Birnir, Bryndis; Bevan, Stuart; Eschalier, Alain; Mallet, Christophe; Gomis, Ana; Högestätt, Edward D

2013-01-01

143

Monoacylglycerols Activate TRPV1 - A Link between Phospholipase C and TRPV1  

PubMed Central

Phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate generates diacylglycerol, inositol 1,4,5-trisphosphate and protons, all of which can regulate TRPV1 activity via different mechanisms. Here we explored the possibility that the diacylglycerol metabolites 2-arachidonoylglycerol and 1-arachidonoylglycerol, and not metabolites of these monoacylglycerols, activate TRPV1 and contribute to this signaling cascade. 2-Arachidonoylglycerol and 1-arachidonoylglycerol activated native TRPV1 on vascular sensory nerve fibers and heterologously expressed TRPV1 in whole cells and inside-out membrane patches. The monoacylglycerol lipase inhibitors methylarachidonoyl-fluorophosphonate and JZL184 prevented the metabolism of deuterium-labeled 2-arachidonoylglycerol and deuterium-labeled 1-arachidonoylglycerol in arterial homogenates, and enhanced TRPV1-mediated vasodilator responses to both monoacylglycerols. In mesenteric arteries from TRPV1 knock-out mice, vasodilator responses to 2-arachidonoylglycerol were minor. Bradykinin and adenosine triphosphate, ligands of phospholipase C-coupled membrane receptors, increased the content of 2-arachidonoylglycerol in dorsal root ganglia. In HEK293 cells expressing the phospholipase C-coupled histamine H1 receptor, exposure to histamine stimulated the formation of 2-AG, and this effect was augmented in the presence of JZL184. These effects were prevented by the diacylglycerol lipase inhibitor tetrahydrolipstatin. Histamine induced large whole cell currents in HEK293 cells co-expressing TRPV1 and the histamine H1 receptor, and the TRPV1 antagonist capsazepine abolished these currents. JZL184 increased the histamine-induced currents and tetrahydrolipstatin prevented this effect. The calcineurin inhibitor ciclosporin and the endogenous “entourage” compound palmitoylethanolamide potentiated the vasodilator response to 2-arachidonoylglycerol, disclosing TRPV1 activation of this monoacylglycerol at nanomolar concentrations. Furthermore, intracerebroventricular injection of JZL184 produced TRPV1-dependent antinociception in the mouse formalin test. Our results show that intact 2-arachidonoylglycerol and 1-arachidonoylglycerol are endogenous TRPV1 activators, contributing to phospholipase C-dependent TRPV1 channel activation and TRPV1-mediated antinociceptive signaling in the brain.

Zygmunt, Peter M.; Ermund, Anna; Movahed, Pouya; Andersson, David A.; Simonsen, Charlotte; Jonsson, Bo A. G.; Blomgren, Anders; Birnir, Bryndis; Bevan, Stuart; Eschalier, Alain; Mallet, Christophe; Gomis, Ana; Hogestatt, Edward D.

2013-01-01

144

OP08 The hydrogen sulfide donor GYY4137 attenuates transient receptor potential vanilloid 1 (TRPV1) antagonist-mediated hyperthermia.  

PubMed

The transient receptor potential vanilloid 1 (TRPV1) ion channel is a member of the TRP superfamily of receptors and a well-known integrator of noxious stimuli. The expression of TRPV1 on primary sensory neurons has been very well characterised, however, recent studies have shown that they are also expressed in non-neuronal tissue [1]. Whilst TRPV1 antagonism is a promising analgesic strategy, early generation antagonists, such as JNJ17203212 [2] resulted in poorly-understood hyperthermia. Hydrogen sulfide (H2S) is a well-known vasodilator [3,4], and inhalation of H2S can suspend animation, which includes a decreased body temperature [5]. We investigated whether the H2S donor GYY4137 [6] would attenuate the hyperthermia caused by JNJ17203212. Male CD1 mice (Charles River, 35-40g) were used for all experiments in accordance with the Scientific Procedures Act (1986). Radiotelemetry devices allowed the measurement of temperature and activity of freely moving, conscious singly-housed mice in their home cages. Probes (TA-T10A, DSI, USA) were surgically implanted into the peritoneal cavity under 2-5% isoflurane anaesthesia. Preoperative analgesia was administered to aid recovery. Mice were left to recover for one week before temperature monitoring began. A 2-h baseline measurement was taken before i.p. treatment of the mice with either: 30mg/kg JNJ17203212 (n=5), 50mg/kg GYY4137 (n=5) or 11mg/kg d,l- propargylglycine (PAG, n=5) or vehicle (10ml/kg). A pre-treatment of 50mg/kg GYY4137 30min before 30mg/kg JNJ17203212 was performed to determine the effect of GYY4137 on JNJ17203212-mediated hyperthermia. Results were analysed using repeated measures 2-way ANOVA and expressed as mean ±SEM. JNJ17203212 (30mg/kg) caused a significant increase in body temperature compared to vehicle (10%DMSO) treated mice at 2-3h post administration (n=5, P<0.01 at 2h, P<0.005 at 3h). 11mg/kg PAG (n=4) and 50mg/kg GYY4137 (n=4) treatment did not significantly change body temperature compared to vehicle (saline) treated mice). Treatment of mice with 50mg/kg GYY4137 30min before 30mg/kg JNJ17203212 resulted in a reduction in amplitude of the JNJ17203212-mediated hyperthermia compared to saline-pre-treated mice (n=6, P<0.01). This study provides an intriguing insight into a possible way of overcoming TRPV1 antagonist-induced hyperthermia. Under physiological conditions, GYY4137 and PAG did not affect core body temperature. The TRPV1 antagonist JNJ17203212 significantly increased body temperature of male CD1 mice compared to vehicle treated mice. The H2S donor GYY4137 reduced the JNJ17203212-mediated increase in body temperature. Further studies will determine whether GYY4137 will affect body temperature under pathological conditions and the mechanism involved in these changes. PMID:24948245

Fernandes, Maria A; Whiteman, Matthew; Keeble, Julie E

2013-09-01

145

Capsaicin and sensory neurones: a historical perspective.  

PubMed

Capsaicin, the pungent ingredient of red pepper has become not only a "hot" topic in neuroscience but its new target-related unique actions have opened the door for the drug industry to introduce a new chapter of analgesics. After several lines of translational efforts with over 1,000 patents and clinical trials, the 8% capsaicin dermal patch reached the market and its long-lasting local analgesic effect in some severe neuropathic pain states is now well established. This introductory chapter outlines on one hand the historical background based on the author's 50 years of experience in this field and on the other hand emphasizes new scopes, fascinating perspectives in pharmaco-physiology, and molecular pharmacology of nociceptive sensory neurons. Evidence for the effect of capsaicin on C-polymodal nociceptors (CMH), C-mechanoinsensitive (CHMi), and silent C-nociceptors are listed and the features of the capsaicin-induced blocking effects of nociceptors are demonstrated. Common and different characteristics of nociceptor-blocking actions after systemic, perineural, local, intrathecal, and in vitro treatments are summarized. Evidence for the misleading conclusions drawn from neonatal capsaicin pretreatment is presented. Perspectives opened from cloning the capsaicin receptor "Transient Receptor Potential Vanilloid 1" (TRPV1) are outlined and potential molecular mechanisms behind the long-lasting functional, ultrastructural, and nerve terminal-damaging effects of capsaicin and other TRPV1 agonists are summarized. Neurogenic inflammation and the long-list of "capsaicin-sensitive" tissue responses are mediated by an unorthodox dual sensory-efferent function of peptidergic TRPV1-expressing nerve terminals which differ from the classical efferent and sensory nerve endings that have a unidirectional role in neuroregulation. Thermoregulatory effects of capsaicin are discussed in detail. It is suggested that since hyperthermia and burn risk due to enhanced noxious heat threshold are the major obstacles of some TRPV1 antagonists, they could be overcome. The special "multisteric" gating function of the TRPV1 cation channel provides the structural ground for blocking chemical activation of TRPV1 without affecting its responsiveness to physical stimuli. A new chapter of potential analgesics targeting nociceptors is now already supported for pain relief in persistent pathological pain states. PMID:24941663

Szolcsányi, János

2014-01-01

146

Small Molecule Positive Allosteric Modulation of TRPV1 Activation by Vanilloids and Acidic pHS?  

PubMed Central

Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a high-conductance, nonselective cation channel strongly expressed in nociceptive primary afferent neurons of the peripheral nervous system and functions as a multimodal nociceptor gated by temperatures greater than 43°C, protons, and small-molecule vanilloid ligands such as capsaicin. The ability to respond to heat, low pH, vanilloids, and endovanilloids and altered sensitivity and expression in experimental inflammatory and neuropathic pain models made TRPV1 a major target for the development of novel, nonopioid analgesics and resulted in the discovery of potent antagonists. In human clinical trials, observations of hyperthermia and the potential for thermal damage by suppressing the ability to sense noxious heat suggested that full-scale blockade of TRPV1 function can be counterproductive and subtler pharmacological approaches are necessary. Here we show that the dihydropyridine derivative 4,5-diethyl-3-(2-methoxyethylthio)-2-methyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1477) behaves as a positive allosteric modulator of both proton and vanilloid activation of TRPV1. Under inflammatory-mimetic conditions of low pH (6.0) and protein kinase C phosphorylation, addition of MRS1477 further increased sensitivity of already sensitized TPRV1 toward capsaicin. MRS1477 does not affect inhibition by capsazepine or ruthenium red and remains effective in potentiating activation by pH in the presence of an orthosteric vanilloid antagonist. These results indicate a distinct site on TRPV1 for positive allosteric modulation that may bind endogenous compounds or novel pharmacological agents. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce a selective analgesia through calcium overload restricted to highly active nociceptive nerve endings at sites of tissue damage and inflammation.

Kaszas, Krisztian; Keller, Jason M.; Coddou, Claudio; Mishra, Santosh K.; Hoon, Mark A.; Stojilkovic, Stanko; Jacobson, Kenneth A.

2012-01-01

147

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

148

Vasorelaxation to capsaicin and its effects on calcium influx in arteries.  

PubMed

Capsaicin, an activator of the transient potential vanilloid receptor type 1 (TRPV1), is a commonly used pharmacological tool for desensitising sensory nerves. Capsaicin can induce vasorelaxation of isolated blood vessels by activating perivascular TRPV1 receptors, causing the release of vasoactive neuropeptides. This study attempted to characterise the vascular effects of capsaicin in the rat isolated aorta and porcine coronary arteries. Capsaicin elicited concentration-dependent vasorelaxation of both rat aortae and porcine coronary arteries. Capsaicin-induced vasorelaxation of rat aorta was unaffected by a chronic pre-treatment of vessels with capsaicin. Moreover, relaxation was insensitive to the presence of capsazepine, a competitive TRPV1 antagonist, in both the rat aorta and porcine coronary artery. It was hypothesised that capsaicin may be inhibiting calcium influx into smooth muscle cells. Indeed, in vessels incubated in a Ca˛?-free high-k? buffer, the presence of 30 ?M capsaicin significantly inhibited the contractile response to the re-introduction of Ca˛?. In porcine coronary arteries 100 ?M capsaicin completely abolished the contractile response to the re-introduction of Ca˛?. In addition, capsaicin also abolished the concentration-dependent contraction of porcine coronary arteries induced by the L-type calcium activator Bay-K 8644. Therefore, we suggest that capsaicin causes vascular responses in arteries through the inhibition of L-type Ca˛? channels. In summary,we have identified a potential mechanism underlying TRPV1-independent capsaicin-induced vasorelaxation. Our results also question the use of chronic capsaicin pre-treatment in experimental pharmacology in order to elucidate the role of sensory nerves in vascular responses. PMID:22532967

Hopps, Jamie J; Dunn, William R; Randall, Michael D

2012-04-15

149

Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain  

PubMed Central

Summary TRPV1 is the founding and best-studied member of the family of temperature-activated transient receptor potential ion channels (thermoTRPs). Voltage, chemicals, and heat amongst other agonists allosterically gate TRPV1. Molecular determinants for TRPV1 activation by capsaicin, allicin, acid, ammonia, and voltage have been identified. However, the structures and mechanisms mediating its pronounced temperature-sensitivity remain unclear. Recent studies of the related channel TRPV3 identified residues within the pore region required for heat activation. Here we use both random and targeted mutagenesis screens of TRPV1 and identify point mutations in the outer pore region that specifically impair temperature-activation. Single channel analysis shows that TRPV1 mutations disrupt heat-sensitivity by ablating long channel openings, that are part of the temperature-gating pathway. We propose that sequential occupancy of short and long open states upon activation provides a mechanism to enhance temperature-sensitivity. Our study suggests that the outer pore plays a general role in heat-sensitivity of thermoTRPs.

Grandl, Jorg; Kim, Sung Eun; Uzzell, Valerie; Bursulaya, Badry; Petrus, Matt; Bandell, Michael; Patapoutian, Ardem

2010-01-01

150

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 H?O? (0.4%) stimulated these afferent fibers. The H?O?-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

2013-10-01

151

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

152

Reciprocal changes in vanilloid (TRPV1) and endocannabinoid (CB1) receptors contribute to visceral hyperalgesia in the water avoidance stressed rat  

Microsoft Academic Search

Background:Increasing evidence suggests that chronic stress plays an important role in the pathophysiology of several functional gastrointestinal disorders. We investigated whether cannabinoid receptor 1 (CB1) and vanilloid receptor 1 (TRPV1; transient receptor potential vanilloid 1) are involved in stress-induced visceral hyperalgesia.Methods:Male rats were exposed to 1 h water avoidance (WA) stress daily for 10 consecutive days. The visceromotor response (VMR)

S Hong; J Fan; E S Kemmerer; S Evans; Y Li; J W Wiley

2009-01-01

153

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

PubMed

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. PMID:22934013

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

2012-01-01

154

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

155

A re-evaluation of 9-HODE activity at TRPV1 channels in comparison with anandamide: enantioselectivity and effects at other TRP channels and in sensory neurons  

PubMed Central

Background and Purpose Two oxidation products of linoleic acid, 9- and 13-hydroxy-octadecadienoic acids (HODEs), have recently been suggested to act as endovanilloids, that is, endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) channels, thereby contributing to inflammatory hyperalgesia in rats. However, HODE activity at rat TRPV1 in comparison with the best established endovanilloid, anandamide, and its enantioselectivity and selectivity towards other TRP channels that are also abundant in sensory neurons have never been investigated. Experimental Approach We studied the effect of 9(R)-HODE, 9(S)-HODE, (+/–)13-HODE, 15(S)-hydroxyanandamide and anandamide on [Ca2+]i in HEK-293 cells stably expressing the rat or human recombinant TRPV1, or rat recombinant TRPV2, TRPA1 or TRPM8, and also the effect of 9(S)-HODE in rat dorsal root ganglion (DRG) neurons by calcium imaging. Key Results Anandamide and 15(S)-hydroxyanandamide were the most potent endovanilloids at human TRPV1, whereas 9(S)-HODE was approximately threefold less efficacious and 75- and 3-fold less potent, respectively, and did not perform much better at rat TRPV1. The 9(R)-HODE and (+/–)13-HODE were almost inactive at TRPV1. Unlike anandamide and 15(S)-hydroxyanandamide, all HODEs were very weak at desensitizing TRPV1 to the action of capsaicin, but activated rat TRPV2 [only (+/–)13-HODE] and rat TRPA1, and antagonized rat TRPM8, at concentrations higher than those required to activate TRPV1. Finally, 9(S)-HODE elevated [Ca2+]i in DRG neurons almost exclusively in capsaicin-sensitive cells but only at concentrations between 25 and 100 ?M. Conclusions and Implications The present data suggest that HODEs are less important endovanilloids than anandamide. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8

De Petrocellis, Luciano; Schiano Moriello, Aniello; Imperatore, Roberta; Cristino, Luigia; Starowicz, Katarzyna; Di Marzo, Vincenzo

2012-01-01

156

Increased function of the TRPV1 channel in small sensory neurons after local inflammation or in vitro exposure to the pro-inflammatory cytokine GRO/KC  

PubMed Central

Objective Inflammation at the level of the sensory dorsal root ganglia (DRG) leads to robust mechanical pain behaviors and the local inflammation has direct excitatory effects on sensory neurons including small, primarily nociceptive, neurons. These neurons express the TRPV1 channel, which integrates multiple signals of pain and inflammation. The aim of this study was to characterize regulation of the TRPV1 channel by local DRG inflammation and by GRO/KC (CXCL1), a cytokine known to be upregulated in inflamed DRGs. Methods Activation of the TRPV1 receptor with capsaicin was studied with patch clamp methods in acutely isolated small diameter rat sensory neurons in primary culture. In vivo, behavioral effects of TRPV1 and GRO/KC were examined by paw injections. Results Neurons isolated from lumbar DRGs 3 days after local inflammation showed enhanced TRPV1 function: tachyphylaxis (the decline in response to repeated applications of capsaicin) was significantly reduced. A similar effect on tachyphylaxis was observed in neurons pre-treated for 4 hours in vitro with GRO/KC. This effect was blocked by H-89, a protein kinase A inhibitor. Consistent with the in vitro results, in vivo behavioral responses to paw injection of capsaicin were enhanced and prolonged by pre-injecting the paw with GRO/KC 4 hours before the capsaicin injection. GRO/KC paw injections alone did not elicit pain behaviors. Conclusions Function of the TRPV1 channel is enhanced by DRG inflammation and these effects are preserved in vitro during short-term culture. The effects (decreased tachyphylaxis) are mimicked by incubation with GRO/KC, which has previously been found to be strongly upregulated in this and other pain models.

Dong, Fei; Du, Yi-Ru; Xie, Wenrui; Strong, Judith A.; He, Xi-Jing; Zhang, Jun-Ming

2012-01-01

157

Transient Receptor Potential Vanilloid Type 1 Channel (TRPV1) Immunolocalization in the Murine Enteric Nervous System Is Affected by the Targeted C-terminal Epitope of the Applied Antibody  

PubMed Central

The expression of transient receptor potential vanilloid type 1 channel (TRPV1) in the enteric nervous system is still the subject of debate. Although a number of studies have reported that TRPV1 is limited to extrinsic afferent fibers, other studies argue for an intrinsic expression of TRPV1. In the present study, reverse transcriptase PCR was employed to establish the expression of TRPV1 mRNA throughout the gastrointestinal tract. Using two antibodies directed against different epitopes of TRPV1, we were able to show at the protein level that the observed distribution pattern of TRPV1 is dependent on the antibody used in the immunohistochemical staining. A first antibody indeed mainly stained neuronal fibers, whereas a second antibody exclusively stained perikarya of enteric neurons throughout the mouse gastrointestinal tract. We argue that these different distribution patterns are due to the antibodies discriminating between different modulated forms of TRPV1 that influence the recognition of the targeted immunogen and as such distinguish intracellular from plasmalemmal forms of TRPV1. Our study is the first to directly compare these two antibodies within the same species and in identical conditions. Our observations underline that detailed knowledge of the epitope that is recognized by the antibodies employed in immunohistochemical procedures is a prerequisite for correctly interpreting experimental results.

Buckinx, Roeland; Van Nassauw, Luc; Avula, Leela R.; Alpaerts, Katrien; Adriaensen, Dirk

2013-01-01

158

Acute myocardial ischemia enhances the vanilloid TRPV1 and serotonin 5-HT3 receptor-mediated Bezold-Jarisch reflex in rats.  

PubMed

The Bezold-Jarisch reflex is characterized by a sudden bradycardia associated with hypotension induced by the activation of the vanilloid TRPV1 and serotonin 5-HT(3) receptors. This reflex is associated with several health conditions, including myocardial infarction. The aim of the present study was to elucidate the influence of acute experimental myocardial ischemia on the reflex bradycardia induced by anandamide and phenylbiguanide, agonists of the TRPV1 and 5-HT(3) receptors, respectively. In urethane-anesthetized rats, the rapid iv injection of anandamide (0.6 ?mol/kg) or phenylbiguanide (0.03 ?mol/kg) decreased heart rate (HR) by about 7-10% of the basal values. Myocardial ischemia (MI) was induced by ligation of the left anterior coronary artery. The agonists were injected 5 min before MI (S(1)) and 10, 20 and 30 min thereafter (S(2)-S(4)). MI potentiated the anandamide-induced reflex bradycardia by approximately 105% at S(2) and 70% at S(3) but had no effect at S(4). This amplificatory effect of MI was virtually abolished by the TRPV1 receptor antagonist capsazepine (1 ?mol/kg) and was not modified by the cannabinoid CB(1) receptor antagonist rimonabant (0.1 ?mol/kg). MI also amplified the reflex bradycardia elicited by phenylbiguanide by approximately 110, 60 and 90% (S(2), S(3) and S(4), respectively), and this effect was sensitive to the 5-HT(3) receptor antagonist ondansetron (3 ?mol/kg). In conclusion, our results suggest that acute myocardial ischemia augments the Bezold-Jarisch reflex induced via activation of TRPV1 and 5-HT(3) receptors located on sensory vagal nerves in the heart. PMID:22358093

Lupi?ski, Sebastian ?; Schlicker, Eberhard; P?dzi?ska-Betiuk, Anna; Malinowska, Barbara

2011-01-01

159

?,?-Unsaturated aldehyde crotonaldehyde triggers cardiomyocyte contractile dysfunction: Role of TRPV1 and mitochondrial function.  

PubMed

Recent evidence has suggested that cigarette smoking is associated with an increased prevalence of heart diseases. Given that cigarette smoking triggers proinflammatory response via stimulation of the capsaicin-sensitive transient receptor potential cation channel TRPV1, this study was designed to evaluate the effect of an essential ?,?-unsaturated aldehyde from cigarette smoke crotonaldehyde on myocardial function and the underlying mechanism with a focus on TRPV1 and mitochondria. Cardiomyocyte mechanical and intracellular Ca(2+) properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), fura-2 fluorescence intensity (FFI), intracellular Ca(2+) decay and SERCA activity. Apoptosis and TRPV1 were evaluated using Western blot analysis. Production of reactive oxygen species (ROS) and DNA damage were measured using the intracellular fluoroprobe 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Our data revealed that crotonaldehyde interrupted cardiomyocyte contractile and intracellular Ca(2+) property including depressed PS, ±dL/dt, ?FFI and SERCA activity, as well as prolonged TR90 and intracellular Ca(2+) decay. Crotonaldehyde exposure increased TRPV1 and NADPH oxidase levels, promoted apoptosis, mitochondrial injury (decreased aconitase activity, PGC-1? and UCP-2) as well as production of ROS and 8-OHdG. Interestingly, crotonaldehyde-induced cardiac defect was obliterated by the ROS scavenger glutathione and the TRPV1 inhibitor capsazepine. Capsazepine (not glutathione) ablated crotonaldehyde-induced mitochondrial damage. Capsazepine, glutathione and the NADPH inhibitor apocynin negated crotonaldehyde-induced ROS accumulation. Our data suggest a role of crotonaldehyde compromises cardiomyocyte mechanical function possibly through a TRPV1- and mitochondria-dependent oxidative stress mechanism. PMID:24705155

Pei, Zhaohui; Zhuang, Zhiqiang; Sang, Hanfei; Wu, Zhenbiao; Meng, Rongsen; He, Emily Y; Scott, Glenda I; Maris, Jackie R; Li, Ruiman; Ren, Jun

2014-04-01

160

TRPV1 induction in airway vagal low-threshold mechanosensory neurons by allergen challenge and neurotrophic factors  

PubMed Central

We addressed the hypothesis that allergic inflammation in guinea pig airways leads to a phenotypic switch in vagal tracheal cough-causing, low-threshold mechanosensitive A? neurons, such that they begin expressing functional transient receptor potential vanilloid (TRPV1) channels. Guinea pigs were actively sensitized to ovalbumin (OVA) and beginning 21 days later exposed via aerosol to OVA daily for 3 days. Tracheal-specific neurons were identified in the nodose ganglion using retrograde tracing techniques. Tracheal specific neurons were isolated, and mRNA expression was evaluated at the single-neuron level using RT-PCR analysis. Electrophysiological studies have revealed that the vast majority of vagal nodose afferent nerves innervating the trachea are capsaicin-insensitive A?-fibers. Consistent with this, we found <20% of these neurons express TRPV1 mRNA or respond to capsaicin in a calcium assay. Allergen exposure induced de novo TRPV1 mRNA in a majority of the tracheal-specific nodose neurons (P < 0.05). The allergen-induced TRPV1 induction was mimicked by applying either brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) to the tracheal lumen. The BDNF-induced phenotypic change observed at the level of mRNA expression was mimicked using a calcium assay to assess functional TRPV1 ion channels. Finally, OVA exposure induced BDNF and GDNF production in the tracheal epithelium, the immediate vicinity of the nodose A? -fibers terminations. The induction of TRPV1 in nodose tracheal A? -fibers would substantively expand the nature of stimuli capable of activating these cough-causing nerves.

Lieu, Tina Marie; Myers, Allen C.; Meeker, Sonya

2012-01-01

161

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

Microsoft Academic Search

\\u000a Capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, has recently been shown to provide neuroprotection\\u000a against brain injury in experimental adult models of cerebral ischemia. Accordingly, in this study, we investigated the way\\u000a in which capsaicin-mediated TRPV1 modulation could attenuate damage in an experimental hypoxic-ischemic (HI) neonatal brain\\u000a injury model. The Rice-Vannucci method was used in 10-day-old rat pups

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

162

Activation of the TRPV1 cation channel contributes to stress-induced astrocyte migration.  

PubMed

Astrocytes provide metabolic, structural, and synaptic support to neurons in normal physiology and also contribute widely to pathogenic processes in response to stress or injury. Reactive astrocytes can undergo cytoskeletal reorganization and increase migration through changes in intracellular Ca(2+) mediated by a variety of potential modulators. Here we tested whether migration of isolated retinal astrocytes following mechanical injury (scratch wound) involves the transient receptor potential vanilloid-1 channel (TRPV1), which contributes to Ca(2+) -mediated cytoskeletal rearrangement and migration in other systems. Application of the TRPV1-specific antagonists, capsazepine (CPZ) or 5'-iodoresiniferatoxin (IRTX), slowed migration by as much as 44%, depending on concentration. In contrast, treatment with the TRPV1-specific agonists, capsaicin (CAP) or resiniferatoxin (RTX) produced only a slight acceleration over a range of concentrations. Chelation of extracellular Ca(2+) with EGTA (1 mM) slowed astrocyte migration by 35%. Ratiometric imaging indicated that scratch wound induced a sharp 20% rise in astrocyte Ca(2+) that dissipated with distance from the wound. Treatment with IRTX both slowed and dramatically reduced the scratch-induced Ca(2+) increase. Both CPZ and IRTX influenced astrocyte cytoskeletal organization, especially near the wound edge. Taken together, our results indicate that astrocyte mobilization in response to mechanical stress involves influx of extracellular Ca(2+) and cytoskeletal changes in part mediated by TRPV1 activation. GLIA 2014;62:1435-1451. PMID:24838827

Ho, Karen W; Lambert, Wendi S; Calkins, David J

2014-09-01

163

Direct Interaction of Adenosine with the TRPV1 Channel Protein  

Microsoft Academic Search

Vanilloid receptor 1 (TRPV1), a nonspecific cation channel expressed primarily in small sensory neurons, mediates inflammatory thermal pain sensation. The function and expression of TRPV1 are enhanced during inflammation and certain neuropathies, leading to sustained hyperalgesia. Activation of TRPV1 in the spinal cord and periphery promotes release of adenosine, which produces analgesia by activating A1 and A2A adenosine receptor (AR)

Preeti Puntambekar; Jeremy Van Buren; Manish Raisinghani; Louis S. Premkumar; Vickram Ramkumar

2004-01-01

164

The C-type Natriuretic Peptide Induces Thermal Hyperalgesia Through a Non-canonical G??-dependent Modulation of TRPV1 Channel  

PubMed Central

Natriuretic peptides (NPs) control natriuresis and normalize changes in blood pressure. Recent studies suggest that NPs are also involved in the regulation of pain sensitivity, although the underlying mechanisms remain largely unknown. Many biological effects of NPs are mediated by guanylate cyclase (GC)-coupled NP receptors, NPR-A and NPR-B, whereas the third NP receptor, NPR-C, lacks the GC kinase domain and acts as the NP clearance receptor. In addition, NPR-C can couple to specific G?i-??-mediated intracellular signaling cascades in numerous cell types. We found that NPR-C is co-expressed in TRPV1-expressing mouse DRG neurons. NPR-C can be co-immunoprecipitated with G?i, and CNP treatment induced translocation of PKC? to the plasma membrane of these neurons, which was inhibited by pertussis toxin pre-treatment. Application of CNP potentiated capsaicin- and proton-activated TRPV1 currents in cultured mouse DRG neurons, and increased neuronal firing frequency, an effect that was absent in DRG neurons from TRPV1?/? mice. CNP-induced sensitization of TRPV1 activity was attenuated by pre-treatment of DRG neurons with the specific inhibitors of G??, PLC? or PKC, but not of PKA, and was abolished by mutations at two PKC phosphorylation sites in TRPV1. Further, CNP injection into mouse hind paw led to the development of thermal hyperalgesia that was attenuated by administration of specific inhibitors of G?? or TRPV1, and was also absent in TRPV1?/? mice. Thus, our work identifies the G??-PLC?-PKC-dependent potentiation of TRPV1 as a novel signaling cascade recruited by CNP in mouse DRG neurons that can lead to enhanced nociceptor excitability and thermal hypersensitivity.

Loo, Lipin; Shepherd, Andrew J.; Mickle, Aaron D.; Lorca, Ramon A.; Shutov, Leonid; Usachev, Yuriy M.; Mohapatra, Durga P.

2012-01-01

165

Expression of transient receptor potential channel vanilloid (TRPV) 1-4, melastin (TRPM) 5 and 8, and ankyrin (TRPA1) in the normal and methimazole-treated mouse olfactory epithelium  

PubMed Central

Conclusion: It is suggested that TRPV1, 2, 3, and 4, TRPM5 and 8, and TRPA1 may play several roles in the olfactory epithelium (OE), contributing to olfactory chemosensation, olfactory adaptation, olfactory-trigeminal interaction, and OE fluid homeostasis. In patients with olfactory disturbance, TRPV1 and TRPM8 may be closely related to a high rate of recognition of curry and menthol odors, while TRPV2 may also play a crucial role in the regeneration of olfactory receptor neurons. Objective: Expression of TRPV1–4, TRPM5 and 8, and TRPA1 in the normal and methimazole-treated mouse OE was analyzed. Methods: The localization of TRPV1–4, TRPM5 and 8, and TRPA1 in the OE of normal and methimazole-treated CBA/J mice was investigated by immunohistochemistry. Results: Normal OE showed a positive immunofluorescent reaction to TRPV1–4, TRPM5 and 8, and TRPA1. In lamina propria, the nerve fibers displayed TRPV 1, 2, and 3, TRPM8 and TRPA1. In the pathological condition, the expression of TRPV3, TRPV4, TRPM5, and TRPA1 was markedly reduced and took a long time to recover. In contrast, expression of TRPM8 was scarcely affected, even in the pathological condition, while TRPV1 and TRPV2 showed early recovery following methimazole treatment.

Nakashimo, Yousuke; Takumida, Masaya; Fukuiri, Takashi; Anniko, Matti; Hirakawa, Katsuhiro

2010-01-01

166

Expression and purification of human TRPV1 in baculovirus-infected insect cells for structural studies  

Microsoft Academic Search

TRPV1 is a ligand-gated cation channel that is involved in acute thermal nociception and neurogenic inflammation. By using the GP67 signal peptide, high levels of full-length human TRPV1 was expressed in High Five insect cells using the baculovirus expression system. The functional activity of the expressed TRPV1 was confirmed by whole-cell ligand-gated ion flux recordings in the presence of capsaicin

Alla Korepanova; Ana Pereda-Lopez; Larry R. Solomon; Karl A. Walter; Marc R. Lake; Bruce R. Bianchi; Heath A. McDonald; Torben R. Neelands; Jianwei Shen; Edmund D. Matayoshi; Robert B. Moreland; Mark L. Chiu

2009-01-01

167

Tumor necrosis factor ? sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine  

Microsoft Academic Search

Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor ? (TNF?), is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNF? and its receptors (TNFR) in dorsal root ganglion (DRG) cells

Diana Spicarova; Jiri Palecek

2010-01-01

168

Cinnamaldehyde up-regulates the mRNA expression level of TRPV1 receptor potential ion channel protein and its function in primary rat DRG neurons in vitro.  

PubMed

Cinnamaldehyde (1) is a pharmacologically active ingredient isolated from cassia twig (Ramulus Cinnamomi), which is commonly used in herbal remedies to treat fever-related diseases. Both TRPV1 and TRPM8 ion channel proteins are abundantly expressed in sensory neurons, and are assumed to act as a thermosensor, with the former mediating the feeling of warmth and the latter the feeling of cold in the body. Both of them have recently been reported to be involved in thermoregulation. The purpose of this paper is to further uncover the antipyretic mechanisms of 1 by investigating its effects on the mRNA expression levels and functions of both TRPV1 and TRPM8. The results showed that 1 could up-regulate the mRNA expression levels of TRPV1 at both 37 and 39 degrees C, and its calcium-mediating function was significantly increased at 39 degrees C, all of which could not be blocked by pretreatment of the neuronal cells with ruthenium red, a general transient receptor potential (TRP) blocker, indicating that the action of 1 was achieved through a non-TRPA1 channel pathway. In conclusion, the findings in our in vitro studies might account for part of the peripheral molecular mechanisms for the antipyretic action of 1. PMID:20390747

Sui, Feng; Lin, Na; Guo, Jian-You; Zhang, Chang-Bin; Du, Xin-Liang; Zhao, Bao-Sheng; Liu, Hong-Bin; Yang, Na; Li, Lan-Fang; Guo, Shu-Ying; Huo, Hai-Ru; Jiang, Ting-Liang

2010-01-01

169

Contribution of TRPV1 receptor-expressing fibers to spinal ventral root after-discharges and mechanical hyperalgesia in a spared nerve injury (SNI) rat model.  

PubMed

Neuropathic pain induces allodynia and hyperalgesia. In the spared nerve injury (SNI) model, marked mechanical hyperalgesia is manifested as prolongation of the duration of paw withdrawal after pin stimulation. We have previously reported that spinal ventral root discharges (after-discharges) after cessation of noxious mechanical stimulation applied to the corresponding hindpaw were prolonged in anesthetized spinalized rats. Since these after-discharges occurred through transient receptor potential (TRP) V1-positive fibers, these fibers could contribute to mechanical hyperalgesia. Therefore, we examined whether selective deletion of TRPV1-positive fibers by resiniferatoxin, an ultrapotent TRPV1 agonist, would affect the behavioral changes and ventral root discharges in SNI rats. Mechanical allodynia in the von Frey test, mechanical hyperalgesia after pin stimulation, and enhancement of ventral root discharges, but not thermal hyperalgesia in the plantar test, appeared in Wistar rats with SNI. Mechanical hyperalgesia was abolished by treatment with resiniferatoxin, whereas mechanical allodynia was not affected. Moreover, resiniferatoxin eliminated after-discharges completely. These results show that TRPV1-positive fibers do not participate in the mechanical allodynia caused by sensitization of A?-fibers, but contribute to the enhancement of after-discharges and mechanical hyperalgesia following SNI. It is suggested that the mechanisms responsible for generating mechanical allodynia differ from those for prolongation of mechanical hyperalgesia. PMID:23238537

Yamamoto, Shohei; Ohsawa, Masahiro; Ono, Hideki

2013-01-01

170

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

171

Is TRPV1 a useful target in respiratory diseases?  

PubMed

This review focuses on the transient receptor potential vanilloid 1 (TRPV1). TRPV1 is a non-selective cation channel predominantly expressed in the cell membranes of sensory afferent fibers, which are activated multi-modally. In the mammalian respiratory system, immunohistochemical and electrophysiological studies have revealed heterogeneous localizations of TRPV1 channels in the airways and their presence in pleural afferents. TRPV1 channels in afferents are not only involved with sensory inputs, but also release several neuropeptides upon stimulation. These processes trigger pathophysiological effects (e.g. reflex bronchoconstriction, hypersecretion, cough, etc.) that cause various symptoms of airway diseases. Recent studies have identified several endogenous and exogenous substances that can activate TRPV1 in the lung. Because of its key role in initiating inflammatory processes, TRPV1 receptor antagonists have been proposed as therapeutic candidates. Therefore, a critical update of recent therapeutic results is also given in this review. PMID:18992356

Takemura, Masaya; Quarcoo, David; Niimi, Akio; Dinh, Q Thai; Geppetti, Pierangelo; Fischer, Axel; Chung, K Fan; Groneberg, David A

2008-12-01

172

Characterization of functional TRPV1 channels in the sarcoplasmic reticulum of mouse skeletal muscle.  

PubMed

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 Ca(2+) channel, it contributes to intracellular calcium concentration ([Ca(2+)]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 Ca(2+) 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 [Ca(2+)]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 Ca(2+) elevation suggesting that TRPV1 may participate to a secondary SR Ca(2+) liberation of greater amplitude. In conclusion, our experiments point out that TRPV1 is a functional SR Ca(2+) leak channel and may crosstalk with RyR1 in adult mouse muscle fibers. PMID:23536811

Lotteau, Sabine; Ducreux, Sylvie; Romestaing, Caroline; Legrand, Claude; Van Coppenolle, Fabien

2013-01-01

173

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

174

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

2009-11-13

175

Unravelling the Mystery of Capsaicin: A Tool to Understand and Treat Pain  

PubMed Central

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes.

Brock, Christina; Olesen, Anne Estrup; Andresen, Trine; Nilsson, Matias; Dickenson, Anthony H.

2012-01-01

176

Unravelling the mystery of capsaicin: a tool to understand and treat pain.  

PubMed

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes. PMID:23023032

O'Neill, Jessica; Brock, Christina; Olesen, Anne Estrup; Andresen, Trine; Nilsson, Matias; Dickenson, Anthony H

2012-10-01

177

Modulation of transient receptor potential vanilloid subtype 1 (TRPV1) and norepinephrine transporters (NET) protect against oxidative stress, cellular injury, and vascular dementia.  

PubMed

Chronic cerebral hypoperfusion (CCH) is a risk factor for the development of vascular dementia (VaD). CCH participates in a negative role in cognitive impairments. Transient receptor potential vanilloid subtype 1 (TRPV1) participates in cognition, ischemic damage and neuroprotection. Selective norepinephrine transporter (NET) inhibitors have a role in cognitive dysfunction and oxidative stress. The role of TRPV1 and NET in CCH induced VaD is still unknown. The present study has been structured to investigate the role of vanillin; a selective agonist of TRPV1 as well as atomoxetine; a selective NET inhibitor in CCH induced VaD in mice. Permanent bilateral common carotid arteries ligation or two vessel occlusion (2VO) technique was used to induce a stage of chronic cerebral hypoperfusion in mice. 2VO animals have shown significant impairment of locomotion (Actophotometer), motor coordination (Rota rod), learning and memory (Morris water maze). 2VO animals have shown significant reduction in brain catalase, glutathione, and superoxide dismutase, with significant increase in brain infarct size (TTC staining), malondialdehyde and acetyl cholinesterase-AChE activity. Whereas, administration of vanillin as well as atomoxetine has significantly attenuated 2VO induced impaired locomotion, motor coordination, learning and memory, brain damage, brain oxidative stress and higher AChE activity. It may be concluded that 2VO induced CCH has elicited VaD, which was attenuated by vanillin and atomoxetine. Thus, modulators of vanilloid receptors and norepinephrine transporter may be explored further for their benefits in CCH induced VaD. PMID:24597602

Gupta, Surbhi; Sharma, Bhupesh; Singh, Prabhat; Sharma, Brij Mohan

2014-05-01

178

Osmotic and thermal control of magnocellular neurosecretory neurons--role of an N-terminal variant of trpv1.  

PubMed

The release of vasopressin (antidiuretic hormone) plays a key role in the osmoregulatory response of mammals to changes in salt or water intake and in the rate of water loss through evaporation during thermoregulatory cooling. Previous work has shown that the hypothalamus encloses the sensory elements that modulate vasopressin release during systemic changes in fluid osmolality or body temperature. These responses depend in part on a synaptic regulation of vasopressin neurons by afferent inputs arising from osmosensory and thermosensory neurons in the preoptic area. However, recent studies in rats and mice have shown that vasopressin neurons in the supraoptic nucleus also display intrinsic osmosensory and thermosensory properties. Isolated vasopressin neurons exposed to increases in perfusate temperature or osmolality generate increases in non-selective cation channel activity that cause membrane depolarization and increase neuronal excitability. These channels are calcium-permeable and can be blocked by ruthenium red. Moreover, intrinsic responses to osmotic and thermal stimuli are absent in magnocellular neurosecretory cells isolated from mice lacking the transient receptor potential vanilloid-1 (trpv1) gene, which encodes the capsaicin receptor. Immunostaining of vasopressin-releasing neurons with anti-TRPV1 antibodies reveals the presence of amino acids present in the carboxy terminus of the protein, but not those lying in the amino terminal domain. Thus, magnocellular neurosecretory neurons appear to express an N-terminal variant of trpv1 which lacks sensitivity to capsaicin, but which enables osmosensing and thermosensing. PMID:21143657

Sudbury, Jessica R; Ciura, Sorana; Sharif-Naeini, Reza; Bourque, Charles W

2010-12-01

179

Capsaicin, transient receptor potential (trp) protein subfamilies and the particular relationship between capsaicin receptors and small primary sensory neurons  

Microsoft Academic Search

A number of subfamilies of the capsaicin receptor, collectively called TRP, have been reported since the discovery of vanilloid\\u000a receptor 1 (VR1). The term ‘TRP’ is derived from ‘transient receptor potential’, which means the transient and rapid defect\\u000a of reaction following long stimulation with light in the photoreceptor cells of mutant Drosophila. The common features of\\u000a TRP family members are

Hiroshi Nakagawa; Akio Hiura

2006-01-01

180

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

2013-09-27

181

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

2013-09-01

182

Synthesis, photolysis studies and in vitro photorelease of caged TRPV1 agonists and antagonists.  

PubMed

The synthesis of a range of caged TRPV1 agonists and antagonists is reported. The photolysis characteristics of these compounds, when irradiated with a 355 nm laser, have been studied and in all cases the desired compound was produced. Photolysis of a caged TRPV1 agonist in cultured trigeminal neurons produced responses that were consistent with the activation of TRPV1 receptors. PMID:19865707

Van Ryssen, Michael P; Avlonitis, Nicolaos; Giniatullin, Rashid; McDougall, Craig; Carr, James L; Stanton-Humphreys, Megan N; Borgström, Emma L A; Brown, C Tom A; Fayuk, Dmitriy; Surin, Alexander; Niittykoski, Minna; Khiroug, Leonard; Conway, Stuart J

2009-11-21

183

TGF-?1 sensitizes TRPV1 through Cdk5 signaling in odontoblast-like cells  

PubMed Central

Background Odontoblasts are specialized cells that form dentin and they are believed to be sensors for tooth pain. Transforming growth factor-?1 (TGF-?1), a pro-inflammatory cytokine expressed early in odontoblasts, plays an important role in the immune response during tooth inflammation and infection. TGF-?1 is also known to participate in pain signaling by regulating cyclin-dependent kinase 5 (Cdk5) in nociceptive neurons of the trigeminal and dorsal root ganglia. However, the precise role of TGF-?1 in tooth pain signaling is not well characterized. The aim of our present study was to determine whether or not in odontoblasts Cdk5 is functionally active, if it is regulated by TGF-?1, and if it affects the downstream pain receptor, transient receptor potential vanilloid-1 (TRPV1). Results We first determined that Cdk5 and p35 are indeed expressed in an odontoblast-enriched primary preparation from murine teeth. For the subsequent analysis, we used an odontoblast-like cell line (MDPC-23) and found that Cdk5 is functionally active in these cells and its kinase activity is upregulated during cell differentiation. We found that TGF-?1 treatment potentiated Cdk5 kinase activity in undifferentiated MDPC-23 cells. SB431542, a specific inhibitor of TGF-?1 receptor 1 (Tgfbr1), when co-administered with TGF-?1, blocked the induction of Cdk5 activity. TGF-?1 treatment also activated the ERK1/2 signaling pathway, causing an increase in early growth response-1 (Egr-1), a transcription factor that induces p35 expression. In MDPC-23 cells transfected with TRPV1, Cdk5-mediated phosphorylation of TRPV1 at threonine-407 was significantly increased after TGF-?1 treatment. In contrast, SB431542 co-treatment blocked TRPV1 phosphorylation. Moreover, TGF-?1 treatment enhanced both proton- and capsaicin-induced Ca2+ influx in TRPV1-expressing MDPC-23 cells, while co-treatment with either SB431542 or roscovitine blocked this effect. Conclusions Cdk5 and p35 are expressed in a murine odontoblast-enriched primary preparation of cells from teeth. Cdk5 is also functionally active in odontoblast-like MDPC-23 cells. TGF-?1 sensitizes TRPV1 through Cdk5 signaling in MDPC-23 cells, suggesting the direct involvement of odontoblasts and Cdk5 in dental nociceptive pain transduction.

2013-01-01

184

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

185

TRPV1: A Target for Next Generation Analgesics  

PubMed Central

Transient Receptor Potential Vanilloid 1 (TRPV1) is a Ca2+ permeant non-selective cation channel expressed in a subpopulation of primary afferent neurons. TRPV1 is activated by physical and chemical stimuli. It is critical for the detection of nociceptive and thermal inflammatory pain as revealed by the deletion of the TRPV1 gene. TRPV1 is distributed in the peripheral and central terminals of the sensory neurons and plays a role in initiating action potentials at the nerve terminals and modulating neurotransmitter release at the first sensory synapse, respectively. Distribution of TRPV1 in the nerve terminals innervating blood vessels and in parts of the CNS that are not subjected to temperature range that is required to activate TRPV1 suggests a role beyond a noxious thermal sensor. Presently, TRPV1 is being considered as a target for analgesics through evaluation of different antagonists. Here, we will discuss the distribution and the functions of TRPV1, potential use of its agonists and antagonists as analgesics and highlight the functions that are not related to nociceptive transmission that might lead to adverse effects.

Premkumar, Louis S; Sikand, Parul

2008-01-01

186

Acid-induced modulation of airway basal tone and contractility: role of acid-sensing ion channels (ASICs) and TRPV1 receptor.  

PubMed

The role of extracellular acidosis in inflammatory airway diseases is not well known. One consequence of tissue acidification is the stimulation of sensory nerves via the polymodal H(+)-gated transmembrane channels ASICs and TRPV1 receptor. The present study investigated the effect of acidosis on airway basal tone and responsiveness in the guinea pig. Acidosis (pH 6.8, 10 min, 37 degrees C) significantly decreased the basal tone of tracheal rings (p<0.01 vs. paired control). Moreover, pH fall raised the maximal contraction of tracheal rings to acetylcholine (p<0.05 vs. paired control). The pH-induced relaxation of airway basal tone was inhibited by pretreatments with ASIC1a or ASIC3/ASIC2a inhibitors (0.5 mM ibuprofen, 0.1 mM gadolinium), nitric oxide synthase inhibitor (1 mM L-NAME), and guanylate cyclase inhibitor (1 microM ODQ). In contrast, the pH-induced relaxation of airway basal tone was not modified by epithelium removal or pretreatments with a TRPV1 antagonist (1 microM capsazepine), a combination of NK(1,2,3) receptor antagonists (0.1 microM each), a blocker of voltage-sensitive Na(+) channels (1 microM tetrodotoxin), a cyclooxygenase inhibitor with no activity on ASICs (1 microM indomethacin) or ASIC3 and ASIC3/ASIC2b inhibitors (10 nM diclofenac, 1 microM aspirin). Furthermore, acid-induced hyperresponsiveness to acetylcholine was inhibited by epithelium removal, capsazepine, NK(1,2,3) receptor antagonists, tetrodotoxin, amiloride, ibuprofen and diclofenac. In summary, the initial pH-induced airway relaxation seems to be independent of sensory nerves, suggesting a regulation of airway basal tone mediated by smooth muscle ASICs. Conversely, the pH-induced hyperresponsiveness involves sensory nerves-dependent ASICs and TRPV1, and an unknown epithelial component in response to acidosis. PMID:17869310

Faisy, Christophe; Planquette, Benjamin; Naline, Emmanuel; Risse, Paul-André; Frossard, Nelly; Fagon, Jean-Yves; Advenier, Charles; Devillier, Philippe

2007-09-01

187

Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin-induced antinociception.  

PubMed Central

1. Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor. 2. In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48 degrees C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root. 3. When capsazepine (50 nM-20 microM) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, capsazepine reversibly antagonized (IC50 = 254 +/- 28 nM) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 +/- 20 nM) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail. 4. In halothane anaesthetized rats, C-fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C-fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 mumol kg-1, s.c.) and this action of capsaicin was antagonized by capsazepine (100 mumol kg-1) administered by the same route.(ABSTRACT TRUNCATED AT 250 WORDS)

Dickenson, A. H.; Dray, A.

1991-01-01

188

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

2013-07-01

189

Phenotyping the Function of TRPV1-Expressing Sensory Neurons by Targeted Axonal Silencing  

PubMed Central

Specific somatosensations may be processed by different subsets of primary afferents. C-fibers expressing heat-sensitive TRPV1 channels are proposed, for example, to be heat but not mechanical pain detectors. To phenotype in rats the sensory function of TRPV1+ afferents, we rapidly and selectively silenced only their activity, by introducing the membrane-impermeant sodium channel blocker QX-314 into these axons via the TRPV1 channel pore. Using tandem mass spectrometry we show that upon activation with capsaicin, QX-314 selectively accumulates in the cytosol only of TRPV1-expressing cells, and not in control cells. Exposure to QX-314 and capsaicin induces in small DRG neurons a robust sodium current block within 30 s. In sciatic nerves, application of extracellular QX-314 with capsaicin persistently reduces C-fiber but not A-fiber compound action potentials and this effect does not occur in TRPV1?/? mice. Behavioral phenotyping after selectively silencing TRPV1+ sciatic nerve axons by perineural injections of QX-314 and capsaicin reveals deficits in heat and mechanical pressure but not pinprick or light touch perception. The response to intraplantar capsaicin is substantially reduced, as expected. During inflammation, silencing TRPV1+ axons abolishes heat, mechanical, and cold hyperalgesia but tactile and cold allodynia remain following peripheral nerve injury. These results indicate that TRPV1-expressing sensory neurons process particular thermal and mechanical somatosensations, and that the sensory channels activated by mechanical and cold stimuli to produce pain in naive/inflamed rats differ from those in animals after peripheral nerve injury.

Brenneis, Christian; Kistner, Katrin; Puopolo, Michelino; Segal, David; Roberson, David; Sisignano, Marco; Labocha, Sandra; Ferreiros, Nerea; Strominger, Amanda; Cobos, Enrique J.; Ghasemlou, Nader; Geisslinger, Gerd; Reeh, Peter W.; Bean, Bruce P.; Woolf, Clifford J.

2013-01-01

190

?--Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-?, PPAR-? and TRPV1, but not CB1 or CB2 receptors  

PubMed Central

BACKGROUND AND PURPOSE The endocannabinoid system may regulate glial cell functions and their responses to pathological stimuli, specifically, Alzheimer's disease. One experimental approach is the enhancement of endocannabinoid tone by blocking the activity of degradative enzymes, such as fatty acid amide hydrolase (FAAH). EXPERIMENTAL APPROACH We examined the role of FAAH in the response of astrocytes to the pathologic form of ?-amyloid (A?). Astrocytes from wild-type mice (WT) and from mice lacking FAAH (FAAH-KO) were incubated with A? for 8, 24 and 48 h, and their inflammatory responses were quantified by elisa, western-blotting and real-time quantitative-PCR. KEY RESULTS FAAH-KO astrocytes were significantly more responsive to A? than WT astrocytes, as shown by the higher production of pro-inflammatory cytokines. Expression of COX-2, inducible NOS and TNF-? was also increased in A?-exposed KO astrocytes compared with that in WTs. These effects were accompanied by a differential pattern of activation of signalling cascades involved in mediating inflammatory responses, such as ERK1/2, p38MAPK and NF? B. PPAR-? and PPAR-? as well as transient receptor potential vanilloid-1 (TRPV1), but not cannabinoid CB1 or CB2 receptors, mediate some of the differential changes observed in A?-exposed FAAH-KO astrocytes. The pharmacological blockade of FAAH did not render astrocytes more sensitive to A?. In contrast, exogenous addition of several acylethanolamides (anandamide, palmitoylethanolamide and oleoylethanolamide) induced an antiinflammatory response. CONCLUSIONS The genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against A? in a process involving PPAR-?, PPAR-? and TRPV1 receptors.

Benito, Cristina; Tolon, Rosa Maria; Castillo, Ana Isabel; Ruiz-Valdepenas, Lourdes; Martinez-Orgado, Jose Antonio; Fernandez-Sanchez, Francisco Javier; Vazquez, Carmen; Cravatt, Benjamin F; Romero, Julian

2012-01-01

191

Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura  

PubMed Central

Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP) family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir) and isolectin B4 (IB4) binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG) neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent neurons. Interestingly, TRPM8-expressing neurons are virtually absent in the dural afferent population, nor do these neurons cluster around dural afferent neurons. Taken together, our results suggest that TRPV1 and TRPA1 but not TRPM8 channels likely contribute to the excitation of dural afferent neurons and the subsequent activation of the headache circuit. These results provide an anatomical basis for understanding further the functional significance of TRP channels in headache pathophysiology.

2012-01-01

192

Expression and purification of human TRPV1 in baculovirus-infected insect cells for structural studies.  

PubMed

TRPV1 is a ligand-gated cation channel that is involved in acute thermal nociception and neurogenic inflammation. By using the GP67 signal peptide, high levels of full-length human TRPV1 was expressed in High Five insect cells using the baculovirus expression system. The functional activity of the expressed TRPV1 was confirmed by whole-cell ligand-gated ion flux recordings in the presence of capsaicin and low pH and via specific ligand binding to the isolated cellular membranes. Efficient solubilization and purification protocols have resulted in milligram amounts of detergent-solubilized channel at 80-90% purity after Ni2+ IMAC chromatography and size exclusion chromatography. Western blot analysis of amino and carboxyl terminal domains and MS of tryptic digestions of purified protein confirmed the presence of the full-length human TRPV1. Specific ligand binding experiments confirmed the protein integrity of the purified human TRPV1. PMID:19121396

Korepanova, Alla; Pereda-Lopez, Ana; Solomon, Larry R; Walter, Karl A; Lake, Marc R; Bianchi, Bruce R; McDonald, Heath A; Neelands, Torben R; Shen, Jianwei; Matayoshi, Edmund D; Moreland, Robert B; Chiu, Mark L

2009-05-01

193

Co-activation of P2Y2 Receptor and TRPV Channel by ATP: Implications for ATP Induced Pain  

Microsoft Academic Search

Summary 1.Extracellular ATP is recognized as a peripheral modulator of pain. Activation of ionotropic P2X receptors in sensory neurons has been implicated in induction of pain, whereas metabotropic P2Y receptors in potentiation of pain induced by chemical or physical stimuli via capsaicin sensitive TRPV1 channel. Here we report that P2Y2 receptor activation by ATP can activate the TRPV1 channel in

Srihasam Lakshmi; Preeti G. Joshi

2005-01-01

194

TRPV1 Expression in Acupuncture Points: Response to Electroacupuncture Stimulation  

PubMed Central

The present study was to examine the distribution of transient receptor potential vanilloid type-1 (TRPV1) receptor immunoreactivity in the acupuncture points (acupoint), and determine the influences of electroacupuncture (EA) stimulation on TRPV1 expression. EA stimulation of BL 40 was conducted in two sessions of 20 min separated by an 80 min interval in anesthetized rats. Sections of skin containing BL 40, and its non-meridian control were examined by immunolabeling with antibodies directed against TRPV1. Without EA, the number of subepidermal nerve fibers expressing TRPV1 was higher in the acupoint than in non-acupoint control skin (p<0.01). The subepidermal nerve fibers showed the co-localization of TRPV1 with peripherine, a marker for the C-fibers and A- ? fibers. The expression of TRPV1 in nerve fibers is significantly increased by EA stimulation in acupoints (p<0.01). However the upregulation in the non acupoint meridian and the non-meridian control skin were short of statistical significance. Double immunostaining of TRPV1 and neuronal nitric oxide synthase (nNOS) revealed their co-localizationin both the subepidermal nerve fibers and in the dermal connective tissue cells. These results show that a high expression of TRPV1 endowed with nNOS in subepidermal nerve fibers exist in the acupoints and the expression is increased by EA. We conclude that the higher expression of TRPV1 in the subepidermal nerve fibers and its upregulation after EA stimulation may play a key role in mediating the transduction of EA signals to the CNS, and its expression in the subepidermal connective tissue cells may play a role in conducting the local effect of the EA.

Abraham, Therese S.; Chen, Ming-Liang; Ma, Sheng-Xing

2011-01-01

195

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

2011-08-01

196

TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception  

PubMed Central

In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity.

Brandt, Michael R.; Beyer, Chad E.; Stahl, Stephen M.

2012-01-01

197

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

198

Differential Effects of TRPV1 Antagonists in Acid-induced Excitation of Esophageal Vagal Afferent Fibers of Rats  

PubMed Central

Gastro-esophageal acid reflux can stimulate esophageal vagal sensory afferents by activating proton-sensitive ion channel transient receptor vanilloid one (TRPV1). The objective of this study was to investigate the response characteristics of vagal afferent fibers of rats to acid (0.1N HCl) and capsaicin (CAP) following esophagitis and differential effects of two classes of TRPV1 antagonists on responses of vagal afferent fibers. The chronic reflux was induced by ligating the fundus of the stomach and partial constriction of pylorus. Extracellular single fiber recordings were made from the cervical vagal afferent fibers from naďve control and fundus-ligated (FL) esophagitis rats. Innervations of fibers were identified to esophageal distension (ED) and subsequently tested to CAP and acid before and after injection of TRPV1 antagonist JYL1421 or AMG9810 (10?mol/kg, i.v.). Seventy-five vagal afferent fibers from 70 rats were identified to ED. Intra-esophageal CAP (0.1ml of 1mg/ml) excited 39.5% (17/43, 5/22 from naďve and 12/21 from FL rats) fibers. In contrast, intravenous (i.v.) injection of CAP (0.03–0.3 ?mol/kg) dose-dependently excited 72% (42/58) fibers. Responses to CAP were significantly greater for fibers from FL rats (n=32) than naďve rats (n=25). TRPV1 antagonists JYL1421 and AMG9810 (10 ?mol/kg) significantly blocked response to CAP. Intra-esophageal acid infusion stimulated 5/17 (29.4%) fibers from naďve rats and 12/28 (42%) from FL rats. Effect of acid was significantly blocked by AMG9810, but not by JYL1421. Results indicate that following esophagitis the number of fibers responsive to CAP and acid is greater than non-inflamed esophagus, which may contribute to esophageal hypersensitivity. Acid-induced excitation of vagal sensory afferents can be differentially attenuated by different classes of TRPV1 antagonists. Therefore, TRPV1 antagonists play a key role in attenuation of hypersensitivity following reflux-induced esophagitis. The use of TRPV1 antagonists could be an alternative to the traditional symptoms based treatment of chronic acid reflux and esophageal hypersensitivity.

Peles, S.; Medda, B. K.; Zhang, Zhihong; Banerjee, B.; Lehmann, A.; Shaker, R.; Sengupta, J.N.

2009-01-01

199

Capsaicin inhibits Porphyromonas gingivalis growth, biofilm formation, gingivomucosal inflammatory cytokine secretion, and in vitro osteoclastogenesis.  

PubMed

The prevention and treatment of periodontitis requires not only the control of causative pathogens, especially Porphyromonas gingivalis, but also the regulation of inflammatory immune response. Investigating auxiliary drugs for periodontitis during conventional treatments is, thus, quite important. Capsaicin, an agonist for the vanilloid receptor subtype 1 (TRPV1), due to its bacteriostatic activity against Gram-negative bacteria and anti-inflammatory effects, appears to be a promising drug. In this work, the antimicrobial activity of capsaicin against P. gingivalis and biofilm formation, inflammatory cytokine levels in experimental periodontitis, osteoclast precursor proliferation, and osteoclastogenesis in vitro were fully investigated. The results showed that capsaicin inhibited P. gingivalis growth with a minimum inhibitory concentration (MIC) and a minimum bactericidal concentration (MBC) of 16 and 64 mg/l, respectively. Capsaicin also inhibited P. gingivalis biofilm formation, with minimum biofilm inhibition concentrations MBIC50 and MBIC90 of 16 and 32 mg/l, respectively, and reduced pre-formed biofilms' viability with a minimum biofilm reduction concentration MBRC50 of 64 mg/l, as demonstrated by confocal laser scanning microscopy. In experimental periodontitis, except for IL-10, TNF-?, IL-1?, IL-6, IL-12, and iNOS were depressed after capsaicin treatment. Moreover, capsaicin also suppressed osteoclast precursor proliferation and osteoclastogenesis, as demonstrated by NF-?B p65. However, this favorable effect was attenuated by the TRPV1 antagonist, camphor. It, thus, suggests that capsaicin is a potential drug for the auxiliary treatment of periodontitis. TRPV1 activation may involve in beneficial roles of capsaicin on periodontitis. PMID:23955115

Zhou, Y; Guan, X; Zhu, W; Liu, Z; Wang, X; Yu, H; Wang, H

2014-02-01

200

Calcium transient evoked by TRPV1 activators is enhanced by tumor necrosis factor-? in rat pulmonary sensory neurons  

PubMed Central

TNF?, a proinflammatory cytokine known to be involved in the pathogenesis of allergic asthma, has been shown to induce hyperalgesia in somatic tissue via a sensitizing effect on dorsal root ganglion neurons expressing transient receptor potential vanilloid type 1 receptor (TRPV1). Because TRPV1-expressing pulmonary sensory neurons play an important role in regulating airway function, this study was carried out to determine whether TNF? alters the sensitivity of these neurons to chemical activators. Responses of isolated nodose and jugular ganglion neurons innervating the rat lungs were determined by measuring the transient increase in intracellular Ca2+ concentration ([Ca2+]i). Our results showed the following. 1) A pretreatment with TNF? (50 ng/ml) for ?24 h increased significantly the peak ?[Ca2+]i evoked by capsaicin (Cap) in these neurons. A pretreatment with the same concentration of TNF? for a longer duration (?48 h) did not further increase the response, but pretreatment for a shorter duration (1 h) or with a lower concentration (25 ng/ml, 24 h) failed to enhance the Cap sensitivity. 2) The same TNF? pretreatment also induced similar but less pronounced and less uniform increases in the responses to acid (pH 6.5–5.5), 2-aminoethoxydiphenyl borate (2-APB), a common activator of TRPV1, V2, and V3 channels, and allyl isothiocyanate (AITC), a selective activator of TRPA1 channel. 3) In sharp contrast, the responses to ATP, ACh, and KCl were not affected by TNF?. 4) The TNF?-induced hypersensitivity to Cap was not prevented by pretreatment with indomethacin (30 ?M). 5) The immunoreactivity to both TNF receptor types 1 and 2 were detected in rat vagal pulmonary sensory neurons. In conclusion, prolonged treatment with TNF? induces a pronounced potentiating effect on the responses of isolated pulmonary sensory neurons to TRPV1 activators. This action of TNF? may contribute in part to the airway hyperresponsiveness induced by this cytokine.

Hu, Youmin; Gu, Qihai; Lin, Ruei-Lung; Kryscio, Richard

2010-01-01

201

Transcription of the pain-related TRPV1 gene requires Runx1 and C/EBP? factors.  

PubMed

Transient Receptor Potential Vanilloid type 1 channel (TRPV1) is an important endogenous transducer of noxious heat and chemical stimuli and is required during development of inflammatory hypersensitivity. The transcription factor Runx1 is known to play a relevant role in sensory neuron differentiation as it controls the expression of several sensory nociceptive receptors, including TRPV1. Here, we show that Runx1 up-regulates TRPV1 transcription activity by interacting directly with the proximal TRPV1 gene promoter sequence. Importantly, C/EBP? a well-established heterodimer partner of Runx1 also binds to the TRPV1 promoter and cooperates with Runx1 to further stimulate TRPV1 transcription. Our results support a mechanism where Runx1-C/EBP?-containing transcription regulatory complexes are recruited to the TRPV1 gene promoter to modulate TRPV1 expression in dorsal root ganglia neurons. PMID:23018770

Ugarte, Giorgia D; Diaz, Emilio; Biscaia, Miguel; Stehberg, Jimmy; Montecino, Martin; van Zundert, Brigitte

2013-04-01

202

Thermoregulatory Phenotype of the Trpv1 Knockout Mouse: Thermoeffector Dysbalance with Hyperkinesis  

PubMed Central

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 (Tb) and thermoeffector activities under basal conditions, as well as thermoregulatory responses to severe heat and cold. Only subtle alterations were found in the basal Tb of Trpv1 KO mice or in their Tb responses to thermal challenges. The main thermoregulatory abnormality of Trpv1 KO mice was a different pattern of thermoeffectors used to regulate Tb. 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.

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.

2012-01-01

203

Effect of cholesterol depletion on the pore dilation of TRPV1  

PubMed Central

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.

2013-01-01

204

Angiotensin II type 2 receptor (AT2R) localization and antagonist-mediated inhibition of capsaicin responses and neurite outgrowth in human and rat sensory neurons  

PubMed Central

Background The angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration. Methods We used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence. Results AT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas. Conclusions AT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.

Anand, U; Facer, P; Yiangou, Y; Sinisi, M; Fox, M; McCarthy, T; Bountra, C; Korchev, YE; Anand, P

2013-01-01

205

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

PubMed

Although the inhibitory effect of cannabinoids on transient receptor potential vanilloid 1 (TRPV1) channel may explain the efficacy of peripheral cannabinoids in antihyperalgesia and antinociceptive actions, the mechanism for cannabinoid-induced inhibition of TRPV1 in primary sensory neurons is not understood. Therefore, we explored how WIN55,212-2 (WIN, a synthetic cannabinoid) inhibited TRPV1 in rat trigeminal ganglion neurons. A "bell"-shaped concentration-dependent curve was obtained from the effects of WIN on TRPV1 channel. The maximal inhibition on capsaicin-induced current (I (cap)) by WIN was at a concentration of 10(-9) M, and at this concentration I (cap) was reduced by 95 ± 1.6%. When the concentration of WIN was at 10(-6) M, it displayed a stimulatory effect on I (cap). In this study, several intracellular signaling transduction pathways were tested to study whether they were involved in the inhibitory effects of WIN on I (cap). We found that the inhibitory effect of WIN on I (cap) was completely reversed by PKA antagonists H-89 and KT5720 as well as by PKC antagonists BIM and staurosporine. It was also found that the inhibitory effect was partly reversed by PKG antagonist PKGi, while G-protein antagonist GDP-?s/pertussis toxin (PTX) and PLC antagonist U-73122 had no effect on the inhibitory effect of WIN on I(cap). These results suggest that several intracellular signaling transduction pathways including PKA and PKC systems underlie the inhibitory effects of WIN on I (cap); however, G protein-coupled receptors CB1 or CB2 were not involved. PMID:21584737

Wang, Wei; Cao, Xuehong; Liu, Changjin; Liu, Lieju

2012-02-01

206

Hypoxia-induced sensitization of transient receptor potential vanilloid 1 involves activation of hypoxia-inducible factor-1 alpha and PKC  

Microsoft Academic Search

The capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), acts as a polymodal detector of pain-producing chemical and physical stimuli in sensory neurons. Hyperglycemia and hypoxia are two main phenomena in diabetes associated with several complications. Although many studies on streptozotocin-induced diabetic rats indicate that early diabetic neuropathy is associated with potentiation of TRPV1 activity in dorsal root ganglion neurons,

Violeta Ristoiu; Koji Shibasaki; Kunitoshi Uchida; Yiming Zhou; Bich-Hoai Thi Ton; Maria-Luiza Flonta; Makoto Tominaga

2011-01-01

207

Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner.  

PubMed

Hyperalgesia is a cardinal symptom of opioid withdrawal. The transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated ion channel expressed on sensory neurons responding to noxious heat, protons, and chemical stimuli such as capsaicin. TRPV1 can be inhibited via ?-opioid receptor (MOR)-mediated reduced activity of adenylyl cyclases (ACs) and decreased cyclic adenosine monophosphate (cAMP) levels. In contrast, opioid withdrawal following chronic activation of MOR uncovers AC superactivation and subsequent increases in cAMP and protein kinase A (PKA) activity. Here we investigated (1) whether an increase in cAMP during opioid withdrawal increases the activity of TRPV1 and (2) how opioid withdrawal modulates capsaicin-induced nocifensive behavior in rats. We applied whole-cell patch clamp, microfluorimetry, cAMP assays, radioligand binding, site-directed mutagenesis, and behavioral experiments. Opioid withdrawal significantly increased cAMP levels and capsaicin-induced TRPV1 activity in both transfected human embryonic kidney 293 cells and dissociated dorsal root ganglion (DRG) neurons. Inhibition of AC and PKA, as well as mutations of the PKA phosphorylation sites threonine 144 and serine 774, prevented the enhanced TRPV1 activity. Finally, capsaicin-induced nocifensive behavior was increased during opioid withdrawal in vivo. In summary, our results demonstrate an increased activity of TRPV1 in DRG neurons as a new mechanism contributing to opioid withdrawal-induced hyperalgesia. PMID:23398938

Spahn, Viola; Fischer, Oliver; Endres-Becker, Jeannette; Schäfer, Michael; Stein, Christoph; Zöllner, Christian

2013-04-01

208

Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors.  

PubMed

A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway. PMID:22922338

Sung, Bokyung; Prasad, Sahdeo; Ravindran, Jayaraj; Yadav, Vivek R; Aggarwal, Bharat B

2012-11-15

209

Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROSg-JNK-CHOP-mediated upregulation of death receptors  

PubMed Central

A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,–9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine’s ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine’s effects appeared to be mediated via JNK, as shown by capsazepine’s ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS–JNK–CHOP-mediated pathway.

Sung, Bokyung; Prasad, Sahdeo; Ravindran, Jayaraj; Yadav, Vivek R.; Aggarwal, Bharat B.

2013-01-01

210

Role of Transient Receptor Potential Vanilloid 1 in Inflammation and Autoimmune Diseases  

PubMed Central

Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is a receptor activated by high temperatures and chemical agonists such as the vanilloids and protons. Because of these properties, TRPV1 has emerged as a polymodal nocisensor of nociceptive afferent neurons. TRPV1 is thought to be a central transducer of hyperalgesia and a prime target for controlling pain pharmacologically because it is a point where many proalgesic pathways converge and it is upregulated and sensitized by inflammation and injury. However, whether TRPV1 agonists promote or inhibit inflammation remains unclear. We recently demonstrated that SA13353 (1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea), a novel TRPV1 agonist, inhibits tumor necrosis factor-a production by the activation of capsaicin-sensitive afferent neurons and reduces the severity of symptoms in kidney injury, lung inflammation, arthritis, and encephalomyelitis. These results suggest that TRPV1 agonists may act as anti-inflammatories in certain inflammatory and autoimmune conditions in vivo. Given the potential deleterious effects of inhibiting the population of channels with a protective function, caution should be taken in the use of potent TRPV1 antagonists as a general strategy to treat inflammation. Further studies are required to clarify the role of TRPV1 and neuropeptides, which are released because of TRPV1 activation in inflammation and autoimmune diseases.

Tsuji, Fumio; Aono, Hiroyuki

2012-01-01

211

TRPV1 acts as proton channel to induce acidification in nociceptive neurons.  

PubMed

The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca(2+)-dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na(+), Mg(2+), and Ca(2+). The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons. PMID:15173182

Hellwig, Nicole; Plant, Tim D; Janson, Wiebke; Schäfer, Michael; Schultz, Günter; Schaefer, Michael

2004-08-13

212

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

213

Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury.  

PubMed

Cannabinoid receptor type 1 (CB1)-induced suppression of transient receptor potential vanilloid type 1 (TRPV1) activation provides a therapeutic option to reduce inflammation and pain in different animal disease models through mechanisms involving dampening of TRPV1 activation and signaling events. As we found in both mouse corneal epithelium and human corneal epithelial cells (HCEC) that there is CB1 and TRPV1 expression colocalization based on overlap of coimmunostaining, we determined in mouse corneal wound healing models and in human corneal epithelial cells (HCEC) if they interact with one another to reduce TRPV1-induced inflammatory and scarring responses. Corneal epithelial debridement elicited in vivo a more rapid wound healing response in wildtype (WT) than in CB1(-/-) mice suggesting functional interaction between CB1 and TRPV1. CB1 activation by injury is tenable based on the identification in mouse corneas of 2-arachidonylglycerol (2-AG) with tandem LC-MS/MS, a selective endocannabinoid CB1 ligand. Suppression of corneal TRPV1 activation by CB1 is indicated since following alkali burning, CB1 activation with WIN55,212-2 (WIN) reduced immune cell stromal infiltration and scarring. Western blot analysis of coimmunoprecipitates identified protein-protein interaction between CB1 and TRPV1. Other immunocomplexes were also identified containing transforming growth factor kinase 1 (TAK1), TRPV1 and CB1. CB1 siRNA gene silencing prevented suppression by WIN of TRPV1-induced TAK1-JNK1 signaling. WIN reduced TRPV1-induced Ca(2+) transients in fura2-loaded HCEC whereas pertussis toxin (PTX) preincubation obviated suppression by WIN of such rises caused by capsaicin (CAP). Whole cell patch clamp analysis of HCEC showed that WIN blocked subsequent CAP-induced increases in nonselective outward currents. Taken together, CB1 activation by injury-induced release of endocannabinoids such as 2-AG downregulates TRPV1 mediated inflammation and corneal opacification. Such suppression occurs through protein-protein interaction between TRPV1 and CB1 leading to declines in TRPV1 phosphorylation status. CB1 activation of the GTP binding protein, G(i/o) contributes to CB1 mediated TRPV1 dephosphorylation leading to TRPV1 desensitization, declines in TRPV1-induced increases in currents and pro-inflammatory signaling events. PMID:23142606

Yang, Y; Yang, H; Wang, Z; Varadaraj, K; Kumari, S S; Mergler, S; Okada, Y; Saika, S; Kingsley, P J; Marnett, L J; Reinach, P S

2013-02-01

214

Intranasal capsaicin in management of nonallergic (vasomotor) rhinitis.  

PubMed

Capsaicin is a selective transient receptor potential vanilloid 1 (TRPV1) ion channel agonist and has been demonstrated to reduce nerve conduction of nociceptive C fibers in the trigeminal nerve without affecting conduction in Adelta fibers. This chapter reviews the classification of chronic rhinitis subtypes, the prevalence and epidemiology of nonallergic rhinitis (NAR), postulated pathophysiology and mechanisms of NAR including the role of transient receptor potential (TRP) ion channels and discusses the potential therapeutic benefits of capsaicin in the treatment of chronic rhinitis subtypes, specifically NAR. Evidence supports that hypersensitivity of TRP ion channels on sensory afferent neurons innervating nasal mucosa is responsible for inducing NAR symptoms. These symptoms, characterized as excessive nasal glandular secretion, nasal congestion, and headache, are mediated through neuropeptide release during axonal and parasympathetic reflexes which are initiated by a spectrum of nonspecific irritants that activate TRP channels. Rational approaches to treat the pathophysiology of NAR would be to develop therapies with selective TRPV1 agonist activity like capsaicin that target desensitization of TRP ion channels on sensory afferent nerves. PMID:24941668

Singh, Umesh; Bernstein, Jonathan A

2014-01-01

215

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

216

The Basal Thermal Sensitivity of the TRPV1 Ion Channel Is Determined by PKC?II.  

PubMed

Peripheral nociceptors are excited by the activation of membrane receptors and ion channels. The heat-sensitive TRPV1 ion channel responds to various noxious chemical and thermal stimuli, causing pain and itch. Here, we show that TRPV1 is coexpressed with PKC?II in a subset of mouse sensory neurons and that, in these neurons, TRPV1 binds directly to PKC?II, leading to the activation and translocation of PKC?II. Activated PKC?II, in turn, significantly increases the responsiveness of TRPV1 by phosphorylating Thr705. The heat sensitivity of TRPV1 is almost eliminated by either knocking down PKC?II or mutating Thr705; however, neither of these manipulations affects the potentiation of TRPV1 caused by the activation of PKC?. PKC?II thus acts as an auxiliary subunit of TRPV1 by forming a population-dependent TRPV1 ion channel complex controlling the sensitivity of TRPV1 and setting the threshold for pain and itch. PMID:24920628

Li, Lin; Hasan, Raquibul; Zhang, Xuming

2014-06-11

217

Moderate extracellular acidification inhibits capsaicin-induced cell death through regulating calcium mobilization, NF-{kappa}B translocation and ROS production in synoviocytes  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Moderate extracellular acidification regulates intracellular Ca{sup 2+} mobilization. Black-Right-Pointing-Pointer Moderate acidification activates NF-{kappa}B nuclear translocation in synoviocytes. Black-Right-Pointing-Pointer Moderate acidification depresses the ROS production induced by capsaicin. Black-Right-Pointing-Pointer Moderate acidification inhibits capsaicin-caused synoviocyte death. -- Abstract: We previously show the expression of transient receptor potential vanilloid 1 (TRPV1) in primary synoviocytes from collagen-induced arthritis (CIA) rats. Capsaicin and lowered extracellular pH from 7.4 to 5.5 induce cell death through TRPV1-mediated Ca{sup 2+} entry and reactive oxygen species (ROS) production. However, under the pathological condition in rheumatoid arthritis, the synovial fluid is acidified to a moderate level (about pH 6.8). In the present study, we examined the effects of pH 6.8 on the TRPV1-mediated cell death. Our finding is different or even opposite from what was observed at pH 5.5. We found that the moderate extracellular acidification (from pH 7.4 to 6.8) inhibited the capsaicin-induced Ca{sup 2+} entry through attenuating the activity of TRPV1. In the mean time, it triggered a phospholipse C (PLC)-related Ca{sup 2+} release from intracellular stores. The nuclear translocation of NF-{kappa}B was found at pH 6.8, and this also depends on PLC activation. Moreover, the capsaicin-evoked massive ROS production and cell death were depressed at pH 6.8, both of which are dependent on the activation of PLC and NF-{kappa}B. Taken together, these results suggested that the moderate extracellular acidification inhibited the capsaicin-induced synoviocyte death through regulating Ca{sup 2+} mobilization, activating NF-{kappa}B nuclear translocation and depressing ROS production.

Hu, Fen; Yang, Shuang; Zhao, Dan; Zhu, Shuyan; Wang, Yuxiang [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China)] [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China); Li, Junying, E-mail: jyli04@nankai.edu.cn [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China)] [Department of Biophysics, School of Physics and Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071 (China)

2012-07-20

218

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

2012-08-31

219

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

220

Involvement of sensory nerves and TRPV1 receptors in the rat airway inflammatory response to two environment pollutants: diesel exhaust particles (DEP) and 1,2-naphthoquinone (1,2-NQ)  

Microsoft Academic Search

The environmental chemical 1,2-naphthoquinone (1,2-NQ) is implicated in the exacerbation of airways diseases induced by exposure\\u000a to diesel exhaust particles (DEP), which involves a neurogenic-mediated mechanism. Plasma extravasation in trachea, main bronchus\\u000a and lung was measured as the local 125I-bovine albumin accumulation. RT-PCR quantification of TRPV1 and tachykinin (NK1 and NK2) receptor gene expression were investigated in main bronchus. Intratracheal

Aila Mirtes Teles; Yoshito Kumagai; Susan D. Brain; Simone A. Teixeira; Ana A. Varriano; Maria Alice A. G. Barreto; Wothan Tavares de Lima; Edson Antunes; Marcelo N. Muscará; Soraia K. P. Costa

2010-01-01

221

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

222

TRPV1 regulates activation and modulation of TRPA1 by Ca2+  

PubMed Central

The transient receptor potential A1 (TRPA1) channel contributes to nociceptive signaling in certain pain models. It has been suggested that Ca2+, which activates and modulates TRPA1, could play a critical regulatory role in this process. Since TRPA1 and TRPV1 channels are co-expressed and interact in neurons, we investigated whether activation and modulation of TRPA1 by Ca2+ is regulated by TRPV1. Cell-attached recordings showed that TRPA1 is activated by extracellular Ca2+ ([Ca2+]e) in concentration-response fashion. This activation, especially by 2mM [Ca2+]e was substantially suppressed by co-expression with TRPV1. Inside-out recordings demonstrated that intracellular Ca2+ ([Ca2+]i)-triggered activation of TRPA1 was attenuated by the presence of TRPV1 only at 2 mM [Ca2+]e, but not in Ca2+-free conditions. Further, depletion of internal Ca2+ stores by thapsigargin generated TRPA1-mediated currents, which is affected by TRPV1 in both Chinee hamster ovary cells and sensory neurons. Since mustard oil current (IMO) is modulated by [Ca2+]e, we next examined whether alterations in the Ca2+-permeability of TRPV1 by mutating Y671 effect IMO properties. First it was demonstrated that the mutations in TRPV1 did not affect association of the TRPA1 and TRPV1 channels. However, these TRPV1 mutations, particularly Y671K, altered the following characteristics of TRPA1: magnitude of IMO in presence and absence of [Ca2+]e; the influence of [Ca2+]e on the voltage-dependency of IMO, and open probability of single-channel IMO. In summary, activation of TRPA1 by [Ca2+]e and [Ca2+]i is controlled by the TRPV1 channel, and characteristics of IMO depend on Ca2+ permeability of the TRPV1 channel.

Patil, Mayur J.; Jeske, Nathaniel A.; Akopian, Armen N.

2010-01-01

223

TRPV1: ON THE ROAD TO PAIN RELIEF  

PubMed Central

Historically, drug research targeted to pain treatment has focused on trying to prevent the propagation of action potentials in the periphery from reaching the brain rather than pinpointing the molecular basis underlying the initial detection of the nociceptive stimulus: the receptor itself. This has now changed, given that many receptors of nociceptive stimuli have been identified and/or cloned. Transient Receptor Potential (TRP) channels have been implicated in several physiological processes such as mechanical, chemical and thermal stimuli detection. Ten years after the cloning of TRPV1, compelling data has been gathered on the role of this channel in inflammatory and neuropathic states. TRPV1 activation in nociceptive neurons, where it is normally expressed, triggers the release of neuropeptides and transmitters resulting in the generation of action potentials that will be sent to higher CNS areas where they will often be perceived as pain. Its activation also will evoke the peripheral release of pro-inflammatory compounds that may sensitize other neurons to physical, thermal or chemical stimuli. For these reasons as well as because its continuous activation causes analgesia, TRPV1 has become a viable drug target for clinical use in the management of pain. This review will provide a general picture of the physiological and pathophysiological roles of the TRPV1 channel and of its structural, pharmacological and biophysical properties. Finally, it will provide the reader with an overall view of the status of the discovery of potential therapeutic agents for the management of chronic and neuropathic pain.

Jara-Oseguera, Andres; Simon, Sidney A.

2009-01-01

224

5HT 7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice  

Microsoft Academic Search

This work aimed to evaluate the potential role of the 5-HT7 receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT7 receptor agonists: AS-19, MSD-5a, E-55888; 5-HT7 receptor antagonists: SB-258719, SB-269970; 5-HT1A receptor agonist: F-13640; 5-HT1A receptor antagonist: WAY-100635) were assessed on capsaicin-induced mechanical hypersensitivity, a pain behavior involving hypersensitivity of

Alex Brenchat; Luz Romero; Mónica García; Marta Pujol; Javier Burgueńo; Antoni Torrens; Michel Hamon; José Manuel Baeyens; Helmut Buschmann; Daniel Zamanillo; José Miguel Vela

2009-01-01

225

Low pH Potentiates Both Capsaicin Binding and Channel Gating of VR1 Receptors  

PubMed Central

Capsaicin ion channels are highly expressed in peripheral nervous terminals and involved in pain and thermal sensations. One characteristic of the cloned VR1 receptor is its multimodal responses to various types of noxious stimuli. The channel is independently activated by capsaicin and related vanilloids at submicromolar range, by heat above 40°C, and by protons at pH below 6.5. Furthermore, simultaneous applications of two or more stimuli lead to cross sensitization of the receptor, with an apparent increase in the sensitivity to any individual stimulus when applied alone. We studied here the mechanism underlying such cross-sensitization; in particular, between capsaicin and pH, two prototypical stimuli for the channel. By analyzing single-channel currents recorded from excised-patches expressing single recombinant VR1 receptors, we examined the effect of pH on burst properties of capsaicin activation at low concentrations and the effect on gating kinetics at high concentrations. Our results indicate that pH has dual effects on both capsaicin binding and channel gating. Lowering pH enhances the apparent binding affinity of capsaicin, promotes the occurrences of long openings and short closures, and stabilizes at least one of the open conformations of the channel. Our data also demonstrate that capsaicin binding and protonation of the receptor interact allosterically, where the effect of one can be offset by the effect of the other. These results provide important basis to further understand the nature of the activation pathways of the channel evoked by different stimuli as well as the general mechanism underling the cross-sensitization of pain.

Ryu, Sujung; Liu, Beiying; Qin, Feng

2003-01-01

226

Mapping the binding site of TRPV1 on AKAP79: implications for inflammatory hyperalgesia.  

PubMed

Inflammation causes hyperalgesia, an enhanced sensitivity to noxious stimuli. Transient receptor potential vanilloid 1 (TRPV1), a thermo-TRP ion channel activated by painful levels of heat, is an important contributor because hyperalgesia is reduced when TRPV1 is either genetically deleted or pharmacologically blocked. Inflammatory mediators such as prostaglandin-E2 or bradykinin cause hyperalgesia by activating cellular kinases that phosphorylate TRPV1, a process that has recently been shown to rely on a scaffolding protein, AKAP79, to target the kinases to TRPV1. Here we use Förster resonance energy transfer, immunoprecipitation, and TRPV1 membrane trafficking experiments to identify a key region on AKAP79, between amino acids 326-336, which is responsible for its interaction with TRPV1. A peptide identical to this domain inhibited sensitization of TRPV1 in vitro, and when covalently linked to a TAT peptide to promote uptake across the cell membrane the peptide inhibited in vivo inflammatory hyperalgesia in mice. Critically, it did so without affecting pain thresholds in the absence of inflammation. These results suggest that antagonizing the TRPV1-AKAP79 interaction will be a useful strategy for inhibiting inflammatory hyperalgesia. PMID:23699529

Btesh, Joan; Fischer, Michael J M; Stott, Katherine; McNaughton, Peter A

2013-05-22

227

Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity  

PubMed Central

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

Pabbidi, Reddy M; Yu, Shuang-Quan; Peng, Siying; Khardori, Romesh; Pauza, Mary E; Premkumar, Louis S

2008-01-01

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

Sensitization and translocation of TRPV1 by insulin and IGF-I  

PubMed Central

Insulin and insulin-like growth factors (IGFs) maintain vital neuronal functions. Absolute or functional deficiencies of insulin or IGF-I may contribute to neuronal and vascular complications associated with diabetes. Vanilloid receptor 1 (also called TRPV1) is an ion channel that mediates inflammatory thermal nociception and is present on sensory neurons. Here we demonstrate that both insulin and IGF-I enhance TRPV1-mediated membrane currents in heterologous expression systems and cultured dorsal root ganglion neurons. Enhancement of membrane current results from both increased sensitivity of the receptor and translocation of TRPV1 from cytosol to plasma membrane. Receptor tyrosine kinases trigger a signaling cascade leading to activation of phosphatidylinositol 3-kinase (PI(3)K) and protein kinase C (PKC)-mediated phosphorylation of TRPV1, which is found to be essential for the potentiation. These findings establish a link between the insulin family of trophic factors and vanilloid receptors.

Van Buren, Jeremy J; Bhat, Satyanarayan; Rotello, Rebecca; Pauza, Mary E; Premkumar, Louis S

2005-01-01

230

P2X3 and TRPV1 functionally interact and mediate sensitization of trigeminal sensory neurons  

PubMed Central

Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) affect a large percentage of the population. Identifying mechanisms underlying hyperalgesia could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. In this study, we provide evidence of functional interactions between two ligand-gated channels, P2X3 and TRPV1, in trigeminal sensory neurons, and propose that the interactions serve as an underlying mechanism for the development of mechanical hyperalgesia. Mechanical sensitivity of the masseter muscle was assessed in lightly anesthetized rats via an electronic anesthesiometer (Ro et al., 2009). Direct intramuscular injection of a selective P2X3 agonist, ??meATP, induced a dose- and time-dependent hyperalgesia. Mechanical sensitivity in the contralateral muscle was unaffected suggesting local P2X3 mediate the hyperalgesia. Anesthetizing the overlying skin had no effect on ??meATP-induced hyperalgesia confirming the contribution of P2X3 from muscle. Importantly, the ??meATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810. P2X3 was co-expressed with TRPV1 in masseter muscle afferents confirming the possibility for intracellular interactions. Additionally, in a subpopulation of P2X3/TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly amplified following P2X3 activation. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal ganglia cultures. Significant phosphorylation was observed at 15 min, the time point at which behavioral hyperalgesia was prominent. Previously, activation of either P2X3 or TRPV1 had been independently implicated in the development of mechanical hyperalgesia. Our data propose P2X3 and TRPV1 interact in a facilitatory manner, which could contribute to the peripheral sensitization known to underlie masseter hyperalgesia.

Saloman, Jami L.; Chung, Man-Kyo; Ro, Jin Y.

2012-01-01

231

TRPV1 and TRPA1 Function and Modulation are Target Tissue-Dependent  

PubMed Central

The NGF and GDNF families of growth factors regulate the sensitivity of sensory neurons. The ion channels TRPV1 and TRPA1 are necessary for development of inflammatory hypersensitivity and are functionally potentiated by growth factors. We have shown previously that inflamed skin exhibits rapid increases in artemin mRNA with slower, smaller increases in NGF mRNA. Here, using mice we show that in inflamed colon, mRNA for both growth factors increased with a pattern distinct from that seen in skin. Differences were also seen in the pattern of TRPV1 and TRPA1 mRNA expression in DRG innervating inflamed skin and colon. Growth factors potentiated capsaicin (a specific TRPV1 agonist) and mustard oil (a specific TRPA1 agonist) behavioral responses in vivo, raising the question as to how these growth factors affect individual afferents. Because individual tissues are innervated by afferents with unique properties, we investigated modulation of TRPV1 and TRPA1 in identified afferents projecting to muscle, skin and colon. Muscle and colon afferents are twice as likely as skin afferents to express functional TRPV1 and TRPA1. TRPV1 and TRPA1 responses were potentiated by growth factors in all afferent types, but compared to skin afferents, muscle afferents were twice as likely to exhibit NGF-induced potentiation and half as likely to exhibit artemin-induced potentiation of TRPV1. Furthermore, skin afferents showed no GDNF-induced potentiation of TRPA1, but 43% of muscle and 38% of colon afferents exhibited GDNF-induced potentiation. These results show that interpretation of afferent homeostatic mechanisms must incorporate properties that are specific to the target tissue.

Malin, Sacha; Molliver, Derek; Christianson, Julie A.; Schwartz, Erica S.; Cornuet, Pam; Albers, Kathryn M.; Davis, Brian M.

2011-01-01

232

Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin Receptor  

Microsoft Academic Search

The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the ``pain'' pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43°C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in

M. J. Caterina; A. Leffler; A. B. Malmberg; W. J. Martin; J. Trafton; K. R. Petersen-Zeitz; M. Koltzenburg; A. I. Basbaum; D. Julius

2000-01-01

233

Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A.  

PubMed

Botulinum neurotoxin type-A (BoNT-A) is clinically used for patients with pain disorders and dystonia. The precise mechanism whereby BoNT-A controls pain remains elusive. Here, we studied how BoNT-A affects the expression of the transient receptor potential vanilloid subfamily member 1 (TRPV1), a cation channel critically implicated in nociception, in the trigeminal system. Histological studies revealed that subcutaneous BoNT-A injection (0.25, 0.5, or 5 ng/kg) into the face targeted the ophthalmic division of trigeminal ganglion (TG) neurons and decreased TRPV1-immunoreactive neurons in the TG and TRPV1-immunoreactive fibers in rat trigeminal terminals. Of note, TG neurons that received projections from the dura mater, a principal site of headache generation, had reduced TRPV1 expression. BoNT-A-induced cleavage of SNAP25 (synaptosomal-associated protein of 25-kDa) in the TG became obvious 2 days after BoNT-A administration and persisted for at least 14 days. Quantitative real-time RT-PCR (reverse transcription-polymerase chain reaction) data indicated that the TRPV1-decreasing effects of BoNT-A were not mediated by transcriptional downregulation. By employing a surface protein biotin-labeling assay, we demonstrated that BoNT-A inhibited TRPV1 trafficking to the plasma membrane in primary TG neurons. Moreover, Y200F-mutated TRPV1, which is incapable of trafficking to the plasma membrane, was expressed in PC12 cells by transfection, and pharmacological studies revealed that TRPV1 in the cytoplasm was more predisposed to proteasome-mediated proteolysis than plasma membrane-located TRPV1. We conclude that the mechanism by which BoNT-A reduces TRPV1 expression involves the inhibition of TRPV1 plasma membrane trafficking and proteasome-mediated degradation in the cytoplasm. This paradigm seems to explain how BoNT-A alleviates TRPV1-mediated pain. Our data reveal a likely molecular mechanism whereby BoNT-A treatment reduces TRPV1 expression in the trigeminal system and provide important clues to novel therapeutic measures for ameliorating craniofacial pain. PMID:22820141

Shimizu, Toshihiko; Shibata, Mamoru; Toriumi, Haruki; Iwashita, Tatsuo; Funakubo, Megumi; Sato, Hitoshi; Kuroi, Toshiya; Ebine, Taeko; Koizumi, Kenzo; Suzuki, Norihiro

2012-12-01

234

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

235

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

2013-01-01

236

Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury  

PubMed Central

Endogenous agonists of transient receptor potential vanilloid-1 (TRPV1) (endovanilloids) are implicated as mediators of lung injury during inflammation. This study tested the hypothesis that endovanilloids produced following lipopolysaccharide (LPS) treatment activate TRPV1 and cause endoplasmic reticulum stress/GADD153 expression in lung cells, representing a mechanistic component of lung injury. The TRPV1 agonist nonivamide induced GADD153 expression and caused cytotoxicity in immortalized and primary human bronchial, bronchiolar/alveolar, and microvascular endothelial cells, proportional to TRPV1 mRNA expression. In CF-1 mice, Trpv1 mRNA was most abundant in the alveoli, and intratracheal nonivamide treatment promoted Gadd153 expression in the alveolar region. Treatment of CF-1 mice with LPS increased Gadd153 in the lung, lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, and lung wet-to-dry weight ratio. Cotreating mice with LPS and the TRPV1 antagonist LJO-328 reduced Gadd153 induction and LDH in BAL but did not inhibit increases in lung wet-to-dry ratio. In Trpv1?/? mice treated with LPS, Gadd153 induction and LDH in BAL were reduced relative to wild-type mice, and the wet-to-dry weight ratios of lungs from both wild-type and Trpv1?/? mice decreased. Organic extracts of blood collected from LPS-treated mice were more cytotoxic to TRPV1-overexpressing cells compared with BEAS-2B cells and extracts from control mice, however, most pure endovanilloids did not produce cytotoxicity in a characteristic TRPV1-dependent manner. Collectively, these data indicate a role for TRPV1, and endogenous TRPV1 agonists, in ER stress and cytotoxicity in lung cells but demonstrate that ER stress and cytotoxicity are not essential for pulmonary edema.

Thomas, Karen C.; Roberts, Jessica K.; Deering-Rice, Cassandra E.; Romero, Erin G.; Dull, Randal O.; Lee, Jeewoo; Yost, Garold S.

2012-01-01

237

Activation of vanilloid receptor type I in the endoplasmic reticulum fails to activate store-operated Ca2+ entry.  

PubMed

To evaluate interaction of vanilloid receptor type 1 (TRPV1) with endogenous Ca(2+) signalling mechanisms, TRPV1 was expressed in Spodoptera frugiperda (Sf 9) insect cells using recombinant baculovirus. Stimulation of TRPV1-expressing cells, but not control Sf 9 cells, with resiniferatoxin (RTX), capsaicin or anandamide, produced an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), with EC(50) values of 166 pM, 24.5 nM and 3.89 microM respectively. In the absence of extracellular Ca(2+), both capsaicin and RTX caused an increase in [Ca(2+)](i) with EC(50) values of approx. 10 microM and 10 nM respectively. This TRPV1-induced release of Ca(2+) from intracellular stores was not blocked by U73122, suggesting that phospholipase C was not involved. Substantial overlap was found between the thapsigargin- and RTX-sensitive internal Ca(2+) pools, and confocal imaging showed that intracellular TRPV1 immunofluorescence co-localized with the endoplasmic reticulum targeting motif KDEL. To determine if TRPV1-induced mobilization of intracellular Ca(2+) activates endogenous store-operated Ca(2+) entry, the effect of 2-aminoethoxydiphenyl borate (2-APB) on Ba(2+) influx was examined. 2-APB blocked thapsigargin-induced Ba(2+) influx, but not RTX-induced Ba(2+) entry. In the combined presence of thapsigargin and a store-releasing concentration of RTX, the 2-APB-sensitive component was essentially identical with the thapsigargin-induced component. Similar results were obtained in HEK-293 cells stably expressing TRPV1. These results suggest that TRPV1 forms agonist-sensitive channels in the endoplasmic reticulum, which when activated, release Ca(2+) from internal stores, but fail to activate endogenous store-operated Ca(2+) entry. Selective activation of intracellular TRPV1, without concomitant involvement of plasmalemmal Ca(2+) influx mechanisms, could play an important role in Ca(2+) signalling within specific subcellular microdomains. PMID:12608892

Wisnoskey, Brian J; Sinkins, William G; Schilling, William P

2003-06-01

238

Activation of vanilloid receptor type I in the endoplasmic reticulum fails to activate store-operated Ca2+ entry.  

PubMed Central

To evaluate interaction of vanilloid receptor type 1 (TRPV1) with endogenous Ca(2+) signalling mechanisms, TRPV1 was expressed in Spodoptera frugiperda (Sf 9) insect cells using recombinant baculovirus. Stimulation of TRPV1-expressing cells, but not control Sf 9 cells, with resiniferatoxin (RTX), capsaicin or anandamide, produced an increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)), with EC(50) values of 166 pM, 24.5 nM and 3.89 microM respectively. In the absence of extracellular Ca(2+), both capsaicin and RTX caused an increase in [Ca(2+)](i) with EC(50) values of approx. 10 microM and 10 nM respectively. This TRPV1-induced release of Ca(2+) from intracellular stores was not blocked by U73122, suggesting that phospholipase C was not involved. Substantial overlap was found between the thapsigargin- and RTX-sensitive internal Ca(2+) pools, and confocal imaging showed that intracellular TRPV1 immunofluorescence co-localized with the endoplasmic reticulum targeting motif KDEL. To determine if TRPV1-induced mobilization of intracellular Ca(2+) activates endogenous store-operated Ca(2+) entry, the effect of 2-aminoethoxydiphenyl borate (2-APB) on Ba(2+) influx was examined. 2-APB blocked thapsigargin-induced Ba(2+) influx, but not RTX-induced Ba(2+) entry. In the combined presence of thapsigargin and a store-releasing concentration of RTX, the 2-APB-sensitive component was essentially identical with the thapsigargin-induced component. Similar results were obtained in HEK-293 cells stably expressing TRPV1. These results suggest that TRPV1 forms agonist-sensitive channels in the endoplasmic reticulum, which when activated, release Ca(2+) from internal stores, but fail to activate endogenous store-operated Ca(2+) entry. Selective activation of intracellular TRPV1, without concomitant involvement of plasmalemmal Ca(2+) influx mechanisms, could play an important role in Ca(2+) signalling within specific subcellular microdomains.

Wisnoskey, Brian J; Sinkins, William G; Schilling, William P

2003-01-01

239

Transient receptor potential vanilloid 1 - a polymodal nociceptive receptor - plays a crucial role in formaldehyde-induced skin inflammation in mice.  

PubMed

Formaldehyde (FA) is irritating to the skin and is the main cause of sick building syndrome. However, the cutaneous reaction induced by long-term FA exposure has not been fully investigated. In our previous study, we demonstrated that repeated painting of 2% - 10% FA on mouse ears caused marked ear swelling and increased mRNA expression of transient receptor potential vanilloid 1 (TRPV1) and neurotrophins in the ear. TRPV1 is reported to be involved in neurogenic inflammation; therefore, in the present study, we investigated the role of TRPV1 in FA-induced skin inflammation using TRPV1 gene-knockout mice. Mice were painted with 5% FA once a week for 5 weeks, and ear swelling and mRNA expression were investigated. Ear swelling and increased expression of neurotrophins mRNA by FA provocation in wild-type mice were attenuated by disruption of the TRPV1 gene. Furthermore, painting with a threshold dose of capsaicin, which does not induce ear swelling in intact mice, caused marked ear swelling after painting the ear 5 times with FA, indicating that inflamed tissues after FA application are hypersensitive to various ligands of TRPV1 in mice. These results demonstrated that neurogenic inflammation via TRPV1 and neurotrophins could be involved in FA-induced dermatitis. PMID:22302023

Usuda, Haruki; Endo, Takumi; Shimouchi, Ayumi; Saito, Asaka; Tominaga, Makoto; Yamashita, Hirotaka; Nagai, Hiroichi; Inagaki, Naoki; Tanaka, Hiroyuki

2012-01-01

240

The functions of TRPA1 and TRPV1: moving away from sensory nerves.  

PubMed

The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation. PMID:22233379

Fernandes, E S; Fernandes, M A; Keeble, J E

2012-05-01

241

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

242

Zingerone enhances glutamatergic spontaneous excitatory transmission by activating TRPA1 but not TRPV1 channels in the adult rat substantia gelatinosa.  

PubMed

Transient receptor potential (TRP) channels are thought to play a role in regulating nociceptive transmission to spinal substantia gelatinosa (SG) neurons. It remains to be unveiled whether the TRP channels in the central nervous system are different in property from those involved in receiving nociceptive stimuli in the peripheral nervous system. We examined the effect of the vanilloid compound zingerone, which activates TRPV1 channels in the cell body of a primary afferent neuron, on glutamatergic excitatory transmission in the SG neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. Bath-applied zingerone reversibly and concentration-dependently increased spontaneous excitatory postsynaptic current (EPSC) frequency. This effect was accompanied by an inward current at -70 mV that was resistant to glutamate receptor antagonists. These zingerone effects were repeated and persisted in Na(+)-channel blocker tetrodotoxin-, La(3+)-, or IP3-induced Ca(2+)-release inhibitor 2-aminoethoxydiphenyl borate-containing or Ca(2+)-free Krebs solution. Zingerone activity was resistant to the selective TRPV1 antagonist capsazepine but sensitive to the nonselective TRP antagonist ruthenium red, the TRPA1 antagonist HC-030031, and the Ca(2+)-induced Ca(2+)-release inhibitor dantrolene. TRPA1 agonist allyl isothiocyanate but not capsaicin inhibited the facilitatory effect of zingerone. On the other hand, zingerone reduced monosynaptically evoked EPSC amplitudes, as did TRPA1 agonists. Like allyl isothiocyanate, zingerone enhanced GABAergic spontaneous inhibitory transmission in a manner sensitive to tetrodotoxin. We conclude that zingerone presynaptically facilitates spontaneous excitatory transmission, probably through Ca(2+)-induced Ca(2+)-release mechanisms, and produces a membrane depolarization in SG neurons by activating TRPA1 but not TRPV1 channels. PMID:23657286

Yue, Hai-Yuan; Jiang, Chang-Yu; Fujita, Tsugumi; Kumamoto, Eiichi

2013-08-01

243

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

244

Osmosensitivity of transient receptor potential vanilloid 1 is synergistically enhanced by distinct activating stimuli such as temperature and protons.  

PubMed

In animals, body-fluid osmolality is continuously monitored to keep it within a narrow range around a set point (?300 mOsm/kg). Transient receptor potential vanilloid 1 (TRPV1), a cation channel, has been implicated in body-fluid homeostasis in vivo based on studies with the TRPV1-knockout mouse. However, the response of TRPV1 to hypertonic stimuli has not been demonstrated with heterologous expression systems so far, despite intense efforts by several groups. Thus, the molecular entity of the hypertonic sensor in vivo still remains controversial. Here we found that the full-length form of TRPV1 is sensitive to an osmotic increase exclusively at around body temperature using HEK293 cells stably expressing rat TRPV1. At an ambient temperature of 24°C, a slight increase in the intracellular calcium concentration ([Ca(2+)](i)) was rarely observed in response to hypertonic stimuli. However, the magnitude of the osmosensitive response markedly increased with temperature, peaking at around 36°C. Importantly, the response at 36°C showed a robust increase over a hypertonic range, but a small decrease over a hypotonic range. A TRPV1 antagonist, capsazepine, and a nonspecific TRP channel inhibitor, ruthenium red, completely blocked the increase in [Ca(2+)](i). These results endorse the view that the full-length form of TRPV1 is able to function as a sensor of hypertonic stimuli in vivo. Furthermore, we found that protons and capsaicin likewise synergistically potentiated the response of TRPV1 to hypertonic stimuli. Of note, HgCl(2), which blocks aquaporins and inhibits cell-volume changes, significantly reduced the osmosensitive response. Our findings thus indicate that TRPV1 integrates multiple different types of activating stimuli, and that TRPV1 is sensitive to hypertonic stimuli under physiologically relevant conditions. PMID:21779403

Nishihara, Eri; Hiyama, Takeshi Y; Noda, Masaharu

2011-01-01

245

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

PubMed Central

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 arthritis model in rats, as well as primary and clonal human synoviocyte cultures were used to understand the reciprocal interactions between reactive nitroxidative species (ROS) and functional TRPV1 channels. ROS generation was monitored with ROS sensitive dyes using live cell imaging in vitro and in spinal tissue histology, as well as with measurement of ROS metabolites in culture media using HPLC. Results Functional responses in the experimental arthritis model, including increased nociceptive responses (thermal and mechanical hyperalgesia and allodynia), knee joint temperature reflecting local blood flow, and spinal cord ROS elevations were reduced by the ROS scavenger PBN after intraperitoneal pretreatment. Increases in TRPV1 and ROS, generated by synoviocytes in vitro, were reciprocally blocked by TRPV1 antagonists and the ROS scavenger. Further evidence is presented that synoviocyte responses to ROS and TRPV1 activation include increases in TNF? and COX-2, both measured as an indicator of the inflammation in vitro. Conclusions The results demonstrate that contributions of ROS to pronociceptive responses and neurogenic inflammation are mediated both centrally and peripherally. Responses are mediated by TRPV1 locally in the knee joint by synoviocytes, as well as by ROS-induced sensitization in the spinal cord. These findings and those of others reported in the literature indicate reciprocal interactions between TRPV1 and ROS play critical roles in the pathological and nociceptive responses active during arthritic inflammation.

2010-01-01

246

Capsaicin-induced relaxation in the rat isolated external urethral sphincter: characterization of the vanilloid receptor and mediation by CGRP.  

PubMed Central

1. The potential role of capsaicin-sensitive nerves in the relaxation of the rat external urethral sphincter (REUS) was evaluated by demonstrating the existence of specific vanilloid (capsaicin) receptors and by investigating the sensory neurotransmitter(s) putatively involved in this relaxation. 2. Capsaicin (1 microM) relaxed REUS strips precontracted with noradrenaline (NA) (0.1 mM). This effect underwent desensitization and it was absent in preparations taken from adult capsaicin-pretreated rats. 3. Capsaicin-induced relaxation of NA-precontracted REUS was mimicked by calcitonin gene-related peptide (CGRP, 0.3-10 microM), but not by substance P (1 microM), vasoactive intestinal polypeptide (VIP, 1 microM), alpha-beta methylene ATP (10 microM), gamma-aminobutyric acid (GABA, 3 mM) or galanin (1 microM). A cross-tachyphylaxis between capsaicin (1 microM) and CGRP (1 microM) was observed. Both capsaicin and CGRP-induced relaxation were partially antagonized by the proposed CGRP antagonist, CGRP (8-37) (10 microM). 4. Electrical field stimulation (EFS, 2.5 Hz, 60 V, 1 ms, trains of 5 s every 5 min) of REUS evoked a contraction characterized by a largely adrenergic slowly developing tonic contraction with superimposed fast twitches due to the striated component of the strips. Both capsaicin (1 microM) and CGRP (0.01-1 microM) produced an almost complete inhibition of EFS-induced tonic contraction. A cross-tachyphylaxis between capsaicin and CGRP was observed. Furthermore, these inhibitory actions were unaffected by CGRP (8-37) (10 microM). 5. [3H]-resiniferatoxin displayed specific, saturable binding to rat urethral membranes. Data were consistent with a single site with a Kd of 105 pM and a Bmax of 40 fmol mg-1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Parlani, M.; Conte, B.; Goso, C.; Szallasi, A.; Manzini, S.

1993-01-01

247

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

248

The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors.  

PubMed

Palmitoylethanolamide (PEA) is an endogenous lipid that is thought to be involved in endogenous protective mechanisms activated as a result of stimulation of inflammatory response. In spite of the well demonstrated anti-inflammatory properties of PEA, its involvement in controlling pain pathways still remains poorly characterized. On this basis, we tested the efficacy of PEA in vivo against a peculiar persistent pain, such as neuropathic one. PEA was administered i.p. to mice with chronic constriction injury of sciatic nerve (CCI) once a day for one week starting the day after the lesion. This therapeutic regimen evoked a relief of both thermal hyperalgesia and mechanical allodynia in neuropathic mice. Various selective receptor antagonists were used in order to clarify the relative contribution of cannabinoid, vanilloid and peroxisome proliferator-activated receptor to PEA-induced effects. The results indicated that CB(1), PPARgamma and TRPV1 receptors mediated the antinociception induced by PEA, suggesting that the most likely mechanism might be the so-called "entourage effect" due to the PEA-induced inhibition of the enzyme catalyzing the endocannabinoid anandamide (AEA) degradation that leads to an enhancement of its tissue levels thus increasing its analgesic action. In addition, the hypothesis that PEA might act through the modulation of local mast cells degranulation is sustained by our findings showing that PEA significantly reduced the production of many mediators such as TNFalpha and neurotrophic factors, like NGF. The findings presented here, in addition to prove the beneficial effects of PEA in chronic pain, identify new potential targets for analgesic medicine. PMID:18602217

Costa, Barbara; Comelli, Francesca; Bettoni, Isabella; Colleoni, Mariapia; Giagnoni, Gabriella

2008-10-31

249

Proton-induced calcitonin gene-related peptide release from rat sciatic nerve axons, in vitro, involving TRPV1.  

PubMed

We have shown previously that rat sciatic nerve axons in vitro express sensitivity to capsaicin and heat and responded to these stimuli with a Ca2+-dependent and graded immunoreactive calcitonin gene-related peptide release. Morphological evidence for stimulated vesicular exocytosis and for the vanilloid receptor TRPV1 in the axolemma of the unmyelinated nerve fibres has also been presented. Here we used solutions of low pH, high K+ or 47 degrees C to stimulate isolated desheathed sciatic nerves measuring immunoreactive calcitonin gene-related peptide release. pH 6.1 increased immunoreactive calcitonin gene-related peptide release by 31% over baseline and pH 5.2 and 4.3 caused a log-linear concentration-dependent increase of 137 and 265%, respectively. The effect of pH 3.4 was out of the linear range and not reversible. Stimulation in Ca2+-free solutions and under increased intracellular Ca2+ buffering capacity strongly reduced the proton responses. The TRPV1 antagonists capsazepine and ruthenium red substantially reduced the effects of pH 5.2 but not pH 6.1. Combining a stimulus of 60 mm K+ with the subliminal pH 6.3 reduced the axonal immunoreactive calcitonin gene-related peptide response by 88%. The noxious heat response at pH 6.3, however, was only reduced by 39%, suggesting a hidden sensitization to heat by low pH. This was supported by an effect of capsazepine to reduce the combined response to half, indicative of an involvement of TRPV1 in the sensitization but not in the axonal heat response itself that was found to be resistant to capsazepine. Axonal calcitonin gene-related peptide release is thought to play a physiological role in activity-dependent autoregulation of endoneurial blood flow. Axonal sensitivity to and sensitization by protons may be a pathophysiological mechanism involved in certain peripheral neuropathies. PMID:12925006

Fischer, Michael J M; Reeh, Peter W; Sauer, Susanne K

2003-08-01

250

Involvement of peripheral TRPV1 in TMJ hyperalgesia induced by ethanol withdrawal  

Microsoft Academic Search

Ethanol withdrawal increases nociception after the injection of formalin into the rat's temporomandibular joint (TMJ). Little is known about the neurological basis for hyperalgesia induced by ethanol withdrawal, but it has been reported that ethanol can potentiate the response of transient receptor potential vanilloid receptor-1 (TRPV1) in superficial tissues. The present study was designed to test the hypothesis that peripheral

Marília Bertoldo Urtado; Gustavo Hauber Gameiro; Cláudia Herrera Tambeli; Luana Fischer; Christiano Bertoldo Urtado; Maria Cecília Ferraz de Arruda Veiga

2007-01-01

251

Mechanisms of transient receptor potential vanilloid 1 activation and sensitization by allyl isothiocyanate.  

PubMed

Allyl isothiocyanate (AITC; aka, mustard oil) is a powerful irritant produced by Brassica plants as a defensive trait against herbivores and confers pungency to mustard and wasabi. AITC is widely used experimentally as an inducer of acute pain and neurogenic inflammation, which are largely mediated by the activation of nociceptive cation channels transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 (TRPV1). Although it is generally accepted that electrophilic agents activate these channels through covalent modification of cytosolic cysteine residues, the mechanism underlying TRPV1 activation by AITC remains unknown. Here we show that, surprisingly, AITC-induced activation of TRPV1 does not require interaction with cysteine residues, but is largely dependent on S513, a residue that is involved in capsaicin binding. Furthermore, AITC acts in a membrane-delimited manner and induces a shift of the voltage dependence of activation toward negative voltages, which is reminiscent of capsaicin effects. These data indicate that AITC acts through reversible interactions with the capsaicin binding site. In addition, we show that TRPV1 is a locus for cross-sensitization between AITC and acidosis in nociceptive neurons. Furthermore, we show that residue F660, which is known to determine the stimulation by low pH in human TRPV1, is also essential for the cross-sensitization of the effects of AITC and low pH. Taken together, these findings demonstrate that not all reactive electrophiles stimulate TRPV1 via cysteine modification and help understanding the molecular bases underlying the surprisingly large role of this channel as mediator of the algesic properties of AITC. PMID:23757176

Gees, Maarten; Alpizar, Yeranddy A; Boonen, Brett; Sanchez, Alicia; Everaerts, Wouter; Segal, Andrei; Xue, Fenqin; Janssens, Annelies; Owsianik, Grzegorz; Nilius, Bernd; Voets, Thomas; Talavera, Karel

2013-09-01

252

Capsaicin stimulates the non-store-operated Ca2+ entry but inhibits the store-operated Ca2+ entry in neutrophils.  

PubMed

Rat neutrophils express the mRNA encoding for transient receptor potential (TRP) V1. However, capsaicin-stimulated [Ca2+]i elevation occurred only at high concentrations (> or = 100 microM). This response was substantially decreased in a Ca2+-free medium. Vanilloids displayed similar patterns of Ca2+ 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 Ca2+ response was not affected by 8-bromo-cyclic ADP-ribose (8-Br-cADPR), the ryanodine receptor blocker, but was slightly attenuated by 1-[6-[17beta-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 Ca2+ (SOC) channels, 2-aminoethyldiphenyl borate (2-APB), the blocker of D-myo-inositol 1,4,5-trisphospahte (IP3) receptor and Ca2+ influx, and by ruthenium red, a blocker of TRPV channels, and enhanced by the Ca2+ channels blocker, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL-12330A) and Na+-deprivation. In addition, capsaicin had no effect on the plasma membrane Ca2+-ATPase activity or the production of nitric oxide (NO) and reactive oxygen intermediates (ROI) or on the total thiols content. Capsaicin (> or = 100 microM) inhibited the cyclopiazonic acid (CPA)-induced store-operated Ca2+ entry (SOCE). In the absence of external Ca2+, the robust Ca2+ entry after subsequent addition of Ca2+ 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. PMID:15882882

Wang, Jih-Pyang; Tseng, Chia-Shun; Sun, Shu-Ping; Chen, Yu-San; Tsai, Chi-Ren; Hsu, Mei-Feng

2005-12-01

253

Role of the transient receptor potential vanilloid type 1 receptor and stretch-activated ion channels in nitric oxide release from endothelial cells of the aorta and heart in rats.  

PubMed

Shear stress stimulates nitric oxide (NO) release in endothelial cells. Stretch-activated ion channels (SACs) and the transient receptor potential vanilloid type 1 (TRPV1) receptor respond to mechanical stimulus and are permeable to Na(+), Ca(2+) and K(+). The influence of SACs and the TRPV1 receptor on NO release on the heart and on the vascular reactivity of the thoracic aorta (TA) was studied. Experiments were performed in isolated perfused heart, cultured endothelial cells and TA rings from Wistar rats. Capsaicin (10 ?M, 30 ?M) was used as a NO release stimulator, capsazepine (6 ?M, 10 ?M) was used as a capsaicin antagonist and gadolinium (3 ?M, 5 ?M) was used as an inhibitor of SACs. NO was measured by the Kelm and Tenorio methods. Left ventricular pressure was recorded and coronary vascular resistance was calculated. Capsaicin increased NO release in the heart by 58% (395±8 pmol/mL to 627±23 pmol/mL). Capsazepine and gadolinium inhibited NO release by 74% and 82%, respectively. This tendency was similar in all experimental models. Capsaicin attenuated the effects of norepinephrine (10 M to 7 M) on TA and had no effect in the presence of N (?)-nitro-L-arginine methyl ester. Therefore, the authors conclude that SACs and the TRPV1 receptor are both present in the coronary endothelium and that both participate in Ca(2+)-dependent NO release. PMID:23620694

Torres-Narváez, Juan Carlos; Mondragón, Leonardo Del Valle; Varela López, Elvira; Pérez-Torres, Israel; Díaz Juárez, Julieta Anabell; Suárez, Jorge; Hernández, Gustavo Pastelín

2012-09-01

254

Role of the transient receptor potential vanilloid type 1 receptor and stretch-activated ion channels in nitric oxide release from endothelial cells of the aorta and heart in rats  

PubMed Central

Shear stress stimulates nitric oxide (NO) release in endothelial cells. Stretch-activated ion channels (SACs) and the transient receptor potential vanilloid type 1 (TRPV1) receptor respond to mechanical stimulus and are permeable to Na+, Ca2+ and K+. The influence of SACs and the TRPV1 receptor on NO release on the heart and on the vascular reactivity of the thoracic aorta (TA) was studied. Experiments were performed in isolated perfused heart, cultured endothelial cells and TA rings from Wistar rats. Capsaicin (10 ?M, 30 ?M) was used as a NO release stimulator, capsazepine (6 ?M, 10 ?M) was used as a capsaicin antagonist and gadolinium (3 ?M, 5 ?M) was used as an inhibitor of SACs. NO was measured by the Kelm and Tenorio methods. Left ventricular pressure was recorded and coronary vascular resistance was calculated. Capsaicin increased NO release in the heart by 58% (395±8 pmol/mL to 627±23 pmol/mL). Capsazepine and gadolinium inhibited NO release by 74% and 82%, respectively. This tendency was similar in all experimental models. Capsaicin attenuated the effects of norepinephrine (10 M to 7 M) on TA and had no effect in the presence of N?-nitro-L-arginine methyl ester. Therefore, the authors conclude that SACs and the TRPV1 receptor are both present in the coronary endothelium and that both participate in Ca2+-dependent NO release.

Torres-Narvaez, Juan Carlos; Mondragon, Leonardo del Valle; Varela Lopez, Elvira; Perez-Torres, Israel; Diaz Juarez, Julieta Anabell; Suarez, Jorge; Hernandez, Gustavo Pastelin

2012-01-01

255

Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig  

PubMed Central

Background and Purpose Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis. Experimental Approach The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined. Key Results SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03–1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ?50% at 10 mg·kg?1 (oral), non-micronized 10 mg·mL?1 or 1 mg·mL?1 micronized SB-705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB-705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg·mL?1, intranasal) inhibited 10% hypertonic saline responses by 70%. Conclusions and Implications The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin-induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB-705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis.

Changani, Kumar; Hotee, Sarah; Campbell, Simon; Pindoria, Kashmira; Dinnewell, Laura; Saklatvala, Paula; Thompson, Sally-Anne; Coe, Diane; Biggadike, Keith; Vitulli, Giovanni; Lines, Marion; Busza, Albert; Denyer, Jane

2013-01-01

256

TRPV1-Dependent and -Independent Alterations in the Limbic Cortex of Neuropathic Mice: Impact on Glial Caspases and Pain Perception  

PubMed Central

During neuropathic pain, caspases are activated in the limbic cortex. We investigated the role of TRPV1 channels and glial caspases in the mouse prelimbic and infralimbic (PL-IL) cortex after spared nerve injury (SNI). Reverse transcriptase-polymerase chain reaction, western blots, and immunfluorescence showed overexpression of several caspases in the PL-IL cortex 7 days postinjury. Caspase-3 release and upregulation of AMPA receptors in microglia, caspase-1 and IL-1? release in astrocytes, and upregulation of Il-1 receptor-1, TRPV1, and VGluT1 in glutamatergic neurons, were also observed. Of these alterations, only those in astrocytes persisted in SNI Trpv1?/? mice. A pan-caspase inhibitor, injected into the PL-IL cortex, reduced mechanical allodynia, this effect being reduced but not abolished in Trpv1?/? mice. Single-unit extracellular recordings in vivo following electrical stimulation of basolateral amygdala or application of pressure on the hind paw, showed increased excitatory pyramidal neuron activity in the SNI PL-IL cortex, which also contained higher levels of the endocannabinoid 2-arachidonoylglycerol. Intra-PL-IL cortex injection of mGluR5 and NMDA receptor antagonists and AMPA exacerbated, whereas TRPV1 and AMPA receptor antagonists and a CB1 agonist inhibited, allodynia. We suggest that SNI triggers both TRPV1-dependent and independent glutamate- and caspase-mediated cross-talk among IL-PL cortex neurons and glia, which either participates or counteracts pain.

Giordano, Catia; Cristino, Luigia; Luongo, Livio; Siniscalco, Dario; Petrosino, Stefania; Piscitelli, Fabiana; Marabese, Ida; Gatta, Luisa; Rossi, Francesca; Imperatore, Roberta; Palazzo, Enza; de Novellis, Vito; Di Marzo, Vincenzo

2012-01-01

257

TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception.  

PubMed

During neuropathic pain, caspases are activated in the limbic cortex. We investigated the role of TRPV1 channels and glial caspases in the mouse prelimbic and infralimbic (PL-IL) cortex after spared nerve injury (SNI). Reverse transcriptase-polymerase chain reaction, western blots, and immunfluorescence showed overexpression of several caspases in the PL-IL cortex 7 days postinjury. Caspase-3 release and upregulation of AMPA receptors in microglia, caspase-1 and IL-1? release in astrocytes, and upregulation of Il-1 receptor-1, TRPV1, and VGluT1 in glutamatergic neurons, were also observed. Of these alterations, only those in astrocytes persisted in SNI Trpv1(-/-) mice. A pan-caspase inhibitor, injected into the PL-IL cortex, reduced mechanical allodynia, this effect being reduced but not abolished in Trpv1(-/-) mice. Single-unit extracellular recordings in vivo following electrical stimulation of basolateral amygdala or application of pressure on the hind paw, showed increased excitatory pyramidal neuron activity in the SNI PL-IL cortex, which also contained higher levels of the endocannabinoid 2-arachidonoylglycerol. Intra-PL-IL cortex injection of mGluR5 and NMDA receptor antagonists and AMPA exacerbated, whereas TRPV1 and AMPA receptor antagonists and a CB(1) agonist inhibited, allodynia. We suggest that SNI triggers both TRPV1-dependent and independent glutamate- and caspase-mediated cross-talk among IL-PL cortex neurons and glia, which either participates or counteracts pain. PMID:22139792

Giordano, Catia; Cristino, Luigia; Luongo, Livio; Siniscalco, Dario; Petrosino, Stefania; Piscitelli, Fabiana; Marabese, Ida; Gatta, Luisa; Rossi, Francesca; Imperatore, Roberta; Palazzo, Enza; de Novellis, Vito; Di Marzo, Vincenzo; Maione, Sabatino

2012-11-01

258

Acute Heat-Evoked Temperature Sensation Is Impaired but Not Abolished in Mice Lacking TRPV1 and TRPV3 Channels  

PubMed Central

The discovery of heat-sensitive Transient Receptor Potential Vanilloid ion channels (ThermoTRPVs) greatly advanced our molecular understanding of acute and injury-evoked heat temperature sensation. ThermoTRPV channels are activated by partially overlapping temperatures ranging from warm to supra-threshold noxious heat. TRPV1 is activated by noxious heat temperature whereas TRPV3 can be activated by warm as well as noxious heat temperatures. Loss-of-function studies in single TRPV1 and TRPV3 knock-out mice have shown that heat temperature sensation is not completely abolished suggesting functional redundancies among these two channels and highlighting the need of a detailed analysis of TRPV1::TRPV3 double knock-out mice (V1V3dKO) which is hampered by the close proximity of the loci expressing the two channels. Here we describe the generation of a novel mouse model in which trpv1 and trpv3 genes have been inactivated using bacterial artificial chromosome (BAC)-based homologous recombination in embryonic stem cells. In these mice, using classical thermosensory tests such hot plate, tail flick and the thermotaxis gradient paradigms, we confirm that TRPV1 is the master channel for sensing noxious heat temperatures and identify a cooperative role of TRPV1 and TRPV3 for sensing a well-defined window of acute moderate heat temperature. Using the dynamic hot plate assay, we unravel an intriguing and unexpected pronounced escape behavior in TRPV1 knock-out mice that was attenuated in the V1V3dKO. Together, and in agreement with the temperature activation overlap between TRPV1 and TRPV3 channels, our data provide in vivo evidence of a cooperative role between skin-derived TRPV3 and primary sensory neurons-enriched TRPV1 in modulation of moderate and noxious heat temperature sensation and suggest that other mechanisms are required for heat temperature sensation.

Reynders, Ana; Gaillard, Stephane; Moqrich, Aziz

2014-01-01

259

Acute Heat-Evoked Temperature Sensation Is Impaired but Not Abolished in Mice Lacking TRPV1 and TRPV3 Channels.  

PubMed

The discovery of heat-sensitive Transient Receptor Potential Vanilloid ion channels (ThermoTRPVs) greatly advanced our molecular understanding of acute and injury-evoked heat temperature sensation. ThermoTRPV channels are activated by partially overlapping temperatures ranging from warm to supra-threshold noxious heat. TRPV1 is activated by noxious heat temperature whereas TRPV3 can be activated by warm as well as noxious heat temperatures. Loss-of-function studies in single TRPV1 and TRPV3 knock-out mice have shown that heat temperature sensation is not completely abolished suggesting functional redundancies among these two channels and highlighting the need of a detailed analysis of TRPV1::TRPV3 double knock-out mice (V1V3dKO) which is hampered by the close proximity of the loci expressing the two channels. Here we describe the generation of a novel mouse model in which trpv1 and trpv3 genes have been inactivated using bacterial artificial chromosome (BAC)-based homologous recombination in embryonic stem cells. In these mice, using classical thermosensory tests such hot plate, tail flick and the thermotaxis gradient paradigms, we confirm that TRPV1 is the master channel for sensing noxious heat temperatures and identify a cooperative role of TRPV1 and TRPV3 for sensing a well-defined window of acute moderate heat temperature. Using the dynamic hot plate assay, we unravel an intriguing and unexpected pronounced escape behavior in TRPV1 knock-out mice that was attenuated in the V1V3dKO. Together, and in agreement with the temperature activation overlap between TRPV1 and TRPV3 channels, our data provide in vivo evidence of a cooperative role between skin-derived TRPV3 and primary sensory neurons-enriched TRPV1 in modulation of moderate and noxious heat temperature sensation and suggest that other mechanisms are required for heat temperature sensation. PMID:24925072

Marics, Irčne; Malapert, Pascale; Reynders, Ana; Gaillard, Stéphane; Moqrich, Aziz

2014-01-01

260

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

261

Ultrastructural analysis of the synaptic connectivity of TRPV1-expressing primary afferent terminals in the rat trigeminal caudal nucleus.  

PubMed

Trigeminal primary afferents that express the transient receptor potential vanilloid 1 (TRPV1) are important for the transmission of orofacial nociception. However, little is known about how the TRPV1-mediated nociceptive information is processed at the first relay nucleus in the central nervous system (CNS). To address this issue, we studied the synaptic connectivity of TRPV1-positive (+) terminals in the rat trigeminal caudal nucleus (Vc) by using electron microscopic immunohistochemistry and analysis of serial thin sections. Whereas the large majority of TRPV1+ terminals made synaptic contacts of an asymmetric type with one or two postsynaptic dendrites, a considerable fraction also participated in complex glomerular synaptic arrangements. A few TRPV1+ terminals received axoaxonic contacts from synaptic endings that contained pleomorphic synaptic vesicles and were immunolabeled for glutamic acid decarboxylase, the synthesizing enzyme for the inhibitory neurotransmitter ?-aminobutyric acid (GABA). We classified the TRPV1+ terminals into an S-type, containing less than five dense-core vesicles (DCVs), and a DCV-type, containing five or more DCVs. The number of postsynaptic dendrites was similar between the two types of terminals; however, whereas axoaxonic contacts were frequent on the S-type, the DCV-type did not receive axoaxonic contacts. In the sensory root of the trigeminal ganglion, TRPV1+ axons were mostly unmyelinated, and a small fraction was small myelinated. These results suggest that the TRPV1-mediated nociceptive information from the orofacial region is processed in a specific manner by two distinct types of synaptic arrangements in the Vc, and that the central input of a few TRPV1+ afferents is presynaptically modulated via a GABA-mediated mechanism. PMID:20878780

Yeo, Eun Jin; Cho, Yi Sul; Paik, Sang Kyoo; Yoshida, Atsushi; Park, Mae Ja; Ahn, Dong Kuk; Moon, Cheil; Kim, Yun Sook; Bae, Yong Chul

2010-10-15

262

Acid potentiation of the capsaicin receptor determined by a key extracellular site  

PubMed Central

The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents.

Jordt, Sven-Eric; Tominaga, Makoto; Julius, David

2000-01-01

263

Acid potentiation of the capsaicin receptor determined by a key extracellular site.  

PubMed

The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents. PMID:10859346

Jordt, S E; Tominaga, M; Julius, D

2000-07-01

264

Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: relationship to peptidergic and nitrergic neurons.  

PubMed

In the gut, transient receptor potential vanilloid (TRPV) 1 activation leads to release of neurotransmitters such as neuropeptides and nitric oxide. However, the distribution of TRPV1 nerve fibers and neurotransmitters released form sensory nerve endings in the enteric nervous system are currently not well understood. The present study investigated the immunohistochemical distribution of TRPV1 channels, sensory neuropeptides, and nitric oxide and their co-localization in mouse large intestine. Numerous TRPV1 and calcitonin gene-related peptide (CGRP) immunoreactivities were detected, mainly in the mucosa, submucosal layer, and myenteric plexus. Abundant substance P (SP), neurokinin A (NKA), and neuronal nitric oxide synthase (nNOS)-immunoreactivity were revealed in muscle layers. Motor function studies of circular and longitudinal muscles found that contractile responses to capsaicin in the rectum were most sensitive among the rectum, and distal, transverse, and proximal colon. Double labeling studies were carried out in horizontal sections of mouse rectum. TRPV1/protein gene product (PGP)9.5 double labeled axons were observed, but PGP9.5 and neuronal nuclear protein immunopositive cell bodies did not express TRPV1 immunoreactivity in the myenteric plexus. In the mucosa, submucosal layer, deep muscular plexus, circular muscle, myenteric plexus and longitudinal muscle layer, TRPV1 nerve fibers were found to contain CGRP, SP and nNOS. SP and NKA were almost entirely colocalized at the axons and cell bodies in all layers. Double labeling with c-Kit revealed that TRPV1 nerve fibers localized adjacent to the interstitial cells of Cajal (ICC). These results suggest that the TRPV1-expressing nerve and its neurotransmitters regulate various functions of the large intestine. PMID:20951772

Matsumoto, K; Hosoya, T; Tashima, K; Namiki, T; Murayama, T; Horie, S

2011-01-13

265

Role of Vanilloid Receptors in the Capsaicin-Mediated Induction of iNOS in PC12 Cells  

Microsoft Academic Search

The vanilloid receptor 1(VR1) is a nonselective cation channel that is activated by pungent vanilloid compound, extracellular protons, or noxious heat. mRNA of VR1 and vanilloid receptor 1–like receptor (VRL1) were expressed in PC12 cells, and only VR1 mRNA was detected in glioma and A10 cell lines. VR1 protein was demonstrated in PC12 cells by immunocytochemistry and Western blotting. Capsaicin

Shanlou Qiao; Weihua Li; Ryoko Tsubouchi; Keiko Murakami; Masataka Yoshino

2004-01-01

266

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

267

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis  

PubMed Central

Objective To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA). Methods The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed. Results The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor ? and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue. Conclusions A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

Valdes, Ana M; De Wilde, Gert; Doherty, Sally A; Lories, Rik J; Vaughn, Frances L; Laslett, Laura L; Maciewicz, Rose A; Soni, Anushka; Hart, Deborah J; Zhang, Weiya; Muir, Kenneth R; Dennison, Elaine M; Wheeler, Margaret; Leaverton, Paul; Cooper, Cyrus; Spector, Tim D; Cicuttini, Flavia M; Chapman, Victoria; Jones, Graeme; Arden, Nigel K; Doherty, Michael

2011-01-01

268

Lutein inhibits the function of the transient receptor potential A1 ion channel in different in vitro and in vivo models.  

PubMed

Transient receptor potential (TRP) ion channels, such as TRP vanilloid 1 and ankyrin repeat domain 1 (TRPV1 and TRPA1), are expressed on primary sensory neurons. Lutein, a natural tetraterpene carotenoid, can be incorporated into membranes and might modulate TRP channels. Therefore, the effects of the water-soluble randomly methylated-?-cyclodextrin (RAMEB) complex of lutein were investigated on TRPV1 and TRPA1 activation. RAMEB-lutein (100 ?M) significantly diminished Ca(2+) influx to cultured rat trigeminal neurons induced by TRPA1 activation with mustard oil, but not by TRPV1 stimulation with capsaicin, as determined with microfluorimetry. Calcitonin gene-related peptide release from afferents of isolated tracheae evoked by mustard oil, but not by capsaicin, was inhibited by RAMEB-lutein. Mustard oil-induced neurogenic mouse ear swelling was also significantly decreased by 100 ?g/ml s.c. RAMEB-lutein pretreatment, while capsaicin-evoked edema was not altered. Myeloperoxidase activity indicating non-neurogenic granulocyte accumulation in the ear was not influenced by RAMEB-lutein in either case. It is concluded that lutein inhibits TRPA1, but not TRPV1 stimulation-induced responses on cell bodies and peripheral terminals of sensory neurons in vitro and in vivo. Based on these distinct actions and the carotenoid structure, the ability of lutein to modulate lipid rafts in the membrane around TRP channels can be suggested. PMID:21541689

Horváth, Györgyi; Szoke, Éva; Kemény, Ágnes; Bagoly, Teréz; Deli, József; Szente, Lajos; Pál, Szilárd; Sándor, Katalin; Szolcsányi, János; Helyes, Zsuzsanna

2012-01-01

269

TRPV1-lineage neurons are required for thermal sensation  

PubMed Central

The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding.

Mishra, Santosh K; Tisel, Sarah M; Orestes, Peihan; Bhangoo, Sonia K; Hoon, Mark A

2011-01-01

270

TRPV1-dependent regulation of synaptic activity in the mouse dorsal motor nucleus of the vagus nerve  

PubMed Central

The dorsal motor nucleus of the vagus (DMV) is a key integrative point of the parasympathetic neuronal network localized in the dorsal vagal complex. Activity of neurons in the DMV is closely regulated by synaptic inputs, and regulation of excitatory and inhibitory synapsis by transient receptor potential vanilloid type 1 (TRPV1) has been demonstrated. Activation of TRPV1 by heat, protons, endovanilloids, endocannabinoids, and inflammatory mediators is well established. In our study we hypothesized that TRPV1 contributes to the synaptic transmission of DMV neurons at physiological range of temperature without additional stimuli. Using whole-cell patch-clamp recordings we evaluated the effect of a rapid increase of temperature on excitatory and inhibitory neurotransmission and the contribution of TRPV1 to this response. Rapid increase of temperature from 25 to 37°C increased the frequency of miniature excitatory post-synaptic currents (mEPSC) by 351.7%. The frequency of miniature inhibitory post-synaptic currents (mIPSC) also increased by 184.7%. 5?-iodoresiniferatoxin (5?-iRFT), a selective TRPV1 antagonist, prevented the increase of mEPSC and mIPSC frequency. In summary, our data demonstrate that at physiological range of temperature TRPV1 contributes to presynaptic neurotransmission of DMV neurons.

Anwar, Imran J.; Derbenev, Andrei V.

2013-01-01

271

TRPV1-dependent regulation of synaptic activity in the mouse dorsal motor nucleus of the vagus nerve.  

PubMed

The dorsal motor nucleus of the vagus (DMV) is a key integrative point of the parasympathetic neuronal network localized in the dorsal vagal complex. Activity of neurons in the DMV is closely regulated by synaptic inputs, and regulation of excitatory and inhibitory synapsis by transient receptor potential vanilloid type 1 (TRPV1) has been demonstrated. Activation of TRPV1 by heat, protons, endovanilloids, endocannabinoids, and inflammatory mediators is well established. In our study we hypothesized that TRPV1 contributes to the synaptic transmission of DMV neurons at physiological range of temperature without additional stimuli. Using whole-cell patch-clamp recordings we evaluated the effect of a rapid increase of temperature on excitatory and inhibitory neurotransmission and the contribution of TRPV1 to this response. Rapid increase of temperature from 25 to 37°C increased the frequency of miniature excitatory post-synaptic currents (mEPSC) by 351.7%. The frequency of miniature inhibitory post-synaptic currents (mIPSC) also increased by 184.7%. 5'-iodoresiniferatoxin (5'-iRFT), a selective TRPV1 antagonist, prevented the increase of mEPSC and mIPSC frequency. In summary, our data demonstrate that at physiological range of temperature TRPV1 contributes to presynaptic neurotransmission of DMV neurons. PMID:24379754

Anwar, Imran J; Derbenev, Andrei V

2013-01-01

272

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

PubMed Central

Primary astrocytomas of World Health Organization grade 3 and grade 4 (HG-astrocytomas) are preponderant among adults and are almost invariably fatal despite multimodal therapy. Here, we show that the juvenile brain has an endogenous defense mechanism against HG-astrocytomas. Neural precursor cells (NPCs) migrate to HG-astrocytomas, reduce glioma expansion and prolong survival by releasing a group of fatty acid ethanolamides that have agonistic activity on the vanilloid receptor (transient receptor potential vanilloid subfamily member-1; TRPV1). TRPV1 expression is higher in HG-astrocytomas than in tumor-free brain and TRPV1 stimulation triggers tumor cell death via the activating transcription factor-3 (ATF3) controlled branch of the ER stress pathway. The anti-tumorigenic 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 hold potential as new HG-astrocytoma therapeutics.

Stock, Kristin; Kumar, Jitender; Synowitz, Michael; Petrosino, Stefania; Imperatore, Roberta; Smith, Ewan St. J.; Wend, Peter; Purfurst, Bettina; Nuber, Ulrike A.; Gurok, Ulf; Matyash, Vitali; Walzlein, 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

2012-01-01

273

Key role of mucosal primary afferents in mediating the inhibitory influence of capsaicin on vagally mediated contractions in the mouse esophagus.  

PubMed

Transient receptor potential ion channel of the vanilloid type 1 (TRPV1)-dependent pathway, consisting of capsaicin-sensitive tachykininergic primary afferent and myenteric nitrergic neurons, was suggested to mediate the inhibitory effect of capsaicin on the vagally mediated striated muscle contractions in the rat esophagus. These primary afferent neurons upon entering into the esophagus are distributed through the myenteric plexus, terminating either in the myenteric ganglia or en route to the mucosa where they branch into a delicate net of fine varicose fibers. Therefore, this study aimed to investigate whether the mucosal primary afferents are a main mediator for the capsaicin inhibitory influence on vagally mediated contractions in the mouse esophagus. For this purpose, the vagally induced contractile activity of a thoracic esophageal segment was measured in the circular direction with a force transducer. Vagal stimulation (30 microsec, 25 V, 1-50 Hz for 1 sec) produced monophasic contractile responses, whose amplitudes were frequency-dependent. These contractions were completely abolished by d-tubocurarine (5 microM) while resistant to atropine (1 microM) and hexamethonium (100 microM). Capsaicin (30 microM) significantly inhibited the vagally induced contractions in esophagi with intact mucosa while its effect on preparations without mucosa was insignificant. Additionally, immunocytochemistry revealed the presence of TRPV1-positive nerve fibers in the tunica mucosa. Taken together, we conclude that in the mouse esophagus, capsaicin inhibits the vagally mediated striated muscle contractions mainly through its action on mucosal primary afferents, which in turn activate the presumed inhibitory local reflex arc. PMID:17485923

Boudaka, Ammar; Wörl, Jürgen; Shiina, Takahiko; Saito, Shouichiro; Atoji, Yasuro; Kobayashi, Haruo; Shimizu, Yasutake; Takewaki, Tadashi

2007-04-01

274

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

275

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

2012-09-01

276

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

2012-01-01

277

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

2013-11-01

278

Depression of presynaptic excitation by the activation of vanilloid receptor 1 in the rat spinal dorsal horn revealed by optical imaging  

Microsoft Academic Search

In this study, we show that capsaicin (CAP) depresses primary afferent fiber terminal excitability by acting on vanilloid receptor 1 (TRPV1 channels) of primary afferent fibers in adenosine 5'-triphosphate (ATP)- and temperature-dependent manner using two optical imaging methods. First, transverse slices of spinal cord were stained with a voltage-sensitive dye and the net excitation in the spinal dorsal horn was

Kei Kusudo; Hiroshi Ikeda; Kazuyuki Murase

2006-01-01

279

Pharmacological characterisation of the plant sesquiterpenes polygodial and drimanial as vanilloid receptor agonists.  

PubMed

This study was designed to assess the participation of transient receptor potential vanilloid 1 (TRPV1) in the biological effects induced by the plant-derived sesquiterpenes polygodial and drimanial. In rat isolated urinary bladder, polygodial and drimanial produced a tachykinin-mediated contraction that was inhibited by combination of NK(1) and NK(2) tachykinin receptor antagonists, SR 140333 and SR 48968. Furthermore, two different TRPV1 antagonists, capsazepine and ruthenium red prevented the contraction induced by both compounds. In addition, capsaicin, polygodial and drimanial displaced in a concentration-dependent manner the specific binding sites of [(3)H]-resiniferatoxin to rat spinal cord membranes, with a IC(50) values of 0.48, 4.2 and 3.2 microM, respectively. Likewise, capsaicin, polygodial and drimanial promoted an increase of [(45)Ca(2+)] uptake in rat spinal cord synaptosomes. In cultured rat trigeminal neurons, polygodial, drimanial and capsaicin were also able to significantly increase the intracellular Ca(2+) levels, effect that was significantly prevented by capsazepine. Together, the present results strongly suggest that the pharmacological actions of plant-derived sesquiterpenes polygodial and drimanial, seem to be partially mediated by activation of TRPV1. Additional investigations are needed to completely define the pharmacodynamic properties of these sesquiterpenes. PMID:16457780

André, Eunice; Campi, Barbara; Trevisani, Marcello; Ferreira, Juliano; Malheiros, Angela; Yunes, Rosendo A; Calixto, Joăo B; Geppetti, Pierangelo

2006-04-14

280

Pharmacological characterization of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel transient receptor potential vanilloid 1 antagonist.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) activation in peripheral sensory nerve is known to be associated with various pain-related diseases, thus TRPV1 has been the focus as a target for drug discovery. In this study, we characterized the pharmacological profiles of (3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (JTS-653), a novel TRPV1 antagonist. JTS-653 displaced [(3)H]resiniferatoxin binding to human and rat TRPV1. JTS-653 competitively antagonized the capsaicin-induced activation of human TRPV1 with pA(2) values of 10.1. JTS-653 also inhibited proton-induced activation of human and rat TRPV1 with IC(50) values of 0.320 and 0.347 nM, respectively. Electrophysiological studies indicated that JTS-653 blocked heat-induced inward currents in rat TRPV1 with IC(50) values of 1.4 nM. JTS-653 showed weak or no inhibitory effects on other TRP channels, receptors, and enzymes. JTS-653 significantly prevented capsaicin-induced mechanical hyperalgesia at 1 mg/kg p.o. and attenuated carrageenan-induced mechanical hyperalgesia at 0.3 mg/kg p.o. JTS-653 significantly attenuated carrageenan-induced thermal hyperalgesia at 0.1 mg/kg p.o. and fully reversed at 0.3 mg/kg p.o. without affecting the volume of the carrageenan-treated paw. JTS-653 showed a transient increase of body temperature at 0.3 mg/kg p.o. These results indicated that JTS-653 is a highly potent and selective TRPV1 antagonist in vitro and in vivo and suggested that JTS-653 is one of the most potent TRPV1 antagonists. The profiles of JTS-653, high potency in vivo and transient hyperthermia, seem to be associated with polymodal inhibition of TRPV1 activation. PMID:22588258

Kitagawa, Yoshihiro; Miyai, Atsuko; Usui, Kenji; Hamada, Yuji; Deai, Katsuya; Wada, Masashi; Koga, Yoshihisa; Sakata, Masahiro; Hayashi, Mikio; Tominaga, Makoto; Matsushita, Mutsuyoshi

2012-08-01

281

Amelioration of neuropathic pain by novel transient receptor potential vanilloid 1 antagonist AS1928370 in rats without hyperthermic effect.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is activated by a variety of stimulations, such as endogenous ligands and low pH, and is believed to play a role in pain transmission. TRPV1 antagonists have been reported to be effective in several animal pain models; however, some compounds induce hyperthermia in animals and humans. We discovered the novel TRPV1 antagonist (R)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-7-quinolyl)-2-[(2-methylpyrrolidin-1-yl)methyl]biphenyl-4-carboxamide (AS1928370) in our laboratory. AS1928370 bound to the resiniferatoxin-binding site on TRPV1 and inhibited capsaicin-mediated inward currents with an IC?? value of 32.5 nM. Although AS1928370 inhibited the capsaicin-induced Ca˛(+) flux in human and rat TRPV1-expressing cells, the inhibitory effect on proton-induced Ca˛(+) flux was extremely small. In addition, AS1928370 showed no inhibitory effects on transient receptor potential vanilloid 4, transient receptor potential ankyrin 1, and transient receptor potential melastatin 8 in concentrations up to 10 ?M. AS1928370 improved capsaicin-induced secondary hyperalgesia and mechanical allodynia in an L5/L6 spinal nerve ligation model in rats with respective ED?? values of 0.17 and 0.26 mg/kg p.o. Furthermore, AS1928370 alleviated inflammatory pain in a complete Freund's adjuvant model at 10 mg/kg p.o. AS1928370 had no effect on rectal body temperature up to 10 mg/kg p.o., although a significant hypothermic effect was noted at 30 mg/kg p.o. In addition, AS1928370 showed no significant effect on motor coordination. These results suggest that blockage of the TRPV1 receptor without affecting the proton-mediated TRPV1 activation is a promising approach to treating neuropathic pain because of the potential wide safety margin against hyperthermic effects. As such, compounds such as ASP1928370 may have potential as new analgesic agents for treating neuropathic pain. PMID:21098091

Watabiki, Tomonari; Kiso, Tetsuo; Kuramochi, Takahiro; Yonezawa, Koichi; Tsuji, Noriko; Kohara, Atsuyuki; Kakimoto, Shuichiro; Aoki, Toshiaki; Matsuoka, Nobuya

2011-03-01

282

A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons  

PubMed Central

Many n-acylethanolamines utilize the anandamide membrane transporter (AMT) to gain facilitated access to the intracellular compartment, hence, we hypothesized that this mechanism might be important for anandamide (AEA)- and N-arachidonoyl-dopamine (NADA)-evoked CGRP release from cultured trigeminal ganglion (TG) neurons. Using [14C]AEA we demonstrated that TG neurons transported AEA in a FAAH- and AMT-inhibitable fashion. Although TRPV1-positive TG neurons were found to express fatty acid amide hydrolase, the application of FAAH inhibitors had no effect on AEA-evoked CGRP release. In contrast, application of the AMT inhibitors OMDM-2 or VDM-11 significantly reduced the potency and efficacy of AEA-, NADA- and capsaicin-evoked CGRP release. Moreover OMDM-2 (IC50 values ranging from 6.4–9.6 ?M) and VDM-11 (IC50 values ranging from 5.3–11 ?M) inhibited CGRP release evoked by EC80 concentrations of AEA, NADA and CAP and these values were consistent with IC50s obtained for inhibition of uptake. OMDM-2 had no effect on CGRP release per se while VDM-11 evoked CGRP release on its own (EC50 ~35 ?M) in a CPZ-insensitive, but ruthenium red (RR)-sensitive fashion. This is the first demonstration that TG sensory neurons possess an AMT-like mechanism suggesting that this mechanism is important for the pharmacological action of AEA and NADA at native TRPV1 channels.

Price, Theodore J.; Patwardhan, Amol M.; Flores, Christopher M.; Hargreaves, Kenneth M.

2007-01-01

283

?-Methylated simplified resiniferatoxin (sRTX) thiourea analogues as potent and stereospecific TRPV1 antagonists.  

PubMed

A series of ?-methylated analogues of the potent sRTX thiourea antagonists were investigated as rTRPV1 ligands in order to examine the effect of ?-methylation on receptor activity. The SAR analysis indicated that activity was stereospecific with the (R)-configuration of the newly formed chiral center providing high binding affinity and potent antagonism while the configuration of the C-region was not significant. PMID:24794110

Kim, Ho Shin; Jin, Mi-Kyoung; Kang, Sang-Uk; Lim, Ju-Ok; Tran, Phuong-Thao; Hoang, Van-Hai; Ann, Jihyae; Ha, Tae-Hwan; Pearce, Larry V; Pavlyukovets, Vladimir A; Blumberg, Peter M; Lee, Jeewoo

2014-06-15

284

Anandamide Capacitates Bull Spermatozoa through CB1 and TRPV1 Activation  

Microsoft Academic Search

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

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

2011-01-01

285

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

2013-10-01

286

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

2013-01-01

287

TRPV1 and TRPV4 play pivotal roles in delayed onset muscle soreness.  

PubMed

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. PMID:23799042

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

2013-01-01

288

An exploration of the estrogen receptor transcription activity of capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays.  

PubMed

Capsaicin has been considered as an alternative template of dichlorodiphenyl trichloroethane (DDT) in antifouling paint. However, information regarding the estrogenic activity of capsaicin analogues is rather limited in comparison to that of DDT analogues and their metabolites. We here explore the ER transcription activity of selected capsaicin analogues via an integrated approach based on in silico prediction and in vitro assays. Molecular simulation and the agonist/antagonist differential-docking screening identified 6-iodonordihydrocapsaicin (6-I-CPS) as a weak ER? agonist, while anti-estrogenicity was expected for N-arachidonoyldopamine, capsazepine, dihydrocapsaicin, trichostatin A, and capsaicin. On the contrary, the large volume of analogues, such as phorbol 12-phenylacetate 13-acetate 20-homovanillate and phorbol 12,13-dinonanoate 20-homovanillate, cannot fit well with the ER cavity. The result of MVLN assay was in accord with the in silico prediction. 6-I-CPS was demonstrated to induce luciferase gene expression, while the other analogues of relatively small molecular volume reduced luciferase gene expression in MVLN cells, both in the absence and presence of estradiol. This finding suggested that the ER transcription activity of capsaicin analogues is generated at least partly through the ER?-mediated pathway. Moreover, receptor polymorphism analysis indicated that capsaicin analogues may exhibit diverse species selectivity for human beings and marine species. PMID:24747365

Li, Juan; Ma, Duo; Lin, Yuan; Fu, Jianjie; Zhang, Aiqian

2014-06-16

289

LASSBio-1135: A Dual TRPV1 Antagonist and Anti-TNF-Alpha Compound Orally Effective in Models of Inflammatory and Neuropathic Pain.  

PubMed

LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-? and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-? production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-? release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg-1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg-1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-? production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-? production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg-1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7-11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-? inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia. PMID:24941071

Lima, Cleverton K F; Silva, Rafael M; Lacerda, Renata B; Santos, Bruna L R; Silva, Rafaela V; Amaral, Luciana S; Quintas, Luís E M; Fraga, Carlos A M; Barreiro, Eliezer J; Guimaraes, Marília Z P; Miranda, Ana L P

2014-01-01

290

LASSBio-1135: A Dual TRPV1 Antagonist and Anti-TNF-Alpha Compound Orally Effective in Models of Inflammatory and Neuropathic Pain  

PubMed Central

LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-? and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-? production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-? release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg?1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg?1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-? production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-? production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg?1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7–11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-? inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia.

Lima, Cleverton K. F.; Silva, Rafael M.; Lacerda, Renata B.; Santos, Bruna L. R.; Silva, Rafaela V.; Amaral, Luciana S.; Quintas, Luis E. M.; Fraga, Carlos A. M.; Barreiro, Eliezer J.; Guimaraes, Marilia Z. P.; Miranda, Ana L. P.

2014-01-01

291

Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway.  

PubMed

Hypoxic preconditioning (HPC) protects rat hearts against ischemia-reperfusion (IR) injury. However, the role of transient receptor potential vanilloid 1 (TRPV1) in HPC-mediated cardioprotection remains unknown. TRPV1 is activated by endovanilloid 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which is synthesized by arachidonate 12-lipoxygenase (ALOX12). Therefore, we examined whether HPC protects the myocardium against IR via the ALOX12/TRPV1 pathway. Compared to hearts of rats kept in room air, the hearts of rats kept in air with 10 % oxygen for 4 weeks had better post-ischemic recovery and less tissue damage when subjected to 30-min global ischemia and 4-h reflow in a Langendorff apparatus. Capsazepine, a specific TRPV1 blocker, administered 5 min before reperfusion markedly attenuated the effects of HPC, confirming that TRPV1 is a downstream effector in HPC-mediated cardioprotection. HPC resulted in the upregulation of ALOX12 and myocardial 12(S)-HETE, and prevented IR-induced 12(S)-HETE reduction. In addition, sarcolemmal ALOX12 expression in HPC hearts mainly co-localized with TRPV1 expression. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-?-cyanocinnamate or baicalein abrogated the effects of HPC, baicalein also decreased 12(S)-HETE expression. Mimicking HPC by given 12(S)-HETE or capsaicin to baicalien-treated hearts enhanced cardiac recovery during reperfusion. The cardiac protein kinase C (PKC) isoforms ?, ?, ?, and ? were preferentially expressed in the sarcolemmal membrane of HPC-treated hearts, indicating their high intrinsic activation state. Capsazepine or co-treatment with baicalein attenuated translocation of PKC?, PKC? and PKC?, but not that of PKC?. We conclude that HPC reduces heart susceptibly to IR via ALOX12/TRPV1/PKC pathway, as shown by increased 12(S)-HETE expression in HPC hearts. PMID:24816396

Lu, Ming-Jen; Chen, Yih-Sharng; Huang, Ho-Shiang; Ma, Ming-Chieh

2014-07-01

292

Structure of the TRPV1 ion channel determined by electron cryo-microscopy  

PubMed Central

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here, we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4Ĺ resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane helices S5–S6 and the intervening pore loop, which is flanked by S1–S4 voltage sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

Liao, Maofu; Cao, Erhu; Julius, David; Cheng, Yifan

2014-01-01

293

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

294

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

2011-08-01

295

Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions.  

PubMed

Members of the transient receptor potential (TRP) family of nonselective cation channels are involved in several pathological and physiological conditions. The search for the molecular targets for naturally occurring substances, especially from plants, allowed the characterization of many TRP channels. In fact, attempts to understand the hot and painful action of the vanillyl group containing compounds capsaicin (from Capsicum sp.) and its ultrapotent analogue resiniferatoxin (RTX, from Euphorbia sp.) led to the cloning of the vanilloid receptor (TRPV1) 7 years ago. TRPV1 is found in sensory fibers and functions as a molecular integrator of several painful stimuli, being especially stimulated during inflammation. Since TRPV1 is involved in several pathological conditions, selective ligands or modulators of this channel are substances of potential interest to treat such diseases. Once again, natural products seem to be also interesting sources of compounds that might be prototype TRPV1 ligands. The cloning of TRPV1 also enabled the discovery of other members of the TRPV family of channels. Similar to TRPV1, these receptors function as molecular detectors of physical and chemical stimuli, such as innocuous and noxious heat, as well as mechanical force. Recently, novel TRP channels sensitive to low temperatures also have been cloned, namely, TRPM8 and TRPA1. Such channels are also activated by naturally occurring substances but knowledge of their involvement in health and disease is in its infancy. In the present review, we focused on the contribution of natural products to the discovery of TRP channels and to the development of novel drugs to treat pathological conditions in which these channels are involved. PMID:15866319

Calixto, Joăo B; Kassuya, Candida A L; André, Eunice; Ferreira, Juliano

2005-05-01

296

Citral Sensing by TRANSient Receptor Potential Channels in Dorsal Root Ganglion Neurons  

PubMed Central

Transient receptor potential (TRP) ion channels mediate key aspects of taste, smell, pain, temperature sensation, and pheromone detection. To deepen our understanding of TRP channel physiology, we require more diverse pharmacological tools. Citral, a bioactive component of lemongrass, is commonly used as a taste enhancer, as an odorant in perfumes, and as an insect repellent. Here we report that citral activates TRP channels found in sensory neurons (TRPV1 and TRPV3, TRPM8, and TRPA1), and produces long-lasting inhibition of TRPV1–3 and TRPM8, while transiently blocking TRPV4 and TRPA1. Sustained citral inhibition is independent of internal calcium concentration, but is state-dependent, developing only after TRP channel opening. Citral's actions as a partial agonist are not due to cysteine modification of the channels nor are they a consequence of citral's stereoisoforms. The isolated aldehyde and alcohol cis and trans enantiomers (neral, nerol, geranial, and geraniol) each reproduce citral's actions. In juvenile rat dorsal root ganglion neurons, prolonged citral inhibition of native TRPV1 channels enabled the separation of TRPV2 and TRPV3 currents. We find that TRPV2 and TRPV3 channels are present in a high proportion of these neurons (94% respond to 2-aminoethyldiphenyl borate), consistent with our immunolabeling experiments and previous in situ hybridization studies. The TRPV1 activation requires residues in transmembrane segments two through four of the voltage-sensor domain, a region previously implicated in capsaicin activation of TRPV1 and analogous menthol activation of TRPM8. Citral's broad spectrum and prolonged sensory inhibition may prove more useful than capsaicin for allodynia, itch, or other types of pain involving superficial sensory nerves and skin.

Stotz, Stephanie C.; Vriens, Joris; Martyn, Derek; Clardy, Jon; Clapham, David E.

2008-01-01

297

Evodiamine and rutaecarpine alkaloids as highly selective transient receptor potential vanilloid 1 agonists.  

PubMed

Despite that among non-camptothecin natural products promising anticancer therapeutics are evodiamine derivatives, involved into mechanism of physiological function of topoisomerase-I. But, more recent findings have been shown that substituted quinazole alkaloids act as transient receptor potential vanilloid 1 agonists. The TRP(V1) is a calcium ion channel, activated by pH, heat and inflammatory activators. I is implicated in pain sensing. TRPV1 agonist is capsaicine (1). Both 1 and evodiamine (2), therefore, produce same physiological response, but are structurally unrelated from chemical viewpoint. Furthermore precise mechanistic aspects of drugs receptor interactions are still not fully understood. This study is the first one, which provides assessment of molecular factors contributing significantly to selectivity of 2 and rutaecarpine (3) as well as their twenty-two new functionalized derivatives towards (TRP)V1. The suggested new functionalization type of molecular skeleton, which is completely different one in respect the known derivatives, which is implicated in treatment of variety of cancer cell lines interacting preferably with topoisomerase-I. It resulted to increasing of the binding affinity and selectivity of the functionalized derivatives specifically to (TRP)V1?1.36-1.72 and ?2.50-3.16 higher than 1-3. PMID:24495556

Ivanova, Bojidarka; Spiteller, Michael

2014-04-01

298

Effects of GABA receptor antagonist on trigeminal caudalis nociceptive neurons in normal and neonatally capsaicin-treated rats.  

PubMed

We have recently demonstrated that significant increases in cutaneous mechanoreceptive field (RF) size and spontaneous activity occur in nociceptive neurons of trigeminal subnucleus caudalis (Vc, the medullary dorsal horn) of adult rats depleted of C-fiber afferents by neonatal treatment with capsaicin. These neuronal changes in capsaicin-treated (CAP) rats are suggestive of central neuroplasticity and involve N-methyl-D-aspartic acid (NMDA) receptor mechanisms. The present study examined whether the GABA(A) receptor antagonist bicuculline (BIC) or the GABA(B) receptor antagonist 2-hydroxysaclofen (SAC) can influence the RF properties and activity of Vc nociceptive neurons classified as either nociceptive-specific or wide-dynamic range in CAP adult rats or in neonatally vehicle-treated (CON) rats. C-fiber depletion was confirmed in the CAP rats by a significant decrease in plasma extravasation of Evans blue dye in a skin area receiving topical application of mustard oil, a small-fiber excitant and inflammatory irritant. As previously reported, marked increases in cutaneous RF size and spontaneous activity occurred in Vc nociceptive neurons of adult CAP rats, compared with CON rats. GABA(A) receptor blockade by BIC (i.t.) in CON rats produced a significant increase in spontaneous activity and in pinch RF size and tactile RF size (or appearance of a tactile area in the RF of nociceptive-specific neurons), as well as a significant lowering of the mechanical threshold and a significant enhancement of responses to pinch stimuli applied to the RF. In CAP rats, GABA(A) receptor blockade also produced significant changes similar to those documented in CON rats, except for a paradoxical and significant decrease in pinch RF size and no noticeable changes in responses to pinch stimuli. GABA(B) receptor blockade by SAC (i.t. ) did not produce any significant changes in Vc nociceptive neurons in either CON or CAP rats. These results suggest that GABA(A) receptor-mediated inhibition may be involved in maintaining the functional expression of Vc nociceptive neuronal properties in normal conditions, and that in animals depleted of their C-fiber afferents, some features of this GABA(A) receptor-mediated modulation may be disrupted such that a GABA(A) receptor-mediated excitation is manifested. PMID:10561395

Chiang, C Y; Kwan, C L; Hu, J W; Sessle, B J

1999-11-01

299

High-Resolution Views of TRPV1 and Their Implications for the TRP Channel Superfamily.  

PubMed

The first high-resolution structures of a near-full-length TRP channel were recently described, structures of the noxious heat receptor TRPV1 in the absence or presence of vanilloid agonists and a spider toxin. Here we briefly review the salient features, including the overall architecture, agonist binding sites, and conformational changes related to channel pore gating. We also discuss some of the structures' implications for the TRP channel family and a few of the many questions still left unanswered. PMID:24961977

Hellmich, Ute A; Gaudet, Rachelle

2014-01-01

300

Rapid Glucocorticoid-Induced Activation of TRP and CB1 Receptors Causes Biphasic Modulation of Glutamate Release in Gastric-Related Hypothalamic Preautonomic Neurons  

PubMed Central

Glucocorticoids rapidly regulate synaptic input to neuroendocrine cells in the hypothalamic paraventricular nucleus (PVN) by inducing the retrograde release of endogenous messengers. Here we investigated the rapid effects of dexamethasone (DEX) on excitatory synaptic input to feeding-related, preautonomic PVN neurons using whole-cell patch-clamp recordings. In ?50% of identified gastric-related preautonomic PVN neurons, DEX elicited a biphasic synaptic response characterized by an initial rapid and transient increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), followed by a decrease in mEPSC frequency within 9?min; remaining cells displayed only a decrease in mEPSC frequency. The late-phase decrease in mEPSC frequency was mimicked by the cannabinoid receptor agonists anandamide (AEA) and WIN 55,212-2, and it was blocked by the CB1 receptor antagonist AM251. The biphasic DEX effect was mimicked by AEA. The early increase in mEPSCs was mimicked by activation of transient receptor potential vanilloid type 1 (TRPV1) receptors with capsaicin and by activation of TRPV4 receptors with 4-?-PDD. The increase was reduced, but not blocked, by selective TRPV1 antagonists and in TRPV1 knockout mice; it was blocked completely by the broad-spectrum TRPV antagonist ruthenium red and by combined application of selective TRPV1 and TRPV4 antagonists. The DEX effects were prevented entirely by intracellular infusion of the G-protein inhibitor, GDP?S. Thus, DEX biphasically modulates synaptic glutamate onto a subset of gastric-related PVN neurons, which is likely mediated by induction of a retrograde messenger. The effect includes a TRPV1/4 receptor-mediated transient increase and subsequent CB1 receptor-mediated suppression of glutamate release. Multiphasic modulation of glutamate input to PVN neurons represents a previously unappreciated complexity of control of autonomic output by glucocorticoids and endogenous cannabinoids.

Boychuk, Carie R.; Zsombok, Andrea; Tasker, Jeffrey G.; Smith, Bret N.

2013-01-01

301

Rapid Glucocorticoid-Induced Activation of TRP and CB1 Receptors Causes Biphasic Modulation of Glutamate Release in Gastric-Related Hypothalamic Preautonomic Neurons.  

PubMed

Glucocorticoids rapidly regulate synaptic input to neuroendocrine cells in the hypothalamic paraventricular nucleus (PVN) by inducing the retrograde release of endogenous messengers. Here we investigated the rapid effects of dexamethasone (DEX) on excitatory synaptic input to feeding-related, preautonomic PVN neurons using whole-cell patch-clamp recordings. In ?50% of identified gastric-related preautonomic PVN neurons, DEX elicited a biphasic synaptic response characterized by an initial rapid and transient increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), followed by a decrease in mEPSC frequency within 9?min; remaining cells displayed only a decrease in mEPSC frequency. The late-phase decrease in mEPSC frequency was mimicked by the cannabinoid receptor agonists anandamide (AEA) and WIN 55,212-2, and it was blocked by the CB1 receptor antagonist AM251. The biphasic DEX effect was mimicked by AEA. The early increase in mEPSCs was mimicked by activation of transient receptor potential vanilloid type 1 (TRPV1) receptors with capsaicin and by activation of TRPV4 receptors with 4-?-PDD. The increase was reduced, but not blocked, by selective TRPV1 antagonists and in TRPV1 knockout mice; it was blocked completely by the broad-spectrum TRPV antagonist ruthenium red and by combined application of selective TRPV1 and TRPV4 antagonists. The DEX effects were prevented entirely by intracellular infusion of the G-protein inhibitor, GDP?S. Thus, DEX biphasically modulates synaptic glutamate onto a subset of gastric-related PVN neurons, which is likely mediated by induction of a retrograde messenger. The effect includes a TRPV1/4 receptor-mediated transient increase and subsequent CB1 receptor-mediated suppression of glutamate release. Multiphasic modulation of glutamate input to PVN neurons represents a previously unappreciated complexity of control of autonomic output by glucocorticoids and endogenous cannabinoids. PMID:23386808

Boychuk, Carie R; Zsombok, Andrea; Tasker, Jeffrey G; Smith, Bret N

2013-01-01

302

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

303

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

304

Intrathecal administration of AS1928370, a transient receptor potential vanilloid 1 antagonist, attenuates mechanical allodynia in a mouse model of neuropathic pain.  

PubMed

Transient receptor potential vanilloid 1 (TRPV1) is primarily expressed in central and peripheral terminals of non-myelinated primary afferent neurons. We previously showed that AS1928370, a novel TRPV1 antagonist that can prevent ligand-induced activation but not proton-induced activation, ameliorates neuropathic pain in rats without hyperthermic effect. In this study, we investigated its analgesic profile in mice. AS1928370 showed good oral bioavailability and high penetration into the brain and spinal cord in mice. The mean plasma-to-brain and plasma-to-spinal cord ratios were 4.3 and 3.5, respectively. Pretreatment with AS1928370 significantly suppressed both capsaicin-induced acute pain and withdrawal response in hot plate test at 10-30 mg/kg per os (p.o.). At lower oral doses (0.3-1.0 mg/kg), AS1928370 improved mechanical allodynia in mice undergoing spinal nerve ligation. Intrathecal administration of AS1928370 (30 µg/body) also significantly suppressed mechanical allodynia. In addition, AS1928370 showed no effect on locomotor activity up to 30 mg/kg p.o. These results suggest that spinal TRPV1 has an important role in the transmission of neuropathic pain and that the central nervous system (CNS) penetrant TRPV1 receptor antagonist AS1928370 is a promising candidate for treating neuropathic pain. PMID:21720020

Watabiki, Tomonari; Kiso, Tetsuo; Tsukamoto, Mina; Aoki, Toshiaki; Matsuoka, Nobuya

2011-01-01

305

Differential TRPV1 and TRPV2 channel expression in dental pulp.  

PubMed

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. PMID:21406609

Gibbs, J L; Melnyk, J L; Basbaum, A I

2011-06-01

306

Bladder Cancer and Urothelial Impairment: The Role of TRPV1 as Potential Drug Target  

PubMed Central

Urothelium, in addition to its primary function of barrier, is now understood to act as a complex system of cell communication that exhibits specialized sensory properties in the regulation of physiological or pathological stimuli. Furthermore, it has been hypothesized that bladder inflammation and neoplastic cell growth, the two most representative pathological conditions of the lower urinary tract, may arise from a primary defective urothelial lining. Transient receptor potential vanilloid channel 1 (TRPV1), a receptor widely distributed in lower urinary tract structures and involved in the physiological micturition reflex, was described to have a pathophysiological role in inflammatory conditions and in the genesis and development of urothelial cancer. In our opinion new compounds, such as curcumin, the major component of turmeric Curcuma longa, reported to potentiate the effects of the chemotherapeutic agents used in the management of recurrent urothelial cancer in vitro and also identified as one of several compounds to own the vanillyl structure required to work like a TRPV1 agonist, could be thought as complementary in the clinical management of both the recurrences and the inflammatory effects caused by the endoscopic resection or intravesical chemotherapy administration or could be combined with adjuvant agents to potentiate their antitumoral effect.

Mistretta, Francesco; Buffi, Nicolo Maria; Lughezzani, Giovanni; Lista, Giuliana; Larcher, Alessandro; Fossati, Nicola; Abrate, Alberto; Dell'Oglio, Paolo; Montorsi, Francesco; Guazzoni, Giorgio; Lazzeri, Massimo

2014-01-01

307

The response of PKD1L3 / PKD2L1 to acid stimuli is inhibited by capsaicin and its pungent analogs  

PubMed Central

Polycystic kidney disease (PKD) 2L1 protein is a member of the transient receptor potential (TRP) ion channel family. In circumvallate and foliate papillae, PKD2L1 is coexpressed with PKD1L3. PKD2L1 and PKD1L3 interact through their transmembrane domain and the resulting heteromer PKD1L3/PKD2L1 owns a unique channel property called ‘off-responses’ to acid stimulation, although PKD2L1 does not own this property by itself. To define the pharmacological properties of the PKD1L3/PKD2L1 channel, we developed a new method to effectively evaluate channel activity using human embryonic kidney 293T cells in which the channel was heterologously expressed. This method was applied to screen substances that potentially regulate it. We found that capsaicin and its analogs, which are TRPV1 agonists, inhibited the response to acid stimuli and that the capsaicin inhibition was reversible with an IC50 of 32.5 ?m. Capsaicin and its analogs are thus useful tools for physiological analysis of PKD1L3/PKD2L1 function. Database Nucleotide sequence data are available in the GenBank database under the accession numbers hTRPA1, BC148423 and hTRPV3, BC104866.

Ishii, Sho; Kurokawa, Azusa; Kishi, Mikiya; Yamagami, Keigo; Okada, Shinji; Ishimaru, Yoshiro; Misaka, Takumi

2012-01-01

308

House dust mite potentiates capsaicin-evoked Ca2+ transients in mouse pulmonary sensory neurons via activation of protease-activated receptor-2  

PubMed Central

House dust mite (HDM) is a major source of allergen in house dust and has been suggested to be involved in the pathogenesis of asthma. In this study, we aimed to investigate whether HDM can modulate the sensitivity of pulmonary sensory neurons, and if so, to elucidate the underlying mechanism. Fura-2 based ratiometric Ca2+ imaging was carried out to determine the effect of HDM extract on the capsaicin-evoked Ca2+ transient in mouse vagal pulmonary sensory neurons. Pretreatment with HDM (50 ?g/ml, 5 min) significantly enhanced the Ca2+ transient evoked by capsaicin in these neurons isolated from wildtype mice. This potentiating effect of HDM was not antagonized by E-64, a selective cysteine protease inhibitor, but was completely prevented by AEBSF, a specific serine protease inhibitor. In addition, the potentiating effect of HDM on capsaicin-evoked Ca2+ transient was absent in the pulmonary sensory neurons isolated from protease-activated receptor-2 (PAR2) knockout mice. Further, the sensitizing effect of HDM was completely abolished by U73122, a PLC inhibitor, or chelerythrine, a PKC inhibitor. In summary, our results demonstrate that HDM, mainly through its serine protease activity, potentiates capsaicin-evoked Ca2+ transient in mouse pulmonary sensory neurons via the activation of PAR2 and PLC-PKC intracellular transduction cascade.

Gu, Qihai; Lee, Lu-Yuan

2011-01-01

309

House dust mite potentiates capsaicin-evoked Ca2+ transients in mouse pulmonary sensory neurons via activation of protease-activated receptor-2.  

PubMed

House dust mite (HDM) is a major source of allergen in house dust and has been suggested to be involved in the pathogenesis of asthma. In this study, we aimed to investigate whether HDM can modulate the sensitivity of pulmonary sensory neurons and, if so, to elucidate the underlying mechanism. Fura-2-based ratiometric Ca(2+) imaging was carried out to determine the effect of HDM extract on the capsaicin-evoked Ca(2+) transient in mouse vagal pulmonary sensory neurons. Pretreatment with HDM (50 ?g ml(-1), 5 min) significantly enhanced the Ca(2+) transient evoked by capsaicin in these neurons isolated from wild-type mice. This potentiating effect of HDM was not antagonized by E-64, a selective cysteine protease inhibitor, but was completely prevented by AEBSF, a specific serine protease inhibitor. In addition, the potentiating effect of HDM on capsaicin-evoked Ca(2+) transient was absent in the pulmonary sensory neurons isolated from protease-activated receptor-2 (PAR(2)) knockout mice. Furthermore, the sensitizing effect of HDM was completely abolished by U73122, a phosholipase C inhibitor, or chelerythrine, a protein kinase C inhibitor. In summary, our results demonstrate that HDM, mainly through its serine protease activity, potentiates capsaicin-evoked Ca(2+) transient in mouse pulmonary sensory neurons via the activation of PAR(2) and the phosholipase C-protein kinase C intracellular transduction cascade. PMID:22125310

Gu, Qihai; Lee, Lu-Yuan

2012-04-01

310

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

311

The effects of pH on the interaction between capsaicin and the vanilloid receptor in rat dorsal root ganglia neurons  

PubMed Central

The vanilloid receptor of sensory neurons is a polymodal nociceptor sensitive to capsaicin, protons, heat and anandamide. Although it is known that interaction occurs between these different mediators the mechanism by which this occurs is poorly understood. In this study capsaicin elicited currents were recorded from vanilloid receptors found in adult rat isolated dorsal root ganglia (DRG) neurons under conditions of varying pH and the mechanism whereby protons can modulate this capsaicin response investigated. Under whole-cell voltage clamp, modulating extracellular pH shifted the position of the capsaicin log(concentration)-response curve. Acidification from pH 9.0 to pH 5.5 lowered the EC50 values from 1150±250?nM to 5±2?nM with coincident change in the mean apparent slope factor from 2.3±0.3 to 0.9±0.2 and no change in maximal response. The magnitude of the potentiation seen on reducing extracellular pH was not significantly affected by changes in extracellular calcium and magnesium concentration. The response to capsaicin was not potentiated by a reduction in intracellular pH suggesting a site of action more accessible from the extracellular than the intracellular side of the membrane. Potentiation by low pH was voltage independent indicating a site of action outside the membrane electric field. At the single channel level, reducing extracellular pH increased channel open probability but had no significant effect on single channel conductance or open time. These results are consistent with a model in which, on reducing extracellular pH, the vanilloid receptor in rat DRG neurons, changes from a state with low affinity for capsaicin to one with high affinity, coincident with a loss of cooperativity. This effect, presumed to be proton mediated, appears to involve one or more sites with pKa value 7.4?–?7.9, outside the membrane electrical field on an extracellularly exposed region of the receptor protein.

McLatchie, L M; Bevan, S

2001-01-01

312

Isolation of coniferyl esters from Capsicum baccatum L., and their enzymatic preparation and agonist activity for TRPV1.  

PubMed

Coniferyl esters--capsiconiate and dihydrocapsiconiate--were isolated from the fruits of the pepper, Capsicum baccatum L. var. praetermissum. Their structures were determined by spectroscopic methods to be coniferyl (E)-8-methyl-6-nonenoate (capsiconiate) and coniferyl 8-methylnonanoate (dihydrocapsiconiate). This finding was further confirmed by the lipase-catalyzed condensation of coniferyl alcohol with its corresponding fatty acid derivative. The agonist activity of the esters for transient receptor potential vanilloid 1 (TRPV1) was evaluated by conducting an analysis of the intracellular calcium concentrations in TRPV1-expressing HEK293 cells. The EC50 values of capsiconiate and dihydrocapsiconiate were 3.2 and 4.2 microM, respectively. PMID:18190936

Kobata, Kenji; Tate, Hitomi; Iwasaki, Yusaku; Tanaka, Yoshiyuki; Ohtsu, Keigo; Yazawa, Susumu; Watanabe, Tatsuo

2008-03-01

313

The ruthenium NO donor, [Ru(bpy)2(NO)SO3](PF6), inhibits inflammatory pain: involvement of TRPV1 and cGMP/PKG/ATP-sensitive potassium channel signaling pathway.  

PubMed

The activation of nitric oxide (NO) production is an analgesic mechanism shared by drugs such as morphine and diclofenac. Therefore, the controlled release of low amounts of NO seems to be a promising analgesic approach. In the present study, the antinociceptive effect of the ruthenium NO donor [Ru(bpy)2(NO)SO3](PF6) (complex I) was investigated. It was observed that complex I inhibited in a dose (0.3-10mg/kg)-dependent manner the acetic acid-induced writhing response. At the dose of 1mg/kg, complex I inhibited the phenyl-p-benzoquinone-induced writhing response and formalin- and complete Freund's adjuvant-induced licking and flinch responses. Additionally, complex I also inhibited transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent overt pain-like behavior induced by capsaicin. Complex I also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity (MPO) in paw skin samples. The inhibitory effect of complex I in the carrageenin-induced hyperalgesia, MPO activity and formalin was prevented by the treatment with ODQ, KT5823 and glybenclamide, indicating that complex I inhibits inflammatory hyperalgesia by activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway. The present study demonstrates the efficacy of a novel ruthenium NO donor and its analgesic mechanisms. PMID:23470198

Staurengo-Ferrari, Larissa; Mizokami, Sandra S; Silva, Jean J; da Silva, Francisco O N; Sousa, Eduardo H S; da França, Luiz G; Matuoka, Mariana L; Georgetti, Sandra R; Baracat, Marcela M; Casagrande, Rubia; Pavanelli, Wander R; Verri, Waldiceu A

2013-04-01

314

The stimulation of capsaicin-sensitive neurones in a vanilloid receptor-mediated fashion by pungent terpenoids possessing an unsaturated 1,4-dialdehyde moiety.  

PubMed Central

1. The irritant fungal terpenoid isovelleral caused protective eye-wiping movements in the rat upon intraocular instillation and showed cross-tachyphylaxis with capsaicin, the pungent principle in hot pepper. 2. Isovelleral induced a dose-dependent calcium uptake by rat dorsal root ganglion neurones cultured in vitro with an EC50 of 95 nM, which was fully inhibited by the competitive vanilloid receptor antagonist capsazepine. 3. Isovelleral inhibited specific binding of [3H]-resiniferatoxin (RTX), an ultrapotent capsaicin analogue, to rat trigeminal ganglion or spinal cord preparations with an IC50 of 5.2 microM; in experiments in which the concentration of [3H]-RTX was varied, isovelleral changed both the apparent affinity (from 16 pM to 37 pM) and the co-operativity index (from 2.1 to 1.5), but not the Bmax. 4. The affinity of isovelleral for inducing calcium uptake or inhibiting RTX binding was in very good agreement with the threshold dose (2.2. nmol) at which it provoked pungency on the human tongue. 5. For a series of 14 terpenoids with an unsaturated 1,4-dialdehyde, a good correlation was found between pungency on the human tongue and affinity for vanilloid receptors on the rat spinal cord. 6. The results suggest that isovelleral-like compounds produce their irritant effect by interacting with vanilloid receptors on capsaicin-sensitive sensory neurones. Since these pungent diterpenes are structurally distinct from the known classes of vanilloids, these data provide new insights into structure-activity relations and may afford new opportunities for the development of drugs targeting capsaicin-sensitive pathways.

Szallasi, A.; Jonassohn, M.; Acs, G.; Biro, T.; Acs, P.; Blumberg, P. M.; Sterner, O.

1996-01-01

315

The induction of long-term potentiation in spinal dorsal horn after peripheral nociceptive stimulation and contribution of spinal TRPV1 in rats.  

PubMed

During chronic pain states, peripheral nociceptive stimulation can induce long-term potentiation (LTP) in the spinal dorsal horn, but it is not clear how quickly spinal LTP develops after peripheral noxious stimulation. Furthermore, transient receptor potential vanilloid type 1 (TRPV1) receptors are abundant in spinal cord dorsal horn, especially in the superficial layers, and are thought to be involved in synaptic plasticity. In this study, we investigated the time frame of LTP induction after inflammatory insult and electrical stimulation and the involvement of TRPV1 receptors. By using extracellular recordings of C-fiber-evoked field potentials in the superficial spinal dorsal horn and teased fiber recording in vivo, we found that subcutaneous injection of complete Freund's adjuvant (CFA) or 5% formalin induced low-frequency, irregular discharges of C-fibers and LTP of the C-fiber-evoked field potentials in the spinal dorsal horn within 3h. Topical application of the TRPV1 receptor antagonist capsazepine onto the spinal cord inhibited the induction of spinal LTP by CFA or formalin. Furthermore, capsazepine and another TRPV1 antagonist, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide, partially or completely blocked the LTP induced by conditioning stimulation with high- and low-frequency electrical stimulation. These results suggest that acute peripheral inflammatory stimulation by CFA or 5% formalin can induce spinal LTP very early after stimulation onset and that TRPV1 receptors in the spinal dorsal horn might contribute to this LTP induction. PMID:24680883

Yang, F; Guo, J; Sun, W-L; Liu, F-Y; Cai, J; Xing, G-G; Wan, Y

2014-06-01

316

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

2013-09-01

317

Intrathecal dihydroergotamine inhibits capsaicin-induced vasodilatation in the canine external carotid circulation via GR127935- and rauwolscine-sensitive receptors.  

PubMed

It has been suggested that during a migraine attack trigeminal nerves release calcitonin gene-related peptide (CGRP), producing central nociception and vasodilatation of cranial arteries, including the extracranial branches of the external carotid artery. Since trigeminal inhibition may prevent this vasodilatation, the present study has investigated the effects of intrathecal dihydroergotamine on the external carotid vasodilatation to capsaicin, ?-CGRP and acetylcholine. Anaesthetized vagosympathectomized dogs were prepared to measure blood pressure, heart rate and external carotid conductance. A catheter was inserted into the right common carotid artery for the continuous infusion of phenylephrine (to restore the carotid vascular tone), whereas the corresponding thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, ?-CGRP and acetylcholine (which dose-dependently increased the external carotid conductance). Another cannula was inserted intrathecally (C(1)-C(3)) for the administration of dihydroergotamine, the ?(2)-adrenoceptor antagonist rauwolscine or the serotonin 5-HT(1B/1D) receptor antagonist GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide hydrochloride monohydrate). Intrathecal dihydroergotamine (10, 31 and 100?g) inhibited the vasodilatation to capsaicin, but not that to ?-CGRP or acetylcholine. This inhibition was: (i) unaffected by 10?g GR127935 or 100?g rauwolscine, but abolished by 31?g GR127935 or 310?g rauwolscine at 10?g dihydroergotamine; and (ii) abolished by the combination 10?g GR127935+100?g rauwolscine at 100?g dihydroergotamine. Thus, intrathecal (C(1)-C(3)) dihydroergotamine seems to inhibit the external carotid vasodilatation to capsaicin by spinal activation of serotonin 5-HT(1B/1D) (probably 5-HT(1B)) receptors and ?(2) (probably ?(2A/2C))-adrenoceptors. PMID:22841658

Marichal-Cancino, Bruno A; González-Hernández, Abimael; Manrique-Maldonado, Guadalupe; Ruiz-Salinas, Inna I; Altamirano-Espinoza, Alain H; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

2012-10-01

318

TRPV1 in the central nervous system: synaptic plasticity, function, and pharmacological implications.  

PubMed

The function of TRPV1 in the peripheral nervous system is increasingly being investigated for its anti-inflammatory and antinociceptive properties in an effort to find a novel target to fight pain that is nonaddictive. However, in recent years, it was discovered that TRPV1 is also associated with a wide array of functions and behaviors in the central nervous system, such as fear, anxiety, stress, thermoregulation, pain, and, more recently, synaptic plasticity, the cellular