Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010200 (cough)
 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transient receptor potential vanilloid type channels (TRPVs) are expressed in several cell types in human and animal lungs. Increasing evidence has demonstrated important roles of these cation channels, particularly TRPV1 and TRPV4, in the regulation of airway function. These TRPVs can be activated by a number of endogenous substances (hydrogen ion, certain lipoxygenase products, etc.) and changes in physiological conditions (e.g., temperature, osmolarity, etc.). Activation of these channels can evoke Ca(2+) influx and excitation of the neuron. TRPV1 channels are generally expressed in non-myelinated afferents innervating the airways and lungs, which also contain sensory neuropeptides such as tachykinins. Upon stimulation, these sensory nerves elicit centrally-mediated reflex responses as well as local release of tachykinins, and result in cough, airway irritation, reflex bronchoconstriction and neurogenic inflammation in the airways. Recent studies clearly demonstrated that the excitability of TRPV1 channels is up-regulated by certain autacoids (e.g., prostaglandin E(2), bradykinin) released during airway inflammatory reaction. Under these conditions, the TRPV1 can be activated by a slight increase in airway temperature or tissue acidity. Indirect evidence also suggests that TRPV channels may play a part in the pathogenesis of certain respiratory diseases such as asthma and chronic cough. Therefore, the potential use of TRPV antagonists as a novel therapy for these diseases certainly merits further investigation.
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PMID:Role of TRPV receptors in respiratory diseases. 1734 45

Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.
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PMID:Currently available cough suppressants for chronic cough. 1790 97

Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current efforts in clinical validation of TRPV1 antagonists revolve around various pain indications; therefore, clinical evaluation of TRPV1 antagonists as antitussive agents will have to await those outcomes.
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PMID:TRPV1 antagonists as potential antitussive agents. 1792 96

The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed, and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Injury or diseases of the nervous system, as well as drugs and disorders of the peripheral organs, can produce lower urinary tract dysfunction. In the overactive bladder (OAB) condition, therapeutic targets for facilitation of urine storage can be found at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain. There is increasing evidence showing that the urothelium has specialized sensory and signaling properties including: (1) expression of nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors, (2) close physical association with afferent nerves, and (3) ability to release chemical molecules such as adenosine triphosphate (ATP), acetylcholine, and nitric oxide. Increased expression and/or sensitivity of these urothelial-sensory molecules that lead to afferent sensitization have been documented as possible pathogenesis of OAB. Targeting afferent pathways and/or bladder smooth muscles by modulating activity of ligand receptors (e.g., neurokinin, ATP, or beta3-adrenergic receptors) and ion channels (e.g., TRPV1 or K) could be effective to suppress OAB. In the stress urinary incontinence condition, pharmacotherapies targeting the neurally mediated urethral continence reflex during stress conditions such as sneezing or coughing could be effective for increasing the outlet resistance. Therapeutic targets include adrenergic and serotonergic receptors in the spinal cord as well as adrenergic receptors at the urethral sphincter, which can enhance urethral reflex activity during stress conditions and increase baseline urethral pressure, respectively.
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PMID:Therapeutic receptor targets for lower urinary tract dysfunction. 1803 30

Chronic cough in gastroesophageal reflux disease (GERD) has been attributed to irritation of the esophagus and/or upper airways by reflux of gastric content. Animal models have provided insight into both of these putative mechanisms. In patients with chronic cough and GERD, stimuli associated with reflex in the esophagus sensitize the cough reflex. This sensitization can be reproduced in the guinea pig and is most likely mediated by the esophageal afferent nerve fibers carried by the vagus nerves. Studies in animals have identified several subtypes of vagal esophageal C-fibers that may subserve this function. The putative nociceptive vagal C-fibers in the guinea pig esophagus are stimulated by acid and express the TRPV1 and TRPA1 receptors that confer responsiveness to disparate noxious stimuli. Acute and/or chronic irritation of the upper airways by reflux may contribute to cough by stimulation and/or sensitization of the airway afferent nerves. Studies in animals have identified airway nerves that likely initiate cough due to aspirated reflux; have characterized their pharmacology; and have provided insight into changes of their sensitivity. Studies in animal models have also described the neurophysiology of reflexes that protect the airways from reflux. In conclusion, animal models provide mechanistic insight into the modulation of cough from the esophagus and the pharmacology of neural pathways mediating cough in GERD.
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PMID:Cough and gastroesophageal reflux: insights from animal models. 1913 51

Preclinical studies suggest that the vanilloid receptor (TRPV1) is an important component of several disease areas such as pain (inflammatory, visceral, cancer and neuropathic), airway disease (including chronic cough), inflammatory bowel disease (IBD), interstitial cystitis, urinary incontinence, pancreatitis and migraine. TRPV1 is a member of a distinct subgroup of the transient receptor potential (TRP) family of ion channels. The neuronally expressed TRPV1 is a non-selective, Ca(2+)-preferring, cation channel. In addition to capsaicin, this channel is activated by a number of different stimuli including heat, acid, certain arachidonic acid derivatives and direct phosphorylation via protein kinase C (PKC). Moreover, there is also evidence that various inflammatory mediators such as adenosine triphosphate (ATP), bradykinin, nerve growth factor (NGF) or prostaglandin E(2) (PGE(2)) may indirectly lead to activation of the TRPV1 channel via activation of their respective receptors. There is strong experimental evidence that the combination of direct and indirect mechanisms finely tune the TRPV1 activity. Each of the different known modes of direct TRPV1 activation (protons, heat and vanilloids) is capable of sensitising the channel to other agonists. Similarly, inflammatory mediators from the external milieu found in disease conditions can indirectly sensitise the receptor. It is this sensitisation of the TRPV1 receptor in inflammatory disease that could hold the key and contribute to the transduction of noxious signalling for normally innocuous stimuli, i.e. either hyperalgesia in the case of chronic pain or airway hyperresponsivness/hypertussive responses in patients with chronic cough. It seems reasonable to suggest that the various mechanisms for sensitisation provide a scenario for TRPV1 to be tonically active and this activity may contribute to the underlying pathology -- providing an important convergence point of multiple pain producing stimuli in the somatosensory system and multiple cough-evoking irritants in the airways. The complex mechanisms and pathways that contribute to the pathophysiology of chronic pain and chronic cough have made it difficult for clinicians to treat patients with current therapies. There is an increasing amount of evidence supporting the hypothesis that the expression, activation and modulation of TRPV1 in sensory neurones appears to be an integral component of pain and cough pathways, although the precise contribution of TRPV1 to human disease has yet to be determined. So the question remains open as to whether TRPV1 therapeutics will be efficacious and safe in man and represent a much needed novel pain and cough therapeutic.
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PMID:TRPV1 receptors in sensitisation of cough and pain reflexes. 1914 28

Chronic cough derives from inflammatory hypersensitivity of tracheobronchial nerve endings, most of which express the polymodal capsaicin receptor-channel transient receptor potential vanilloid (TRPV) type 1 and the secretory neuropeptide calcitonin gene-related peptide (CGRP). An isolated mouse trachea preparation was established to measure chemically and thermally stimulated CGRP release as an index for sensory transduction of potential cough-inducing stimuli. TRPV1 knockout mice were employed to assess the TRPV1 contribution to tracheal responsiveness and sensitization. Graded heat-induced CGRP release depended entirely on extracellular calcium and partly on TRPV1; knockout mice showed 60% less CGRP release at 45 degrees C (for 5 min) than wild-types. This heat response was facilitated by the TRPV1 agonist ethanol and the TRPV1-3 agonist 2-aminoethoxydiphenyl borate, effects that were reduced or absent in TRPV1(-/-), respectively. The TRPV1 antagonists ruthenium red and N-(4-t-butylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide were ineffective on the basal heat response. A step increase of temperature from 22 to 40 degrees C caused a TRPV1-independent CGRP release that was doubled by bradykinin in wild-types but not TRPV1(-/-). Proton stimulation resulted in a bell-shaped concentration-response curve with threshold at pH 6.7 and a maximum at pH 5.7; responses were greatly reduced but not abolished in TRPV1(-/-). Coadministration of amiloride (30 microm), the blocker of acid-sensing ion channels, was ineffective in both TRPV1 genotypes. The data suggest that tracheal acid sensing mainly involves TRPV1 but not acid-sensing ion channels, whereas noxious heat responsiveness partly depends and (inflammatory) sensitization to heat largely depends on the capsaicin receptor in tracheal nerve endings. Lowering of their heat threshold to near body temperature may sustain hypersensitivity and neurogenic inflammation of the upper airways.
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PMID:TRPV1 controls acid- and heat-induced calcitonin gene-related peptide release and sensitization by bradykinin in the isolated mouse trachea. 1947 41

Sneezing, cough, mucus secretion, and bronchoconstriction represent the main components of a coordinated and efficient reaction direct to expel or neutralize irritant agents from the respiratory system. A dense network of sensory nerves localized from the nose to the lower airways beneath the epithelium subserves this function. A variety of receptors and channels present in sensory nerve terminals by sensing irritant stimuli activate the system in emergence and initiate protective reflex responses, including cough. Previous and recent literature highlights the prominent role of some transient receptor potential (TRP) ion channels, and specifically the vanilloid 1 (TRPV1) and the ankyrin 1 (TRPA1) as sensors of airway irritation and initiators of the cough reflex.
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PMID:Cough: The Emerging Role of the TRPA1 Channel. 2009 Oct 46

Occupational and environmental irritants play a role in the pathogenesis of chronic cough. An irritant is a non-corrosive chemical, which causes a reversible inflammatory change on living tissue by chemical action at the site of contact. The clinical and pathologic spectrum of chemically induced respiratory tract irritation ranges from neurogenically mediated alterations in regional blood flow, mucus secretion, and airway caliber to the initiation of cough. In an evolutionary perspective, two types of cough reflexes were created for different protective purposes, but each type used the same anatomic and physiologic neural and muscular structures. The mechanosensory type evolved as human ancestors adapted phonation over olfaction and the larynx moved in close proximity to the esophageal opening. The chemosensory type evolved to protect against an injured lung from a respiratory tract infection or after inhaling high levels of irritant gases and particulates that accumulated in confined quarters of early times. For this latter type of cough reflex, normally quiescent transient receptor potential (TRP) cation channels TRPV1(vanilloid) and TRPA1 (ankyrin) become activated or hyperactivated after lung injury, with lung inflammation, or in response to chemicals. Although animal and laboratory investigations support the possibility of human TRPpathies, further investigations are essential for the further elucidation of the role of TRP cationic channels in instigating chronic cough in humans.
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PMID:Occupational, environmental, and irritant-induced cough. 2017 59

A subpopulation of nociceptive primary sensory neurons expresses six different transient receptor potential (TRP) ion channels of the vanilloid (V1, V2, V3 and V4), melastatin (M8) and ankyrin (A1) subtypes. TRPV1 mediates the tussive action of capsaicin, which is widely used in cough provocation studies. The upregulation of TRPV1 expression and function has been reported in asthma and other inflammatory conditions. TRPA1 is targeted by a series of byproducts of oxidative and nitrative stress, including acrolein, 4-hydroxy-2-nonenal and hydrogen peroxide. Proinflammatory neuropeptides are released from nociceptive nerve terminals after TRPV1/TRPA1 stimulation, thereby causing airway neurogenic inflammation. In addition, the early inflammatory response to cigarette smoke is mediated entirely by neuronal TRPA1. TRPV1 and TRPA1 antagonists may therefore represent potential antitussive and anti-inflammatory therapeutics for respiratory airway diseases.
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PMID:Transient receptor potential channels as novel drug targets in respiratory diseases. 2041 99


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