TRPV1 and cough
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《胸》
Correspondence to:
Associate Professor G P Anderson PhD
Lung Disease Research Laboratories, Research Director, CRC for Chronic Inflammatory Diseases, Departments of Pharmacology and Medicine, University of Melbourne, Parkville, VIC 3010, Australia; gpa@unimelb.edu.au
Iodo-resiniferatoxin, a new TRPV1 inhibitor, shows promising antitussive activity in an animal model
Abbreviations: TRPV1, transient receptor potential vanilloid-1
Keywords: cough; transient receptor potential vanilloid-1 (TRPV1); iodo-resiniferatoxin
Cough is one of the most common respiratory complaints and intractable cough remains one of the most distressing and difficult to treat conditions of the lung. It is ironical that the billions of dollars spent worldwide on proprietary over the counter remedies of questionable efficacy1 for cough exceeds, by orders of magnitude, the money spent on basic cough research. It is therefore not surprising that the cough pharmacopoeia has altered little in the last 50 years, with no important advances over opiate based compounds and cromones. However, basic researchers have not been idle. In this issue of Thorax Trevisani and colleagues2 present new information pointing to a causative role for an ion channel called transient receptor potential vanilloid-1 (TRPV1) in cough. They show that the highly selective and potent TRPV1 inhibitor iodo-resiniferatoxin, derived from a plant toxin found in Euphorbia species, strongly suppresses cough induced by inhaled capsaicin or citric acid in conscious guinea pigs, a widely used animal cough model.
The basis of this work is careful molecular dissection of precisely why coughing occurs when irritants are inhaled. It has been known for years that irritants such as citric acid and capsaicin (the pungent tongue burning constituent of hot chilli peppers) trigger coughing. It has also been known for decades from electrophysiological studies that such irritants activate respiratory tract sensory fibres—especially unmyelinated C fibres—to discharge information via the vagus to the medullary cough centre.3 From this early work it was inferred that the cough receptor on sensory fibres might be an ion channel able to rapidly depolarise afferent nerve membranes and hence trigger cough inducing impulses. This view was reinforced by the inhibitory activity of crude agents such as the dye ruthenium red. The discovery that capsazepine, a capsaicin derivative and a known ion channel blocker, had antitussive activity in animal models4 focused attention on the vanilloid receptor family as candidate ion channels.
The TRPV1 channel is a so-called receptor operated ion channel. It is moulded from six transmembrane domains that cluster forming a molecular "gate" which regulates the flow of cations across membranes when activated by a soluble ligand. TRPV1 is encoded on chromosome 17p13.3 and is also known as the capsaicin receptor, and the vanilloid receptor subtype 1 (VR1). This channel has been of interest to pain researchers for some time as it is known that the TRPV1 channel can be activated by painful heat (>43°C) and acid (pH <6.5). Its expression, however, is not confined to sensory nerves; TRPV1 has also recently been found on glial cells, endothelium, epithelium and keratinoctyes, suggesting that it may have a much broader role in regulating responses to tissue injury. Indeed, as there is no good evolutionary reason why the lower lung should respond to hot pepper extracts, it has been strongly suspected that there must be one or more endogenous ligands for TRPV1. To date, three putative "endovanilloids" including N-acyldopamines, arachidonic acid lipoxygenase metabolites, and anandamide (the endogenous ligand for cannabis receptors) have been identified.5 It is quite conceivable that these endoligands may be upregulated—together with kinins, histamine, and other known cough triggers—in lung diseases, but their specific relationship to cough is unknown.
TRPV1 therefore has the attraction of being a common activation point for coughing induced by different stimuli. As always, there are caveats. The cough reflex has important survival benefits and it is likely that multiple cough pathways have co-evolved. Mice breathe too rapidly and too shallowly to generate the airflow turbulence necessary to clear mucus by coughing, but they have a highly conserved afferent fibre TRPV1 which has strong homology with the human form. Elegant research by Kollarik and Undem6 has very recently identified TRPV1 independent discharges in bronchopulmonary vagal afferent fibres to bradykinin and acid in TRPV1 knock-out mice, indicating that at least one "back up" mechanism must exist. These findings are consistent with earlier studies showing that capsazepine did not block all cough inducing stimuli.4 It is also clear that patients with chronic cough have a reduced threshold for stimulation of cough, most probably because their afferent sensory fibres have become sensitised in a manner analogous to hyperalgesia in chronic pain. It is thought that this sensitisation may have both a peripheral and a CNS component. The role of TRPV1 in the induction or reversal of sensitisation—which may underlie very intractable cough—remains unknown. Moreover, the causes of cough in humans range from the physiological to the existential. While it is reasonable to hope that TRPV1 targeted treatments might benefit cough in very common clinical settings such as chronic obstructive pulmonary disease, post-viral cough syndromes, and cough associated with gastro-oesophageal reflux disease, it seems unlikely that the concept would benefit "psychogenic" cough at all.
Notwithstanding these limitations, the work of Trevisani and coworkers showing a therapeutic benefit of inhibiting TRPV1 with iodo-resiniferatoxin (and the more than 60 patents already filed in this field) suggests that there may soon be safer and more effective agents to deal with this perennial problem.
FOOTNOTES
Funded by the National Health and Medical Research Council (NHMRC) of Australia and the Cooperative Research Center (CRC) for Chronic Inflammatory Diseases.
REFERENCES
Schroeder K, Fahey T, Over-the-counter medications for acute cough in children and adults in ambulatory settings (Cochrane Review). In: The Cochrane Library. Chichester: John Wiley & Sons, 2004.
Trevisani M, Milan A, Gatti R, et al. Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 2004;59:769–72.
Coleridge JC, Coleridge HM. Lower respiratory tract afferents stimulated by inhaled irritants. Am Rev Respir Dis 1985;131:S51–4.
Lalloo UG, et al. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 1995;79:1082–7.
Van Der Stelt M, Di Marzo V. Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem 2004;271:1827–34.
Kollarik M, Undem BJ. Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice. J Physiol 2004;555 (Pt 1):115–23.(G P Anderson)
Associate Professor G P Anderson PhD
Lung Disease Research Laboratories, Research Director, CRC for Chronic Inflammatory Diseases, Departments of Pharmacology and Medicine, University of Melbourne, Parkville, VIC 3010, Australia; gpa@unimelb.edu.au
Iodo-resiniferatoxin, a new TRPV1 inhibitor, shows promising antitussive activity in an animal model
Abbreviations: TRPV1, transient receptor potential vanilloid-1
Keywords: cough; transient receptor potential vanilloid-1 (TRPV1); iodo-resiniferatoxin
Cough is one of the most common respiratory complaints and intractable cough remains one of the most distressing and difficult to treat conditions of the lung. It is ironical that the billions of dollars spent worldwide on proprietary over the counter remedies of questionable efficacy1 for cough exceeds, by orders of magnitude, the money spent on basic cough research. It is therefore not surprising that the cough pharmacopoeia has altered little in the last 50 years, with no important advances over opiate based compounds and cromones. However, basic researchers have not been idle. In this issue of Thorax Trevisani and colleagues2 present new information pointing to a causative role for an ion channel called transient receptor potential vanilloid-1 (TRPV1) in cough. They show that the highly selective and potent TRPV1 inhibitor iodo-resiniferatoxin, derived from a plant toxin found in Euphorbia species, strongly suppresses cough induced by inhaled capsaicin or citric acid in conscious guinea pigs, a widely used animal cough model.
The basis of this work is careful molecular dissection of precisely why coughing occurs when irritants are inhaled. It has been known for years that irritants such as citric acid and capsaicin (the pungent tongue burning constituent of hot chilli peppers) trigger coughing. It has also been known for decades from electrophysiological studies that such irritants activate respiratory tract sensory fibres—especially unmyelinated C fibres—to discharge information via the vagus to the medullary cough centre.3 From this early work it was inferred that the cough receptor on sensory fibres might be an ion channel able to rapidly depolarise afferent nerve membranes and hence trigger cough inducing impulses. This view was reinforced by the inhibitory activity of crude agents such as the dye ruthenium red. The discovery that capsazepine, a capsaicin derivative and a known ion channel blocker, had antitussive activity in animal models4 focused attention on the vanilloid receptor family as candidate ion channels.
The TRPV1 channel is a so-called receptor operated ion channel. It is moulded from six transmembrane domains that cluster forming a molecular "gate" which regulates the flow of cations across membranes when activated by a soluble ligand. TRPV1 is encoded on chromosome 17p13.3 and is also known as the capsaicin receptor, and the vanilloid receptor subtype 1 (VR1). This channel has been of interest to pain researchers for some time as it is known that the TRPV1 channel can be activated by painful heat (>43°C) and acid (pH <6.5). Its expression, however, is not confined to sensory nerves; TRPV1 has also recently been found on glial cells, endothelium, epithelium and keratinoctyes, suggesting that it may have a much broader role in regulating responses to tissue injury. Indeed, as there is no good evolutionary reason why the lower lung should respond to hot pepper extracts, it has been strongly suspected that there must be one or more endogenous ligands for TRPV1. To date, three putative "endovanilloids" including N-acyldopamines, arachidonic acid lipoxygenase metabolites, and anandamide (the endogenous ligand for cannabis receptors) have been identified.5 It is quite conceivable that these endoligands may be upregulated—together with kinins, histamine, and other known cough triggers—in lung diseases, but their specific relationship to cough is unknown.
TRPV1 therefore has the attraction of being a common activation point for coughing induced by different stimuli. As always, there are caveats. The cough reflex has important survival benefits and it is likely that multiple cough pathways have co-evolved. Mice breathe too rapidly and too shallowly to generate the airflow turbulence necessary to clear mucus by coughing, but they have a highly conserved afferent fibre TRPV1 which has strong homology with the human form. Elegant research by Kollarik and Undem6 has very recently identified TRPV1 independent discharges in bronchopulmonary vagal afferent fibres to bradykinin and acid in TRPV1 knock-out mice, indicating that at least one "back up" mechanism must exist. These findings are consistent with earlier studies showing that capsazepine did not block all cough inducing stimuli.4 It is also clear that patients with chronic cough have a reduced threshold for stimulation of cough, most probably because their afferent sensory fibres have become sensitised in a manner analogous to hyperalgesia in chronic pain. It is thought that this sensitisation may have both a peripheral and a CNS component. The role of TRPV1 in the induction or reversal of sensitisation—which may underlie very intractable cough—remains unknown. Moreover, the causes of cough in humans range from the physiological to the existential. While it is reasonable to hope that TRPV1 targeted treatments might benefit cough in very common clinical settings such as chronic obstructive pulmonary disease, post-viral cough syndromes, and cough associated with gastro-oesophageal reflux disease, it seems unlikely that the concept would benefit "psychogenic" cough at all.
Notwithstanding these limitations, the work of Trevisani and coworkers showing a therapeutic benefit of inhibiting TRPV1 with iodo-resiniferatoxin (and the more than 60 patents already filed in this field) suggests that there may soon be safer and more effective agents to deal with this perennial problem.
FOOTNOTES
Funded by the National Health and Medical Research Council (NHMRC) of Australia and the Cooperative Research Center (CRC) for Chronic Inflammatory Diseases.
REFERENCES
Schroeder K, Fahey T, Over-the-counter medications for acute cough in children and adults in ambulatory settings (Cochrane Review). In: The Cochrane Library. Chichester: John Wiley & Sons, 2004.
Trevisani M, Milan A, Gatti R, et al. Antitussive activity of iodo-resiniferatoxin in guinea pigs. Thorax 2004;59:769–72.
Coleridge JC, Coleridge HM. Lower respiratory tract afferents stimulated by inhaled irritants. Am Rev Respir Dis 1985;131:S51–4.
Lalloo UG, et al. Capsazepine inhibits cough induced by capsaicin and citric acid but not by hypertonic saline in guinea pigs. J Appl Physiol 1995;79:1082–7.
Van Der Stelt M, Di Marzo V. Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem 2004;271:1827–34.
Kollarik M, Undem BJ. Activation of bronchopulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wild-type and TRPV1-/- mice. J Physiol 2004;555 (Pt 1):115–23.(G P Anderson)