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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD There is evidence that TRPV1 plays a role in the development of pathophysiological changes and symptoms in several diseases. TRPV1 Receptor: A Target for the Treatment of Pain, Cough, Airway Disease and Urinary Incontinence by Yanlin Jia, Robbie L. McLeod and John A. Hey Summary The TRPV1 channel is mainly expressed in sensory nerves. Activation of the channel induces neuropeptide release from central and peripheral sensory nerve terminals, resulting in the sensation of pain, neurogenic inflammation, smooth muscle contraction and cough. The TRPV1 channel can be activated by vanilloids such as capsaicin, as well as endogenous stimulators including H+, heat, lipoxygenase products and anandamide. TRPV1 channel function is upregulated by several endogenous mediators present in inflammatory conditions, which decreases the threshold for activation of the channel. Under these conditions, TRPV1 can be activated by physiological body temperature, slight acidification or lower concentration of TRPV1 agonists. There is evidence that TRPV1 plays a role in the development of pathophysiological changes and symptoms in several diseases. In this review, we discuss TRPV1 channel activation and regulation in normal and diseased conditions, the role of TRPV1 in pain, cough, asthma and urinary incontinence, and the potential use of TRPV1 antagonists as a novel therapy for these diseases. © 2005 Prous Science. All rights reserved. Capsaicin, the pungent ingredient of hot pepper, was first isolated in 1846 and synthesized in 1930.1,2 The capsaicin-like bioactivity of capsaicin was described over half a century ago.3,4 The existence of the capsaicin receptor was demonstrated by the specific binding of [3H] (resiniferatoxin, RTX), an analogue of capsaicin.5 In 1997, the capsaicin receptor was cloned from a rat dorsal root ganglia (DRG) cDNA library and termed type 1 vanilloid receptor (VR1).6 As a prominent cation channel in the transient receptor potential (TRP) family, VR1 receptor is presently designated TRPV1 for type 1 transient receptor potential vanilloid. The distribution, structure and function of TRPV1 have been studied in detail during the last decade. TRPV1 is mainly expressed in sensory nerves from peripheral terminals to central endings.7 These nerves include those emanating from DRG and vagal sensory neurons (nodose ganglia and jugular ganglia), which innervate various visceral organs. Moreover, TRPV1-expressing neurons are also found in certain areas of rat and human brain.8 TRPV1 is a membrane protein consisting of six transmembrane domains and a pore-loop between the fifth and sixth membrane-spanning regions. There are three protein kinase phosphorylation sites on the TRPV1 protein that are involved in the regulation of channel activity.9 Like other channels in TRPV family, TRPV1 channel is a nonspecific cation channel with preference for Ca2+. This channel can be activated by vanilloids such as capsaicin and RTX. TRPV1 can also be activated by a number of endogenous stimuli including heat and protons.6,10 Additionally, many inflammatory mediators, such as lipoxygenase products, can also activate the channel.11 Phosphorylation of TRPV1 by protein kinases increases channel activity and decreases the threshold for channel activation by heat, acidification and other TRPV1 activators. Activation of TRPV1 channels on sensory nerves induces Ca2+ influx into the neuronal cell, and subsequent neuropeptide release from both peripheral and central nerve terminals, which may result in a number of physiologically responses, such as sensation of pain, neurogenic inflammation, smooth muscle contraction, cough and bladder voiding response (Fig. 1). These neuropeptides include substance P, neurokinin A and calcitonin gene-related peptide (CGRP). There is evidence that TRPV1 plays a role in the development of several diseases. In this review, we discuss the TRPV1 channel activation and regulation in normal and diseased conditions, and the role of TRPV1 in the development of pain, cough, airway disease and urinary incontinence. Also, the potential use of TRPV1 antagonists as a novel therapy for these diseases is reviewed.
Fig. 1. Activation and regulation of TRPV1 channels in sensory nerves. TRPV1 channels are activated by endogenous stimulators including H+, heat, lipoxygenase products and anandamide. TRPV1 activity is upregulated by protein kinase A (PKA) and protein kinase C (PKC) phosphorylation of the channel. Inflammatory mediators such as bradykinin and PGE2 sensitize the TRPV1 channel to the activators through PKC and PKA activation. TRPV1 activation in sensory nerves induces Ca2+ influx and neuropeptide release from both central and peripheral terminals, resulting in physiological changes in normal and diseased conditions. Activation and sensitization of TRPV1 channels by endogenous activators As previously stated, TRPV1 can be activated by exogenous vanilloids such as capsaicin and RTX. Nonetheless, there is an abundance of lit-erature demonstrating that TRPV1 channels may also be sensitized and activated by potential endogenous activators and regulators produced in inflammatory and damaged tissues. A brief description of these activators are discussed below and summarized in Figure 1. Acidification Acidification of extracellular fluid can be found in a variety of pathophysiological conditions including tissue inflammation and ischemia.12-14 Endogenous airway acidification is also observed in asthmatic patients.15 Protons not only activate TRPV1 channels directly but also increase TRPV1 response to other activators. Proton activation of the channel is determined by E648 site of the channel, while proton potentiation of TRPV1 channel activity is determined by an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the pore-forming region of the channel.16 Decreased extracellular pH activates TRPV1 channels in TRPV1 transfected cells.6,10 The threshold pH for activation of TRPV1 depends on the temperature. TRPV1 is activated by pH 5.4 at room temperature and by pH 6.4 at 37 oC.10 Therefore, at physiological body temperature, slight acidification may become an endogenous TRPV1 activator. Acidification also increases the TRPV1 channel sensitivity to a variety of other activators. For example, acidification increases capsaicin-activated and heat-activated TRPV1 responses in TRPV1 transfected cells10 and in DRG/trigeminal neurons.17-19 Acid-induced TRPV1 potentiation is through the increase of channel open probability with no effect on single channel conductance.20 Heat Increased temperature activates the TRPV1 channel on TRPV1 transfected cells.6,10 The temperature threshold for TRPV1 activation varies in different conditions. For example, TRPV1 is activated by heat with a threshold of 42 oC at physiological pH.21 The threshold temperature decreases to 37 oC at pH 6.4.10 Bradykinin, which is released in inflammatory tissues, lowers the threshold temperature to a level well below 37 oC in a concentration-dependent manner through protein kinase C (PKC) activation.22 In the presence of ATP, which is released in damaged tissues, the temperature threshold for TRPV1 activation is reduced from 42 oC to 35 oC.21 In these conditions, physiological body temperature becomes an endogenous TRPV1 activator and activates the channel. When the TRPV1 channel is activated, sensory nerve neuropeptides are released from peripheral and central endings and play a role in the development of the physiological changes and symptoms in diseases. Lipoxygenase (LO) products Products derived from lipoxygenation of arachidonic acid are released in inflammatory tissues such as asthmatic lungs.23 The proinflammatory and hyperalgesia effects of lipoxygenation products, which mimic TRPV1 activation, were observed decades ago.23,24 The direct activation of TRPV1 by lipoxygenation products was demonstrated recently,11 adding them to the list of potential endogenous TRPV1 agonists in diseased conditions. Anandamide Anandamide, an endogenous neuronal lipid mediator, is the ethanolamine amide of arachidonic acid first isolated from porcine brain.25 Anandamide is synthesized in the nervous system26 as well as in peripheral tissues such as lungs.27 Anandamide was previously known as a cannabinoid receptor agonist. Recent evidence shows that anandamide also activates human and rat TRPV1 receptors in TRPV1 transfected cells and in rat DRG cells.28-30 The anandamide affinity to TRPV1 is similar to capsaicin, but the potency is significantly lower.31 Anandamide is found to be either a partial or a full agonist, depending on the tissue tested.31 The effect of endogenous anandamide on the TRPV1 channel may vary in different tissues and be dependent on physiological conditions. For example, as a partial agonist, anandamide may decrease the channel response to full TRPV1 agonists, while in conditions in which TRPV1 activity is upregulated, anandamide may serve as an endogenous agonist and activate the channel. Other activators A potent endogenous TRPV1 agonist, N-arachidonoyl-dopamine, has recently been isolated from the central nervous system.32 Its effect on physiological function is not known. TRPV1 channel regulation The TRPV1 channel can be upregulated by many endogenous regulators including protein kinases and inflammatory mediators. Among them, regulation of TRPV1 channel activity by PKC has been studied in detail. It has been shown that activation of PKC results in direct phosphorylation of TRPV1.33,34 PKC phosphorylation of TRPV1 increases TRPV1 channel activity induced by capsaicin, protons, heat and anandamide in TRPV1 transfected cells,33,35,36 and in rat dorsal root ganglia neurons.36 Two serine residues, Ser502 and Ser 800, are involved in the potentiation of the TRPV1 activity by PKC phosphorylation.33,34 PMA, a PKC activator, decreases the threshold temperature for TRPV1 activation from 42 oC to 32 oC, so that a physiological body temperature is capable of activating TRPV1.33 The TRPV1 channel can also be phosphorylated by protein kinase A (PKA).37 PKA activation enhances capsaicin-induced currents and neuropeptide release in cultured DRG cells.38-40 Inhibition of desensitization may contribute to the increased channel activity.37 In addition, ATP also increases the capsaicin- and acid-induced current and reduces the temperature threshold for TRPV1 activation from 42 oC to 35 oC.21 It is suggested that ATP-induced upregulation of TRPV1 activity is through a purinergic P2Y1 receptor and PKC-dependent mechanism.21 Other inflammatory mediators may also be involved in the sensitization of TRPV1 in inflammatory conditions. Prostaglandin E2 (PGE2) potentiates capsaicin-induced currents in pulmonary vagal sensory neurons from rats.41 Bradykinin, a nonapeptide released into inflamed tissues, decreases the temperature threshold for TRPV1 activation,22 induces pain and evokes hyperalgesia to heat.42 The combination of bradykinin, 5-HT and PGE2 induces TRPV1 currents in rat DRG cells at pH 6.1.43 The PGE2- and bradykinin-induced potentiation of TRPV1 channel activity is believed to be through a PKA and PKC-dependent mechanism.22,40 Moreover, in inflammatory tissues, in addition to increased channel activity, the TRPV1 expression level is also upregulated.44 Taken together, this evidence indicates that in inflammatory conditions the TRPV1 channel may be sensitized, which promotes the activation of the channel by a lower level of endogenous activators such as slight acidification, physiological body temperature and low concentration of endogenous TRPV1 agonists. Thus, TRPV1 activation may result in physiological changes in inflammatory tissues and contribute to various pathophysiological conditions. Role of TRPV1 in the development of diseases Evidence indicates that TRPV1 may play a role in the development of several diseases and symptoms. This evidence includes: 1) TRPV1 activation induces pathophysiological responses in human and animals; 2) pathophysiological responses were reversed by TRPV1 antagonists or in mice lacking TRPV1; 3) TRPV1 activity is increased in patients; and 4) endogenous TRPV1 activators are present in diseased tissues. The following summarizes the evidence for the role of TRPV1 in the pathophysiological changes in some diseases. TRPV1 in pain TRPV1 activation by capsaicin resulting in pain and hyperalgesia in humans has long been observed.45,46 A growing body of evidence shows that TRPV1 plays a role in inflammatory and neuropathic pain. For example, pharmacological inhibition of TRPV1 receptors prevents hyperalgesia responses in inflammatory and neuropathic pain model in animals.47 BCTC, an oral active TRPV1 antagonist, reduced mechanical and thermal hyperalgesia in Freund's complete adjuvant-induced inflammation in rats. BCTC also inhibits mechanical hyperalgesia in a partial sciatic nerve injury model in rats.47 Capsazepine, a TRPV1 antagonist, reverses mechanical hyperalgesia in a model of neuropathic pain in guinea pigs.48 Capsazepine also reverses mechanical and thermal hyperalgesia in an inflammation pain model in guinea pigs.48 In addition, the hyperalgesic neural response induced by inflammation was blocked by capsazepine.49 Mice lacking TRPV1 receptors showed little thermal hypersensitivity induced by mustard oil inflammation.50 Taken together, these results suggest that TRPV1 plays an important role in hyperalgesia induced by inflammation and by neuropathic damage. Capsaicin cream, which desensitizes TRPV1 receptors, has been proved to be effective in the treatment of some types of pain in humans.51-53 The effect of TRPV1 inhibition on pain has not been tested in humans because of the lack of pharmacological tools. It appears that inhibition of the TRPV1 receptor by TRPV1 antagonists may be a potential treatment for some type of pain, such as inflammatory and neuropathic pain. Therefore, pain is currently a major indication for TRPV1 antagonist in the treatment of diseases. Role of TRPV1 in cough and airway diseases Capsaicin-sensitive TRPV1 is expressed in vagal sensory nerves including afferent fibers that innervate the airways. In vagal nodose ganglion, 82% of neurons express TRPV1 mRNA, which is higher than in DRG cells (47%).54 TRPV1 is also detected in guinea pig and human airways by radiolabeled ligand binding.55 Activation of TRPV1 in the airway induces neuropeptide release, including neuropeptide A, substance P, and CGRP. These sensory nerve-derived neuropeptides induce many of the airway responses observed in inflammatory lung diseases. For example, tachykinins are potent contractors of human and animal airways.56,57 Substance P causes microvascular leakage and stimulates mucus secretion from submucosal glands and epithelial goblet cells.56 Substance P, neurokinin A and CGRP induces histamine release from human lung mast cells.58-60 TRPV1 activation also induces cough and neurogenic inflammation in the airways. Cough Cough is arguably the most common symptom associated with pulmonary diseases such as asthma, chronic obstructive pulmonary disease and the common cold.61-63 This respiratory defense mechanism is facilitated by a coordinated effort of neuromuscular elements that comprises a complex reflex arc. The reflex arc includes a vagal sensory afferent limb, a central processing center located in the lower brainstem referred to as the "cough center" and an efferent motor limb. Interestingly, TRPV1 has been thought to play a significant role in the genesis of cough. The evidence for this linkage between TRPV1 and cough is supported by several observations. Firstly, TPRV1 receptors are found on sensory airway nerves that are important in the cough reflex.25,55,64-67 Secondly, TRPV1 agonists, such as capsaicin, elicit cough in animals and humans.68-71 It is also important to point out that capsaicin-induced cough responses are increased in cough-related inflammatory lung diseases such as asthma, bronchitis, COPD and post-viral infection,72-74 indicating an increased TRPV1 sensitivity in these diseases. In summary, cough is a serious and prominent pathophysiological feature of a diverse range of airway diseases. The role of TRPV1 in cough continues to be defined. Nonetheless, the utility of TRPV1 antagonists in the treatment of cough awaits clinical validation of efficacy and safety benchmarked against opioids, such as codeine. Asthma Asthma is a chronic inflammatory disease characterized by reversible airway obstruction and bronchial hyperresponsiveness to various stimuli. There is a great deal of evidence showing that neuropeptides released from airway sensory nerves are involved in the development of asthma.56,75 TRPV1 may be a receptor for sensory nerve activation. Endogenous TRPV1 activators, such as airway acidification and lipoxygenase products, have been detected in asthma patients.15 Inhaled capsaicin induces bronchoconstriction in 40% of asthma patients but not in normal subjects.70 Capsaicin-induced cough response is increased in asthma patients,72,74 indicating an increased TRPV1 activity in asthma. In allergic animal models, capsaicin pretreatment, which depletes airway sensory nerves, inhibits allergen-induced airway constriction in sensitized guinea pigs76 and airway hyperresponsiveness in allergic rabbits,77 suggesting a role of airway sensory nerves in this response. In a mouse model of nonatopic asthma, dinitrofluorobenzene sensitization and challenge induces inflammatory cell accumulation and airway hyperresponsiveness. These responses can also be inhibited by capsaicin pretreatment.78 However, capsaicin pretreatment is not sufficient to investigate the role of TRPV1 in diseases, since it also blocks sensory nerve activation by receptors other than TRPV1. Therefore, specific TRPV1 inhibition or the use of animals lacking TRPV1 are required to elucidate this. Unfortunately, mice have no capsaicin-induced airway responses (e.g., cough, airway contraction), limiting the value of TRPV1 airway studies using TRPV1-/- mice. The chronic effect of TRPV1 antagonists on asthmatic airway response such as airway inflammation, hyperresponsiveness, airway remodeling and airway obstruction in animal models deserves further investigation to validate the role of TRPV1 in asthma. Other airway diseases Exposure to airway-borne particulate matter is associated with increased motility and morbidity due to airway diseases. TRPV1 channels are expressed in cultured human airway epithelial cells. Particulate matter increases intracellular Ca2+. This re-sponse is inhibited by capsazepine in 70% of the cells. Particulate matter also induces epithelial apoptosis through the TRPV1 receptor. Therefore, pharmacological inhibition of TRPV1 receptors could be used to prevent some of the pathological actions by particulate matter.79 TRPV1 in urinary incontinence TRPV1 has been detected in fine and thick sensory nerve fibers in the human and rat bladder80 and is involved in the regulation of bladder function in normal and diseased conditions. Acute intravesical capsaicin treatment, which activates TRPV1, significantly decreases voiding interval, micturition volume and bladder capacity in rats, suggesting that TRPV1 activation potentiates voiding response.81 In mice lacking the TRPV1 receptor, bladder capacity is increased, providing evidence that TRPV1 is indeed involved in the regulation of bladder capacity.82 Sensory nerves can be desensitized by pretreatment with capsaicin or RTX. Sensory nerve desensitization increases voiding interval, threshold volume and bladder capacity in rats and guinea pigs in vivo,81,83 indicating an important role of TRPV1 expressing sensory nerves in the regulation of bladder voiding response. It is known that both TRPV1 and purinergic P2X3 receptors are expressed in bladder sensory nerves and desensitization of sensory nerves by RTX or capsaicin may antagonize the response through both receptors. RTX pretreatment abolished capsaicin-induced but not ATP-induced bladder responses in rats,81 indicating that RTX treatment acts through a TRPV1-dependet but not purinergic receptor-dependent mechanism. This is consistent with the notion that RTX treatment only desensitizes the TRPV1 channel on sensory nerves but does not deplete neuropeptide in the nerve. In this case, TRPV1 channel inhibition may achieve a similar effect as RTX/capsaicin desensitization on bladder function. Clinical studies show that RTX or capsaicin treatment improves incontinence frequency and cystometric capacity in spinal hyperreflexia and idiopathic detrusor instability syndromes.84 Intravesicular RTX also increases bladder capacity by 2.6 times in patients with neurogenic detrusor overactivity.84 If this effect is through desensitization of the TRPV1 channel, as observed in animals, TRPV1 inhibition may achieve a similar effect and become a novel treatment for urinary incontinence. Current status on drug discovery Several TRPV1 antagonists are under investigation for the treatment of pain, urinary incontinence and asthma, as summarized in Table I. AMG-9810 is a TRPV1 antagonist discovered by Amgen Inc. AMG-9810 is competitive with capsaicin and reverses hyperalgesia in inflammatory pain animal models. Investigational New Drug-enabling studies for TRPV1 antagonists by Amgen are underway. PAC-20030 was discovered by Amore Pacific (South Korea) as a TRPV1 antagonist. This compound is licensed by Schwarz Pharma AG (Germany) for drug development in human diseases. Neurogen and Merck are investigating a series of small-molecule TRPV1 antagonists for the potential treatment of pain, urinary incontinence and asthma. Among these compounds, NGV1 reduces capsaicin-induced pain in mice and rats and inhibits carrageenan-induced hyperalgesia in rats. Renovis Inc. and Digital Biotech Co. Ltd. are also investigating TRPV1 antagonists for the treatment of pain. Renovis Inc. plans to initiate a phase I clinical study in early 2005.
Conclusions Increasing evidence suggests that TRPV1 activated by endogenous activators is involved in the development of pathophysiological changes and symptoms in disease conditions including inflammatory and neuropathic pain, cough, asthma and urinary incontinence. In animal models, some pathophysiological changes are reversed or inhibited by TRPV1 antagonists or in TRPV1-/- animals. However, clinical studies to test the effect of TRPV1 inhibition on patients are required to confirm the role of TRPV1 in these diseases. If confirmed, TRPV1 will be a novel target for the treatment of these diseases. References 1. Thresh, L.T. Isolation of capsaicin. Pharm J 1846, 6: 941. 2. Spath E. and Darling S.F. Synthesis of capsaicin. Ber Chem Ges 1930, 63B: 737-40. 3. Toh, C.C., Lee, T.S. and Kiang, A.K. The pharmacological actions of capsaicin and analogues. Br J Pharmacol 1955, 10: 175-81. 4. Porszasz, J., Gyorgy, L. and Porszasz-Gibiszer, K. 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Hey are Researchers at Pulmonary and Peripheral Neurobiology, Schering-Plough Research Institute, Kenilworth, New Jersey, U.S.A. *Correspondence: Dr. Yanlin Jia, Pulmonary and Peripheral Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, U.S.A. Tel: 908-740-2472; Fax: 908-740-7175; E-mail: yanlin.jia@spcorp. com. Drug News & Perspectives
Vol. 18, No. 3, 2005, pp. 165-171
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