Biomolecules & Therapeutics 2024; 32(2): 192-204  https://doi.org/10.4062/biomolther.2023.118
Inhaled Volatile Molecules-Responsive TRP Channels as Non-Olfactory Receptors
Hyungsup Kim1, Minwoo Kim2 and Yongwoo Jang2,3,*
1Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792,
2Department of Medical and Digital Engineering, College of Engineering, Hanyang University, Seoul 04736,
3Department of Pharmacology, College of Medicine, Hanyang University, Seoul 04736, Republic of Korea
*E-mail: ywjang@hanyang.ac.kr
Tel: +82-2-2220-0665, Fax: +82-2-958-7034
Received: June 20, 2023; Revised: July 8, 2023; Accepted: July 12, 2023; Published online: August 8, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Generally, odorant molecules are detected by olfactory receptors, which are specialized chemoreceptors expressed in olfactory neurons. Besides odorant molecules, certain volatile molecules can be inhaled through the respiratory tract, often leading to pathophysiological changes in the body. These inhaled molecules mediate cellular signaling through the activation of the Ca2+-permeable transient receptor potential (TRP) channels in peripheral tissues. This review provides a comprehensive overview of TRP channels that are involved in the detection and response to volatile molecules, including hazardous substances, anesthetics, plant-derived compounds, and pheromones. The review aims to shed light on the biological mechanisms underlying the sensing of inhaled volatile molecules. Therefore, this review will contribute to a better understanding of the roles of TRP channels in the response to inhaled molecules, providing insights into their implications for human health and disease.
Keywords: Transient receptor potential channel, TRPV1, TRPA1, Volatile organic compound, Non-olfactory receptors
INTRODUCTION

There are various volatile molecules present in the surrounding air that pass through the respiratory tract, which is connected from the nasal cavity to the lungs. Among those, odorant molecules transmit scent information to the brain by activating the olfactory receptors of olfactory nerve cells within the olfactory epithelium. These volatile compounds can originate from various sources, including industrial processes, vehicle emissions, and consumer products. As harmful substances, it is important to note that when inhaled, they can pose a substantial risk to human health (Lee et al., 2023). Extensive studies have supported that these inhaled molecules play a role in mediating cellular signaling by activating the Ca2+-permeable transient receptor potential (TRP) channels in peripheral tissues. For instance, it has been established that unsaturated aldehydes such as crotonaldehyde, which is present in tobacco smoke, can activate the TRPA1 channel (Facchinetti et al., 2007; Andrè et al., 2008). This channel is involved in essential protective mechanisms in the body, such as coughing or respiratory suppression. Interestingly, inhalation anesthetics have been reported to stimulate several TRP channels as a side effect, despite their primary purpose of inducing and maintaining anesthesia (Bahnasi et al., 2008; Cornett et al., 2008; Eilers et al., 2010; Kichko et al., 2015b).

This review focuses on the biological functions of TRP channels that respond to volatile molecules including hazardous, anesthetic, and plant-derived compounds as well as pheromones (Fig. 1). The review aims to discuss the potential implications of these compounds in human health. Moreover, we will delve into the mechanisms through which TRP channels can be targeted to control pain, regulate respiratory and immune system function, and prevent adverse responses to harmful volatile molecules.

Figure 1. A schematic overview of the inhaled volatile compounds and the TRP channels that respond within the body.
TRP CHANNELS

Transient receptor potential channels are non-selective cation channels that primarily facilitate the influx of Ca2+ into the cell. Thus, TRP channels play a crucial role in intracellular calcium signaling pathways, which regulate a wide range of cellular processes, including neurotransmitter release, proliferation, differentiation, gene transcription, cell death, and inflammation (Jang et al., 2012). Based on their sequence homology and functional properties, TRP channels are largely classified into six distinct subfamilies, namely TRPV (TRPV1–TRPV6), TRPA (TRPA1), TRPM (TRPM1–TRPM7), TRPC (TRPC1–TRPC7), TRPP (TRPP1–TRPP3), and TRPML (TRPML1–TRPML3) (Nilius and Owsianik, 2011). TRP channels exhibit responsiveness to a diverse array of stimuli, including chemical substances, temperature changes, and mechanical stress. This unique characteristic highlights their potential as sensors capable of detecting and responding to various environmental changes that surround our bodies. As a representative example, distinct physiological temperatures are regulated by thermo-sensitive TRP channels including TRPA1 (<17°C), TRPM8 (<23°C), TRPV4 (>27°C) TRPV3 (>32°C) TRPV1 (>42°C), and TRPV2 (>52°C) (Patapoutian et al., 2003). These channels play a crucial role in sensing and responding to temperature changes in the body, contributing to the maintenance of thermal homeostasis (Wang and Siemens, 2015). In addition, several TRP channels are activated by pungent chemicals such as capsaicin (TRPV1), allicin (TRPA1), allyl isothiocyanate (TRPA1), and menthol (TRPM8) in sensory neurons (Caterina et al., 1997; Peier et al., 2002; Bandell et al., 2004; Macpherson et al., 2005). These TRP channels play a key role in detecting and responding to the sensation of pungency, which is the characteristic sharp, tingling, or spicy sensation caused by certain chemicals.

Interestingly, TRP channels are expressed in various cell types within the olfactory and respiratory system, including airway epithelial cells, smooth muscle, and nociceptive C-fibers that innervate this region (Nassenstein et al., 2008; Caceres et al., 2009; Lin et al., 2021). TRP channels are involved in the detection of inhaled irritants such as hazardous molecules, anesthetics, and ozone. The encounter of volatile molecules with TRP channels leads to the influx of ions into the cells, triggering a cascade of events that modulate physiological processes such as pain, inflammation, airway smooth muscle tone, and mucus secretion (Fig. 2).

Figure 2. An overview of the types of molecules that elicit activation of TRP channels and the associated symptoms.
HAZARDOUS COMPOUNDS

Volatile compounds with aldehyde functional group

Aldehydes are organic compounds in which a carbon atom shares a double bond with an oxygen atom (C=O-R-H). Majority of aldehyde-containing compounds are likely to exist as vapors in the surrounding air owing to their low boiling point. Aldehyde-containing volatile organic compounds (VOCs) are commonly generated in the ambient air through incomplete combustion processes from various sources like motor vehicles and chemical industrial plants. Additionally, they can also be formed through photochemical reactions involving precursor molecules and ozone. Aldehydes are recognized for their higher toxicity and reactivity compared to other VOCs because of the presence of a carbonyl group, which enables them to engage in various chemical reactions. Chronic exposure to aldehydes is associated with the development of serious diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and sick building syndrome (Win-Shwe et al., 2013). Studies have reported that a wide range of aldehydes can activate TRP channels (Table 1). Understanding the mechanism of activation is necessary to better predict the potential risks associated with hazardous compounds.

Table 1 Summary of aldehydes modulating TRP channels

AldehydesTRPA1TRPV1TRPV3TRPM8
Effects: inflammation, arrhythmia, hyperemia,
headache, respiratory inhibition, adrenaline secretion
AcroleinActivationEnhancement
FormaldehydeActivationSynergistic Effect
AcetaldehydeActivation
CrotonaldehydeActivation
CinnamaldehydeActivation
VanillinActivationActivationActivation


Acrolein, a toxic aldehyde utilized in various industries and generated through incomplete combustion, exhibits toxicity and acts as an irritant to the respiratory and sensory systems upon exposure (Achanta and Jordt, 2017). A majority of studies have primarily focused on the TRP channels present in somatosensory nerve endings, which play an important role in generating pain and irritation responses. The involvement of TRP channels became evident when the administration of a non-selective TRP channel blocker, ruthenium red, was found to inhibit the acrolein-induced calcium influx. This observation highlights the role of TRP channels in mediating the cellular response to acrolein exposure (Inoue and Bryant, 2005). Notably, identifying TRPA1 as an ion channel expressed in C-fibers has established it as the primary sensor responsible for detecting acrolein (Bautista et al., 2006). The calcium influx elicited by acrolein in sensory neurons was absent in mice lacking the TRPA1 gene (Macpherson et al., 2007). Furthermore, it was observed that TRPA1 mediates acrolein-induced neurogenic inflammation by triggering the release of pro-inflammatory neuropeptides in sensory nerve endings located in the lungs, trachea, and larynx (Andrè et al., 2008). Additionally, the inhibition of TRPA1 significantly alleviates inflammation in animal models of asthma, thus highlighting the important role of TRPA1 in the development and progression of this respiratory condition (Caceres et al., 2009). The inhalation of acrolein vapor by normal mice has been observed to cause immediate and transient inhibition of breathing, whereas TRPA1-null mice exhibited increased acrolein-induced mortality (Conklin et al., 2017). Moreover, when mice were treated with a TRPA1 inhibitor called HC-030031, they showed higher respiratory rates upon exposure to acrolein, leading to improved survival rates. Recent studies have reported an association between cough and single-nucleotide polymorphisms (SNPs) in TRPA1 and TRPV1. These SNPs in the genetic sequence of TRPA1 and TRPV1 have been found to be linked to the occurrence or severity of cough symptoms (Yoon et al., 2022). These findings highlight the role of TRPA1 in the inflammatory response associated with acrolein exposure in these respiratory tissues. In addition to respiratory problems, exposure to acrolein is also associated with cardiac arrhythmia and cardiovascular distress, thereby increasing the risk of heart failure or stroke. The involvement of TRPA1 in this process is indicated by the abolition of acrolein-induced arrhythmia through genetic deletion of TRPA1 (Perez et al., 2015; Kurhanewicz et al., 2017). Further, acrolein-induced TRPA1 activation is implicated in the heightened meningeal blood flow response, which can result in headaches (Kunkler et al., 2014).

Another volatile aldehyde, formaldehyde, is widely used in various industries and poses health risks to humans. Short-term exposure to formaldehyde can lead to eye and respiratory tract irritation, causing symptoms such as coughing, wheezing, chest pain, and bronchitis. Additionally, formaldehyde has been linked to the development of various cancers, including myeloid leukemia and brain, nasopharyngeal, sinonasal, and lymphohematopoietic cancers (Soffritti et al., 2002). The inhalation of formalin has also been associated with toxicity in the bone marrow and impairments in learning and memory processes in the brain (Lu et al., 2008; Yu et al., 2014). The activation of TRPA1 by formaldehyde has been demonstrated through the induction of acute pain using formalin injection, which is frequently employed in animal pain models (McNamara et al., 2007). In addition, formaldehyde exposure activates TRPA1 receptors located in the endothelium of blood vessels, thereby causing postprandial hyperemia owing to the relaxation of the superior mesenteric artery (Jin et al., 2019). The observed synergistic effect between formaldehyde and cold temperature activation of human TRPA1 channels is of particular interest. Co-exposure to temperatures below 16°C and inhalation of formaldehyde induce increased mucus hypersecretion and inflammation in the lungs, thereby exacerbating the symptoms of allergic asthma (Wu et al., 2020). In this regard, the administration of antagonists targeting both TRPM8 and TRPA1 channels has resulted in a significant reduction in inflammatory factors. Consequently, these ion channels represent potential therapeutic targets for managing asthma (Wu et al., 2020).

Acetaldehyde is characterized by a fruity odor and is classified as an extremely very volatile organic compound (VVOC) that is easily absorbed into the body through various pathways such as the respiratory tract, gastrointestinal tract, and dermal routes (Fouw, 1995; Salthammer, 2016). Acetaldehyde is produced from burning sources such as woodstoves, fireplaces, coffee roasting, tobacco burning, and vehicle exhaust. It is also formed as a metabolite of ethanol in the human body. Acute nociceptive behaviors are evoked in mouse footpads upon intradermal administration of acetaldehyde, and these behaviors are effectively abolished by the TRPA1 inhibitor camphor (Bang et al., 2007).

Crotonaldehyde, also referred to as crotonal, is an unsaturated aldehyde, which is produced during the combustion of fuels and in tobacco smoke. It exerts several detrimental effects on human health. Exposure to crotonaldehyde can lead to mutagenic and cytotoxic effects and trigger inflammatory responses and cell death. This compound has been implicated in causing damage to the genetic material, adversely affecting cellular function, and promoting inflammation and cell death. Within the human body, crotonaldehyde activates TRPA1 receptors located in airway epithelial cells and vasculature. This activation triggers a cascade of events that can result in injury to the airway tissues and the initiation of an inflammatory response. The interaction between crotonaldehyde and TRPA1 receptors contributes to the pathogenesis of airway tissue damage and inflammation (Andrè et al., 2008; Lin et al., 2021).

Cinnamaldehyde, derived from the Cinnamomum genus, is commonly utilized as a flavoring agent because of its characteristic aroma and taste. It is also utilized as a fragrance in various products and has applications as a fungicide, filtering agent, and corrosion inhibitor in different industries (Cocchiara et al., 2005). A remarkable study has demonstrated that cinnamaldehyde can induce nociceptive behavior in mice by activating the TRPA1 channel. This activation of TRPA1 leads to the perception of pain or discomfort in response to cinnamaldehyde exposure (Bandell et al., 2004). Intravenous injection of cinnamaldehyde stimulates the secretion of adrenaline by activating TRPA1 in sensory and adrenal sympathetic nerves (Iwasaki et al., 2008). These findings highlight the role of TRPA1 as a molecular sensor for cinnamaldehyde and in the nociceptive response and adrenaline secretion.

Vanillin, a flavor compound primarily extracted from vanilla seeds, is commonly used in a variety of food products because of its pleasant aroma. However, excessive consumption of vanillin has been linked to potential liver and kidney damage. It is important to note that high levels of vanillin intake may have adverse effects on these organs. Nevertheless, several reports have indicated the potential therapeutic applications of vanillin in promoting liver regeneration and regressing liver fibrosis (Ni et al., 2005; Fouad and Al-Melhim, 2018; Ghanim et al., 2021). Further research is needed to elucidate the effects of vanillin on liver health and its potential benefits in liver fibrosis treatment. Although vanillin activates several receptors, such as TRPV1, TRPV3, and TRPA1, in trigeminal neurons, the precise physiological functions of vanillin remain unclear (Xu et al., 2006; Lübbert et al., 2013). Extensive research is required to unravel the complete picture of how vanillin affects the body and to uncover its potential implications in various physiological functions.

Tobacco smoke

Tobacco smoke has been widely recognized as a leading cause of irritation in the tracheal and bronchial mucosa. Extensive research has been conducted to elucidate the mechanisms through which cigarette smoke exerts its irritant effects on the respiratory tract (Table 2). In 1983, Lundberg et al. demonstrated that pretreatment with capsaicin, an activator of TRPV1, inhibited airway mucosa sensitization to cigarette smoke (CS), suggesting that TRPV1 plays a crucial role in detecting CS (Lundberg and Saria, 1983). Upon inhalation, CS activates capsaicin-sensitive neurons expressing TRPV1, leading to the triggering of neurogenic inflammation. This activation results in the release of neuropeptides such as substance P and neurokinin A (Lundberg and Saria, 1983; Delay-Goyet and Lundberg, 1991). However, it was observed that the selective TRPV1 receptor antagonist, capsazepine, failed to prevent CS-induced plasma extravasation (Geppetti et al., 1993). Although TRPV1-expressed sensory nerves are involved in CS irritation, TRPV1 itself does not mediate the neuronal activation. In contrast, the non-specific TRP channel blocker ruthenium red inhibits CS-induced extravasation, indicating the potential involvement of other TRP channels in CS reactions (Geppetti et al., 1993). Afterwards, the observation of TRPA1 expression in the lung nerves of mice suggested its potential involvement as a novel channel activated by CS (Bautista et al., 2006; Nassenstein et al., 2008).

Table 2 Summary of the components of tobacco smoke modulating TRP channels

Tobacco smokeTRPA1TRPV1TRPM8
Effects: inflammation plasma extravasation,
lung cancer
Effects: mucin secretion,
inflammation, ROS production
Smoke aldehydesActivation
NicotineActivation
MentholActivation
ROS by smokingActivationActivation


Cigarette smoke contains a complex mixture of chemicals, including acrolein, acetaldehyde, and various unsaturated aldehydes (Huber et al., 1991; Facchinetti et al., 2007; Kim et al., 2023). Several experiments have provided evidence that specific components in CS collectively activate the TRPA1 channel. First, a study demonstrated that CS extract induces an elevation in intracellular calcium levels in cells expressing TRPA1 heterogeneously (Andrè et al., 2008). Additionally, certain aldehydes present in CS, such as crotonaldehyde and methacrolein, have been identified as TRPA1 agonists (Andrè et al., 2008; Escalera et al., 2008). CS has been found to stimulate the trachea by activating TRPA1. This is evidenced by the increased tracheal plasma extravasation, which is predominantly inhibited by TRPA1 blockers or genetic ablation of TRPA1 (Andrè et al., 2008). Moreover, TRPA1 knockout mice exhibit an 80% decrease in CS-induced release of CGRP from the superfused trachea, whereas TRPV1 knockout mice show no considerable reduction (Kichko et al., 2015b). Notably, TRPA1 has been implicated in the development of small cell lung cancer (SCLC) associated with smoking. It is upregulated in cancer cells, leading to the elevation of intracellular calcium levels and suppression of apoptosis, which potentially promote the progression of SCLC (Schaefer et al., 2013).

Nicotine, a highly addictive component of cigarettes, has the ability to vaporize in its unprotonated form and enter the gaseous phase. Although nicotine primarily acts on nicotinic acetylcholine receptors to induce stimulation, it has been observed that its activation pathway is not involved in the irritation caused by nicotine. In fact, the acetylcholine receptor antagonist mecamylamine failed to completely inhibit the release of CGRP (Kichko et al., 2015a). Subsequently, Kichko et al. (2015a) showed that TRPA1 knockout mice had a substantial decrease in CS-induced CGRP levels in the trachea and larynx. Another study has demonstrated that nicotine facilitates airway constriction in animal models through the activation of TRPA1 (Talavera et al., 2009).

Reactive oxidative stress (ROS) generated from smoking activates lung vagal C-fiber effects (LVCAs), which can be effectively suppressed by antioxidants (Lin et al., 2010). In this regard, TRPV1 and TRPA1 have been proposed as potential targets for activation by ROS (Weng et al., 2013). Subsequent studies have reported that TRPV1 and TRPA1 can be activated through treatment with H2O2, as confirmed using patch clamp and calcium imaging techniques (Sawada et al., 2008; DelloStritto et al., 2016). In the context of oxidation sensing by TRP channels, cysteine oxidation has been regarded as the principal mechanism. Takahashi et al. (2011) identified Cys421 and Cys621 of human TRPA1 to be responsible for TRPA1 activation. Similarly, Ogawa et al. (2016) proposed that Cys-258 and Cys-742 of human TRPV1 are crucial sites for activation. These findings highlight the potential role of oxidative stress in modulating TRPV1 and TRPA1 activity, suggesting their involvement in cellular responses to oxidative damage and inflammation induced by cigarette smoking.

Menthol, a widely used compound added to cigarettes, is known for its cooling effect, which is achieved through its binding to the TRPM8 (Peier et al., 2002). Tobacco smoke has the potential to exacerbate inflammation through the activation of the TRPM8 pathway, which is expressed in the lungs and nasal mucosa (Liu et al., 2015, 2018; Nair et al., 2020). Indeed, inhibition of TRPM8 has been presented to alleviate airway inflammation in asthma model mice treated with cold air stimulus The combined exposure to cold air and CS has been found to induce excessive mucus secretion through the activation of TRPM8 (Li et al., 2012). It has been observed that TRPM8 is involved in the generation of reactive oxygen species (ROS) subsequent to menthol binding (Nair et al., 2020).

Other hazardous compounds

Inhalation of ozone poses a substantial health risk, particularly in industrialized nations, because of its detrimental effects on respiratory function. Ozone stimulates nociceptive bronchopulmonary nerves and elicits action potentials by activating TRPA1 channels. When TRPA1 is heterologously expressed in HEK293T cells, it leads to calcium influx upon ozone treatment. Notably, TRPA1 knockout mice do not exhibit activation of bronchopulmonary nerves in response to ozone exposure (Taylor-Clark and Undem, 2010). Furthermore, current evidence links ozone exposure with an increased risk of developing allergic asthma and exacerbating existing asthma conditions. According to a previous study, TRPV1 is indirectly involved in ozone-induced respiratory diseases. The inhibition of TRPV1 by melatonin has been proposed as a prospective therapeutic target for ozone-induced asthma exacerbation (Li et al., 2019; Chen et al., 2021). Recently, Li et al. (2022) demonstrated the efficacy of both TRPA1 and TRPV1 antagonists in preventing airway inflammation induced by ozone exposure. These findings highlight the potential of TRPA1 and TRPV1 as therapeutic targets for ozone-induced respiratory diseases.

Additionally, there are numerous hazardous compounds associated with resin additives that have the ability to cause irritation by affecting TRP channels. Specifically, TRPA1 has been investigated for its potential activation by certain alcohols, such as 2-ethyl-1-hexanol (2-EH), 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate (Texanol) (Mori et al., 2023). Trigeminal nociceptive fibers present in the nasal organs express a diverse range of ion channels that respond to various irritants. Among these channels, TRPV1 expressed in trigeminal ganglion neurons is associated with aversive responses to irritants such as benzaldehyde, cyclohexanol, eugenol, and toluene. However, in vitro studies have revealed that benzaldehyde and toluene do not activate the TRPV1 ion channel (Silver et al., 2006; Saunders et al., 2013). Moreover, chemosensory cells in the nasal cavities that express TRPM5 respond to a wide range of odorous irritants (Lin et al., 2008).

ANESTHETIC COMPOUNDS

Volatile general anesthetics (VGAs) comprise a diverse group of volatile and gaseous substances used as anesthetics, which share the common ability to suppress the central nervous system (Franks, 2008). VGAs induce symptoms such as hypnosis (unconsciousness), amnesia (memory loss), and muscle relaxation (Miller et al., 2002). These effects are desired during surgical procedures to ensure patient comfort and facilitate medical interventions. General anesthetics target numerous ion channels to inhibit the central nervous system. VGAs activate GABAA receptors, which are inhibitory receptors in the brain, and potassium (K+) channels, which help regulate neuronal activity. They simultaneously inhibit glutamate (excitatory) receptors and inhibit the release of neurotransmitters from presynaptic terminals (Franks and Lieb, 1988; Wakamori et al., 1991; van Swinderen et al., 1999; Yamakura and Harris, 2000). These actions contribute to the overall depressant effects of general anesthetics on the CNS. However, the exact mechanisms underlying the complete anesthetic effect are not fully understood and may involve additional factors.

VGAs stimulate peripheral neurons to cause side effects such as coughing, laryngeal spasms, irritation of the airway mucosa, and secretion, which may result in part from stimulation of laryngeal C-fibers (Mutoh et al., 1998; Mutoh and Tsubone, 2003). The expression of TRPV1 in afferent nerves sensitive to capsaicin, which triggers pulmonary defense responses such as apnea, cough, and cardiovascular effects, has been reported in numerous animal studies (Coleridge and Coleridge, 1984; Tsubone et al., 1991; Coleridge and Coleridge, 1994; Mutoh et al., 1998). There are various inhalation anesthetics, including halothane, isoflurane, desflurane, and sevoflurane, which are used to induce and maintain general anesthesia. Each of these anesthetics exhibits different reactivity towards several TRP channels, and accumulated studies have demonstrated that these VGAs can modulate the activation of TRP channels.

In previous studies, it was discovered that isoflurane alone did not activate TRPV1. Further investigations have revealed that VGAs potentiate the TRPV1 currents evoked by capsaicin, heat, or protons, which are mediated by protein kinase C in a dependent manner (Cornett et al., 2008). The interaction between emulsified isoflurane and TRPV1 can enhance nociceptive inhibition by QX-314, a blocker of voltage-activated sodium channels (Zhou et al., 2014). In contrast, a recent study has suggested that TRPV1 is directly activated by both isoflurane and halothane, which was inhibited by capsazepine (Vanden Abeele et al., 2019). VGA-induced TRPV1 activation is associated with the development of malignant hyperthermia, a pharmacogenetic disorder characterized by uncontrolled calcium release in the muscles triggered by inhalational anesthetics. Notably, among patients with malignant hyperthermia, those with identified TRPV1 variants exhibited higher sensitivity to VGAs compared to that of patients without TRPV1 variants (Vanden Abeele et al., 2019).

In addition, TRPA1 can be directly activated by isoflurane and desflurane in a concentration-dependent manner. Halothane and sevoflurane failed to generate TRPA1-induced currents (Matta et al., 2008). Exposure to desflurane resulted in an elevation of laryngeal C-fiber activity in the respiratory tract, which was effectively suppressed by a selective blocker of TRPA1 but not by an inhibitor of TRPV1. This finding highlights the substantial involvement of TRPA1 in mediating neuronal activation induced by VGAs (Mutoh et al., 2013).

A recent study (2020) has discovered that although VGAs have the ability to activate TRPA1, they also inhibit the activation of TRPA1 currents in response to specific ligands such as allyl isothiocyanate (AITC) (Ton et al., 2020). Thus, the bimodal control of TRPA1 by volatile VGAs was suggested as a potential important feature for modulating nociceptive signaling and ischemia. As TRPA1 is a molecular sensor of hypoxia (Takahashi et al., 2011), this TRPA1 inhibition by VGA may contribute to the vasodilation of cerebral arteries during ischemia (Pires and Earley, 2018).

Accumulated studies have demonstrated that VGA-induced TRP channel activation is involved in pain transmission and inflammation. The activation of TRPV1 by desflurane and isoflurane leads to an increase in the release of CGRP in the trachea, which was reduced by approximately 75% in mice that lacked TRPV1 (Kichko et al., 2015b).

Remarkably, desflurane-induced CGRP release was completely inhibited in TRPA1-deficient mice (Kichko et al., 2015b). The stronger activation of TRPA1 by isoflurane leads to a greater extent of neuroinflammation compared to that induced by sevoflurane (Matta et al., 2008). Moreover, Eilers et al. (2010) reported that isoflurane induces mechanical hyperalgesia through a TRPA1-dependent mechanism. Additionally, isoflurane was shown to elicit TRPA1-dependent constriction of isolated bronchi (Eilers et al., 2010).

Furthermore, Li et al. (2015) investigated the physiological implications of VGAs on TRPV1 and TRPA1 channels using TRPA1 and TRPV1 knockout mice. Consequently, TRPA1-deficient mice exhibited a shortened induction latency during isoflurane anesthesia, but not sevoflurane anesthesia, compared to wild-type mice (Li et al., 2015). In contrast, the response of TRPV1-deficient mice to both isoflurane and sevoflurane was similar to that of wild-type mice. Based on these results, the increased sensitivity to isoflurane anesthesia in TRPA1-deficient mice suggests that TRPA1 channels may play a role in altering respiration patterns during isoflurane anesthesia. In contrast, the absence of TRPV1 genes did not considerably affect the response of mice to anesthesia.

Other TRP channels, such as TRPC and TRPM, have also been implicated in the effects of VGAs. In the peripheral nervous system, TRPC5-mediated calcium entry is inhibited by halothane and chloroform (Bahnasi et al., 2008). Also, TRPM8 is activated by halothane, isoflurane, desflurane, and sevoflurane, resulting in immediate calcium influx (Vanden Abeele et al., 2013). However, prolonged exposure eventually leads to continuous inhibition of TRPM8 (Vanden Abeele et al., 2013). This sustained inhibition of TRPM8 may contribute to the occurrence of hypothermia. Notably, TRPM8 deficient mice displayed a partial reduction in both hypothermia and the inhibition of respiratory drive induced by VGAs (Vanden Abeele et al., 2013).

On the contrary, halothane, chloroform, isoflurane, and sevoflurane exert an inhibitory effect on the activation of TRPM3 in both heterologously expressed cells and neurons in a concentration-dependent manner (Kelemen et al., 2020).

The modulations of TRP channels by VGAs and their physiological effects are summarized in Table 3.

Table 3 Summary of the volatile general anesthetics modulating TRP channels

VGAsTRPA1TRPV1TRPM3TRPM8TRPC5
Effects: CGRP release, respiratory inhibitionEffects: CGRP release, hyperthermiaEffects: Hypothermia respiratory inhibition
IsofluraneActivationEnhancementActivation (Inhibition by prolonged exposure)
DesfluraneActivationEnhancementActivation (Inhibition by prolonged exposure)
SevofluraneEnhancementInhibitionActivation (Inhibition by prolonged exposure)
HalothaneActivationInhibitionActivation (Inhibition by prolonged exposure)Inhibition
ChloroformInhibitionInhibition

PLANT-DERIVED COMPOUNDS

Volatile compounds derived from a variety of foods or aromatic plants have been used historically for their medicinal properties in the treatment of various ailments, including diarrhea, coughing, and ulcers. These volatile compounds have applications in therapeutics, perfume, and food industries. Moreover, they have been the subject of preclinical studies exploring their potential as antitumor, anti-inflammatory, antioxidants, and antibacterial agents (Bakkali et al., 2008; Edris, 2007; Saviuc et al., 2015; Korinek et al., 2021). The effects of volatile compounds on modulating TRP channels, whether by activating or suppressing them, are of particular interest, as understanding the precise mechanisms is promising for the development of novel therapeutic interventions (Jang et al., 2015; Soares et al., 2021).

Numerous studies have documented the effects of volatile ingredients found in food on TRP channels in various pathophysiological conditions. For instance, allyl isothiocyanate found in wasabi, allicin and diallyl disulfide derived from garlic, and cinnamon aldehyde present in cinnamon have been identified as substances that interact with TRPA1 channels. Among those, gallic-derived sulfide components have also been found to activate TRPV1 channels (Macpherson et al., 2005). In particular, allicin exhibits a wide range of biological activities, including antimicrobial effects. Allicin vapor has been reported to exhibit antimicrobial properties against lung pathogenic bacteria, including multi-drug resistant strains, from the genera Pseudomonas, Streptococcus, and Staphylococcus, which suggests its potential as a treatment for pulmonary mycoses (Reiter et al., 2017). Given the absence of volatile antibiotics for pulmonary infections, the inclusion of allicin, particularly at sublethal doses in conjunction with oral antibiotics, could serve as a valuable adjunct to the existing treatment options.

Menthol, derived from mint plants, is commonly used as a flavor additive in a wide range of consumer and medicinal products. The TRPM8 channel, expressed in whole lung tissue and human bronchial epithelial cells, plays a role in the mechanism of menthol-induced cough suppression (Li et al., 2011). Indeed, the activation of TRPM8 by menthol has long been employed as a means to suppress cough (Laude et al., 1994; Grace et al., 2014). Furthermore, genome-wide association studies have identified a connection between TRPM8 and conditions such as migraine and allodynia, indicating the potential of menthol for use in targeted approach for personalized migraine treatment (Dussor and Cao, 2016; Ling et al., 2019). The activation of meningeal TRPM8 by external agonists can have controversial effects, both inducing and alleviating headache behaviors, which highlight the intricate involvement of TRPM8 in the pathology of migraine (Borhani Haghighi et al., 2010; Dussor and Cao, 2016).

Inhalation of certain plant ingredients has been associated with the onset of headaches. For example, Umbellularia californica, commonly referred to as the ‘headache tree,’ is known to induce severe headache when its vapors are inhaled. The leaves of this plant contain umbellulone, which is a monoterpene ketone known for its irritant properties. Activation of TRPA1 has been proposed as a potential mechanism underlying headache, as it can lead to the release of CGRP in trigeminal neurons (Nassini et al., 2012). Further electrophysiological analysis has determined that umbellulone acts as a bimodal activator of TRPA1 and a weak activator of TRPM8 (Zhong et al., 2011).

In addition, various volatile compounds derived from herbal plants have been identified as agonists for TRP channels, indicating their potential role in modulating TRP channel activity. In more detail, eugenol, a compound found in basil and clove, exhibits anti-inflammatory properties by inhibiting the cyclooxygenase enzyme. Additionally, eugenol has been shown to activate TRPV1 and TRPV3 channels (Xu et al., 2006). Given that several inhibitors of TRPV1 and V3 have also been reported to exert anti-pruritic and anti-inflammatory effects, further research is needed to elucidate the conflicting mechanisms associated with TRPV3 activation (Bujak et al., 2019; Han et al., 2021). Similarly, thymol, obtained from thyme (Thymus vulgaris), activates the TRPV3 channel and has been documented as an anti-inflammatory and wound healing agent (Xu et al., 2006). Linalool, commonly present in the Lamiaceae family, activates both TRPA1 and TRPV1 (Wang et al., 2022). Intriguingly, although linalool can independently activate TRPA1, it also exhibits inhibitory properties against the activation of TRPA1 by other agonists, such as AITC (Hashimoto et al., 2023). Consequently, this inhibition leads to a reduction in TRPA1-mediated nociceptive behaviors (Hashimoto et al., 2023). Vanillin, extracted from Vanilla planifolia, elicits mild effects on the central nervous system. The anti-inflammatory effect of vanillin has gained attention, prompting further research into its relationship with the activation of TRPV channels (Ghanim et al., 2021; Ciciliato et al., 2022). Taken together, the investigation of volatile compounds derived from plants and their interactions with TRP channels has garnered considerable interest in the quest for potential novel therapeutic drugs. The identification of these compounds as agonists or modulators of TRP channels provides insights into their potential pharmacological effects and opens up possibilities for developing targeted therapies in various fields, including pain management, inflammation, respiratory disorders, and neurological conditions. Further research in this area may unveil new avenues for drug discovery and lead to the development of innovative treatments.

PHEROMONES

Pheromones are chemical signals known as semiochemicals that carry information within a particular species (Jones and Parker, 2005). These chemical compounds are produced and released by individuals, influencing the behavior or physiology of other members of the same species. Pheromones play a crucial role in various biological processes, including communication, mate selection, territorial marking, alarm signaling, and social organization (Fan and Ting, 2014). They are detected by specialized sensory receptors in organisms, triggering specific physiological or behavioral responses.

Pheromones exhibit varying volatility based on their chemical structure (Jones and Parker, 2005). The volatility of a pheromone is influenced by its chemical structure. Generally, volatile pheromones are composed of small molecules that have low molecular weight and high vapor pressure. These properties allow them to easily evaporate and disperse in the surrounding environment, enabling efficient transmission and detection by potential receivers (Zhou and Rui, 2010). Alternately, non-volatile pheromones are typically larger molecules with higher molecular weight and lower vapor pressure. These molecules are less likely to evaporate and disperse into the air, making them better suited for close-range communication or direct contact with conspecifics (Cardé and Millar, 2009). This differentiation significantly impacts the transmission and detection of pheromones by conspecifics.

In plants, certain volatile compounds function as pheromone-like signals. They attract pollinators and seed dispersers, while also serving as a defense mechanism against pests and pathogens. These volatile compounds play a crucial role in plant reproduction and protection (Bouwmeester et al., 2019). Additionally, in C. elegans, the TRPV family member OSM-9 is involved in sensing attractant odorants such as diacetyl and pyrazine (Colbert et al., 1997). TRPC channels have been reported to be essential for detecting chemicals, such as nicotine, that regulate behavior of C.elegans (Feng et al., 2006). Similarly, certain volatiles in insects function as pheromones, guiding social behavior and serving as cues for locating hosts or prey. For instance, Drosophila melanogaster TRPA1 is essential for the avoidance response to citronellal, a widely used insect repellent (Kwon et al., 2010). In this regard, citronella indirectly activates Drosophila TRPA1 through a G protein/PLC signaling cascade, whereas it directly activates the TRPA1 channel in African mosquitoes (Kwon et al., 2010). A recent study has challenged previous findings and proposed that citronellal acts as a direct agonist for TRPA1 in Drosophila, human, and African mosquito species (Du et al., 2015).

In rodents, pheromones convey information such as animal location, food or threat presence, sexual attraction, courtship, and dam-pup interactions. The TRPC2 channel is specifically found in neurons of the vomeronasal organ (VNO) in rodents, primarily in the sensory microvilli of VNO neurons. Pheromones binding to V1 and V2 receptors in the vomeronasal organ activate the phospholipase C (PLC) pathway through G protein signaling (Matsunami and Buck, 1997). DAG (diacylglycerol), which is produced as a result of the activation of the PLC pathway, stimulates TRPC2 channels. This stimulation leads to a depolarizing influx of Na+ and Ca2+ in VNO neurons, resulting in an increase in the firing rate of these neurons (Zhang et al., 2010) (Fig. 3). Unlike other mammals, including rodents, humans have non-functional TRPC2 owing to genetic mutations (Vannier et al., 1999). These mutations lead to the formation of premature stop codons in the TRPC2 gene, resulting in the production of a severely truncated protein. As a result, humans are believed to have lost the functionality of TRPC2 in pheromone detection and signaling, making us less reliant on these chemical cues for social and reproductive behaviors compared to other species.

Figure 3. The pheromone sensing mechanism by the TRPC2 channel. In the vomeronasal organ, the pheromone signal transduction pathway begins at vomeronasal receptors. Upon pheromones binding, the V1R/V2R activates G-proteins. The activated G-proteins stimulate the cleavage of PIP2 into IP3 and DAG via PLC. DAG activates TRPC2 channel, leading to influx of cationic ions. Ca2+/calmodulin directly inhibits the activity of TRPC2. The human TRPC2 gene is a pseudogene that generates premature stop codons, resulting in a severely truncated protein. DAG, diacylglycerol; GDP, guanosine diphosphate; GTP, guanosine triphosphate; Ins(1,4,5)P3, inositol 1,4,5-trisphosphate; PIP, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase C; CaM, calmodulin.
CONCLUSIONS AND PERSPECTIVES

From air, various volatile molecules can be inhaled through the respiratory tract, which can subsequently induce pathophysiological changes in humans. Peripheral nerves located in the nose, mouth, and throat play a crucial role in protecting the body against chemical hazards by initiating perceptions and reflexes. These sensory nerves serve as the first line of defense, detecting and responding to potentially harmful chemicals in the environment. Sensory irritation caused by chemical stimuli can induce a concentration-dependent decrease in respiratory rate, a phenomenon referred to as “respiratory braking.” This mechanism serves as a protective response to prevent the inhalation of toxic substances. When the sensory nerves in the respiratory system detect irritants, they transmit signals to the brain, triggering a reflexive decrease in respiratory rate.

In humans, TRP channel-mediated calcium influx plays a critical role as a signaling mechanism to maintain physiological homeostasis and detect potential threats. This review comprehensively explored the biological functions of TRP channels in response to volatile molecules. It highlighted the role of TRP channels as molecular sensors in detecting and responding to environmental cues, and discussed their involvement in various physiological processes and pathological conditions related to the inhalation of volatile substances. Certainly, unraveling the mechanisms of TRP channel activation is crucial for assessing the potential risks associated with hazardous compounds and identifying potential therapeutic targets. By gaining insights into the specific molecular interactions and signaling pathways involved in TRP channel activation, we can better understand how these channels contribute to the physiological responses and pathological effects induced by volatile molecules. Such knowledge can aid in the development of strategies for risk assessment, prevention, and treatment of conditions associated with exposure to these substances.

ACKNOWLEDGMENTS

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI22C1973000022).

CONFLICT OF INTEREST

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References
  1. Achanta, S. and Jordt, S. E. (2017) TRPA1: acrolein meets its target. Toxicol. Appl. Pharmacol. 324, 45-50.
    Pubmed KoreaMed CrossRef
  2. Andrè, E., Campi, B., Materazzi, S., Trevisani, M., Amadesi, S., Massi, D., Creminon, C., Vaksman, N., Nassini, R., Civelli, M., Baraldi, P. G., Poole, D. P., Bunnett, N. W., Geppetti, P. and Patacchini, R. (2008) Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Invest. 118, 2574-2582.
    CrossRef
  3. Bahnasi, Y. M., Wright, H. M., Milligan, C. J., Dedman, A. M., Zeng, F., Hopkins, P. M., Bateson, A. N. and Beech, D. J. (2008) Modulation of TRPC5 cation channels by halothane, chloroform and propofol. Br. J. Pharmacol. 153, 1505-1512.
    Pubmed KoreaMed CrossRef
  4. Bakkali, F., Averbeck, S., Averbeck, D. and Idaomar, M. (2008) Biological effects of essential oils--a review. Food Chem. Toxicol. 46, 446-475.
    Pubmed CrossRef
  5. Bandell, M., Story, G. M., Hwang, S. W., Viswanath, V., Eid, S. R., Petrus, M. J., Earley, T. J. and Patapoutian, A. (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849-857.
    Pubmed CrossRef
  6. Bang, S., Kim, K. Y., Yoo, S., Kim, Y. G. and Hwang, S. W. (2007) Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur. J. Neurosci. 26, 2516-2523.
    Pubmed CrossRef
  7. Bautista, D. M., Jordt, S. E., Nikai, T., Tsuruda, P. R., Read, A. J., Poblete, J., Yamoah, E. N., Basbaum, A. I. and Julius, D. (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269-1282.
    Pubmed CrossRef
  8. Borhani Haghighi, A., Motazedian, S., Rezaii, R., Mohammadi, F., Salarian, L., Pourmokhtari, M., Khodaei, S., Vossoughi, M. and Miri, R. (2010) Cutaneous application of menthol 10% solution as an abortive treatment of migraine without aura: a randomised, double-blind, placebo-controlled, crossed-over study. Int. J. Clin. Pract. 64, 451-456.
    Pubmed CrossRef
  9. Bouwmeester, H., Schuurink, R. C., Bleeker, P. M. and Schiestl, F. (2019) The role of volatiles in plant communication. Plant J. 100, 892-907.
    Pubmed KoreaMed CrossRef
  10. Bujak, J. K., Kosmala, D., Szopa, I. M., Majchrzak, K. and Bednarczyk, P. (2019) Inflammation, cancer and immunity-implication of TRPV1 channel. Front. Oncol. 9, 1087.
    Pubmed KoreaMed CrossRef
  11. Caceres, A. I., Brackmann, M., Elia, M. D., Bessac, B. F., del Camino, D., D'Amours, M., Witek, J. S., Fanger, C. M., Chong, J. A., Hayward, N. J., Homer, R. J., Cohn, L., Huang, X., Moran, M. M. and Jordt, S. E. (2009) A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Natl. Acad. Sci. U. S. A. 106, 9099-9104.
    Pubmed KoreaMed CrossRef
  12. Cardé, R. T. and Millar, J. G. (2009) Chapter 195 - Pheromones. In: Encyclopedia of Insects, 2nd ed. (V. H. Resh and R. T. Cardé, Eds.), pp. 766-772. Academic Press, San Diego.
    CrossRef
  13. Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D. and Julius, D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816-824.
    Pubmed CrossRef
  14. Chen, Y., Wu, X., Yang, X., Liu, X., Zeng, Y. and Li, J. (2021) Melatonin antagonizes ozone-exacerbated asthma by inhibiting the TRPV1 channel and stabilizing the Nrf2 pathway. Environ. Sci. Pollut. Res. Int. 28, 59858-59867.
    Pubmed CrossRef
  15. Ciciliato, M. P., de Souza, M. C., Tarran, C. M., de Castilho, A. L. T., Vieira, A. J. and Rozza, A. L. (2022) Anti-inflammatory effect of vanillin protects the stomach against ulcer formation. Pharmaceutics 14, 755.
    Pubmed KoreaMed CrossRef
  16. Cocchiara, J., Letizia, C. S., Lalko, J., Lapczynski, A. and Api, A. M. (2005) Fragrance material review on cinnamaldehyde. Food Chem. Toxicol. 43, 867-923.
    Pubmed CrossRef
  17. Colbert, H. A., Smith, T. L. and Bargmann, C. I. (1997) OSM-9, a novel protein with structural similarity to channels, is required for olfaction, mechanosensation, and olfactory adaptation in Caenorhabditis elegans. J. Neurosci. 17, 8259-8269.
    Pubmed KoreaMed CrossRef
  18. Coleridge, H. M. and Coleridge, J. C. (1994) Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu. Rev. Physiol. 56, 69-91.
    Pubmed CrossRef
  19. Coleridge, J. C. and Coleridge, H. M. (1984) Afferent vagal C fibre innervation of the lungs and airways and its functional significance. Rev. Physiol. Biochem. Pharmacol. 99, 1-110.
    Pubmed CrossRef
  20. Conklin, D. J., Haberzettl, P., Jagatheesan, G., Kong, M. and Hoyle, G. W. (2017) Role of TRPA1 in acute cardiopulmonary toxicity of inhaled acrolein. Toxicol. Appl. Pharmacol. 324, 61-72.
    Pubmed KoreaMed CrossRef
  21. Cornett, P. M., Matta, J. A. and Ahern, G. P. (2008) General anesthetics sensitize the capsaicin receptor transient receptor potential V1. Mol. Pharmacol. 74, 1261-1268.
    Pubmed CrossRef
  22. Delay-Goyet, P. and Lundberg, J. M. (1991) Cigarette smoke-induced airway oedema is blocked by the NK1 antagonist, CP-96,345. Eur. J. Pharmacol. 203, 157-158.
    Pubmed CrossRef
  23. DelloStritto, D. J., Connell, P. J., Dick, G. M., Fancher, I. S., Klarich, B., Fahmy, J. N., Kang, P. T., Chen, Y. R., Damron, D. S., Thodeti, C. K. and Bratz, I. N. (2016) Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction. Basic Res. Cardiol. 111, 21.
    Pubmed KoreaMed CrossRef
  24. Du, E. J., Ahn, T. J., Choi, M. S., Kwon, I., Kim, H. W., Kwon, J. Y. and Kang, K. (2015) The mosquito repellent citronellal directly potentiates drosophila TRPA1, facilitating feeding suppression. Mol. Cells 38, 911-917.
    Pubmed KoreaMed CrossRef
  25. Dussor, G. and Cao, Y. Q. (2016) TRPM8 and migraine. Headache 56, 1406-1417.
    Pubmed KoreaMed CrossRef
  26. Edris, A. E. (2007) Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: a review. Phytother. Res. 21, 308-323.
    Pubmed CrossRef
  27. Eilers, H., Cattaruzza, F., Nassini, R., Materazzi, S., Andre, E., Chu, C., Cottrell, G. S., Schumacher, M., Geppetti, P. and Bunnett, N. W. (2010) Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction. Anesthesiology 112, 1452-1463.
    Pubmed CrossRef
  28. Escalera, J., von Hehn, C. A., Bessac, B. F., Sivula, M. and Jordt, S.-E. (2008) TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J. Biol. Chem. 283, 24136-24144.
    Pubmed KoreaMed CrossRef
  29. Facchinetti, F., Amadei, F., Geppetti, P., Tarantini, F., Di Serio, C., Dragotto, A., Gigli, P. M., Catinella, S., Civelli, M. and Patacchini, R. (2007) Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages. Am. J. Respir. Cell Mol. Biol. 37, 617-623.
    Pubmed CrossRef
  30. Fan, A. M. and Ting, D. (2014) Pheromones. In: Encyclopedia of Toxicology, 3rd ed. (P. Wexler, Ed.), pp. 898-901. Academic Press, Oxford.
    CrossRef
  31. Feng, Z., Li, W., Ward, A., Piggott, B. J., Larkspur, E. R., Sternberg, P. W. and Xu, X. Z. (2006) A C. elegans model of nicotine-dependent behavior: regulation by TRP family channels. Cell 127, 621-633.
    Pubmed KoreaMed CrossRef
  32. Fouad, A. A. and Al-Melhim, W. N. (2018) Vanillin mitigates the adverse impact of cisplatin and methotrexate on rat kidneys. Hum. Exp. Toxicol. 37, 937-943.
    Pubmed CrossRef
  33. Fouw, J. D. .
  34. Franks, N. P. (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat. Rev. Neurosci. 9, 370-386.
    Pubmed CrossRef
  35. Franks, N. P. and Lieb, W. R. (1988) Volatile general anaesthetics activate a novel neuronal K+ current. Nature 333, 662-664.
    Pubmed CrossRef
  36. Geppetti, P., Bertrand, C., Baker, J., Yamawaki, I., Piedimonte, G. and Nadel, J. A. (1993) Ruthenium red, but not capsazepine reduces plasma extravasation by cigarette smoke in rat airways. Br. J. Pharmacol. 108, 646-650.
    Pubmed KoreaMed CrossRef
  37. Ghanim, A. M. H., Younis, N. S. and Metwaly, H. A. (2021) Vanillin augments liver regeneration effectively in Thioacetamide induced liver fibrosis rat model. Life Sci. 286, 120036.
    Pubmed CrossRef
  38. Grace, M. S., Baxter, M., Dubuis, E., Birrell, M. A. and Belvisi, M. G. (2014) Transient receptor potential (TRP) channels in the airway: role in airway disease. Br. J. Pharmacol. 171, 2593-2607.
    Pubmed KoreaMed CrossRef
  39. Han, Y., Luo, A., Kamau, P. M., Takomthong, P., Hu, J., Boonyarat, C., Luo, L. and Lai, R. (2021) A plant-derived TRPV3 inhibitor suppresses pain and itch. Br. J. Pharmacol. 178, 1669-1683.
    Pubmed CrossRef
  40. Hashimoto, M., Takahashi, K. and Ohta, T. (2023) Inhibitory effects of linalool, an essential oil component of lavender, on nociceptive TRPA1 and voltage-gated Ca(2+) channels in mouse sensory neurons. Biochem. Biophys. Rep. 34, 101468.
    Pubmed KoreaMed CrossRef
  41. Huber, G. L., First, M. W. and Grubner, O. (1991) Marijuana and tobacco smoke gas-phase cytotoxins. Pharmacol. Biochem. Behav. 40, 629-636.
    Pubmed CrossRef
  42. Inoue, T. and Bryant, B. P. (2005) Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons. Pain 117, 193-203.
    Pubmed CrossRef
  43. Iwasaki, Y., Tanabe, M., Kobata, K. and Watanabe, T. (2008) TRPA1 agonists--allyl isothiocyanate and cinnamaldehyde--induce adrenaline secretion. Biosci. Biotechnol. Biochem. 72, 2608-2614.
    Pubmed CrossRef
  44. Jang, Y., Lee, W. J., Hong, G. S. and Shim, W. S. (2015) Red ginseng extract blocks histamine-dependent itch by inhibition of H1R/TRPV1 pathway in sensory neurons. J. Ginseng Res. 39, 257-264.
    Pubmed KoreaMed CrossRef
  45. Jang, Y., Lee, Y., Kim, S. M., Yang, Y. D., Jung, J. and Oh, U. (2012) Quantitative analysis of TRP channel genes in mouse organs. Arch. Pharm. Res. 35, 1823-1830.
    Pubmed CrossRef
  46. Jin, L., Jagatheesan, G., Guo, L., Nystoriak, M., Malovichko, M., Lorkiewicz, P., Bhatnagar, A., ivastava, S. Sr and Conklin, D. J. (2019) Formaldehyde induces mesenteric artery relaxation via a sensitive transient receptor potential ankyrin-1 (TRPA1) and endothelium-dependent mechanism: potential role in postprandial hyperemia. Front. Physiol. 10, 277.
    Pubmed KoreaMed CrossRef
  47. Jones, G. R. and Parker, J. E. (2005) Pheromones. In: Encyclopedia of Analytical Science, 2nd ed. (P. Worsfold, A. Townshend and C. Poole, Eds.), pp. 140-149. Elsevier, Oxford.
    CrossRef
  48. Kelemen, B., Lisztes, E., Vladár, A., Hanyicska, M., Almássy, J., Oláh, A., Szöllősi, A. G., Pénzes, Z., Posta, J., Voets, T., Bíró, T. and Tóth, B. I. (2020) Volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 (TRPM3). Biochem. Pharmacol. 174, 113826.
    Pubmed CrossRef
  49. Kichko, T. I., Kobal, G. and Reeh, P. W. (2015a) Cigarette smoke has sensory effects through nicotinic and TRPA1 but not TRPV1 receptors on the isolated mouse trachea and larynx. Am. J. Physiol. Lung Cell. Mol. Physiol. 309, L812-L820.
    Pubmed KoreaMed CrossRef
  50. Kichko, T. I., Niedermirtl, F., Leffler, A. and Reeh, P. W. (2015b) Irritant volatile anesthetics induce neurogenic inflammation through TRPA1 and TRPV1 channels in the isolated mouse trachea. Anesth. Analg. 120, 467-471.
    Pubmed CrossRef
  51. Kim, M., Kim, H., Park, T., Ahn, B. J., Lee, S., Lee, M., Lee, J., Oh, U. and Jang, Y. (2023) Rapid quantitative analysis of tobacco smoking in saliva using a TRPA1 ion channel-mediated bioelectronic tongue inspired by the human sensory system. Sens. Actuators B Chem. 393, 134149.
    CrossRef
  52. Korinek, M., Handoussa, H., Tsai, Y. H., Chen, Y. Y., Chen, M. H., Chiou, Z. W., Fang, Y., Chang, F. R., Yen, C. H., Hsieh, C. F., Chen, B. H., El-Shazly, M. and Hwang, T. L. (2021) Anti-inflammatory and antimicrobial volatile oils: fennel and cumin inhibit neutrophilic inflammation via regulating calcium and MAPKs. Front. Pharmacol. 12, 674095.
    Pubmed KoreaMed CrossRef
  53. Kunkler, P. E., Ballard, C. J., Pellman, J. J., Zhang, L., Oxford, G. S. and Hurley, J. H. (2014) Intraganglionic signaling as a novel nasal-meningeal pathway for TRPA1-dependent trigeminovascular activation by inhaled environmental irritants. PLoS One 9, e103086.
    Pubmed KoreaMed CrossRef
  54. Kurhanewicz, N., McIntosh-Kastrinsky, R., Tong, H., Ledbetter, A., Walsh, L., Farraj, A. and Hazari, M. (2017) TRPA1 mediates changes in heart rate variability and cardiac mechanical function in mice exposed to acrolein. Toxicol. Appl. Pharmacol. 324, 51-60.
    Pubmed KoreaMed CrossRef
  55. Kwon, Y., Kim, S. H., Ronderos, D. S., Lee, Y., Akitake, B., Woodward, O. M., Guggino, W. B., Smith, D. P. and Montell, C. (2010) Drosophila TRPA1 channel is required to avoid the naturally occurring insect repellent citronellal. Curr. Biol. 20, 1672-1678.
    Pubmed KoreaMed CrossRef
  56. Laude, E. A., Morice, A. H. and Grattan, T. J. (1994) The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs. Pulm. Pharmacol. 7, 179-184.
    Pubmed CrossRef
  57. Lee, S., Kim, M., Ahn, B. J. and Jang, Y. (2023) Odorant-responsive biological receptors and electronic noses for volatile organic compounds with aldehyde for human health and diseases: a perspective review. J. Hazard. Mater. 455, 131555.
    Pubmed CrossRef
  58. Li, C., Zhang, H., Wei, L., Liu, Q., Xie, M., Weng, J., Wang, X., Chung, K. F., Adcock, I. M., Chen, Y. and Li, F. (2022) Role of TRPA1/TRPV1 in acute ozone exposure induced murine model of airway inflammation and bronchial hyperresponsiveness. J. Thorac. Dis. 14, 2698-2711.
    Pubmed KoreaMed CrossRef
  59. Li, F., Guo, C. J., Huang, C. C., Yu, G., Brown, S. M., Xu, S. and Liu, Q. (2015) Transient receptor potential A1 activation prolongs isoflurane induction latency and impairs respiratory function in mice. Anesthesiology 122, 768-775.
    Pubmed CrossRef
  60. Li, J., Chen, Y., Chen, Q. Y., Liu, D., Xu, L., Cheng, G., Yang, X., Guo, Z. and Zeng, Y. (2019) Role of transient receptor potential cation channel subfamily V member 1 (TRPV1) on ozone-exacerbated allergic asthma in mice. Environ. Pollut. 247, 586-594.
    Pubmed CrossRef
  61. Li, M., Li, Q., Yang, G., Kolosov, V. P., Perelman, J. M. and Zhou, X. D. (2011) Cold temperature induces mucin hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin 8 (TRPM8)-mediated mechanism. J. Allergy Clin. Immunol. 128, 626-34.e1.
    Pubmed CrossRef
  62. Li, M. C., Perelman, J. M., Kolosov, V. P. and Zhou, X. D. (2012) Mechanisms of mucus hypersecretion in airway of rats induced by synergies between cold air and cigarette smoke inhalation and intervention effects of drugs. Zhonghua Yi Xue Za Zhi 92, 2283-2287.
  63. Lin, J., Taggart, M., Borthwick, L., Fisher, A., Brodlie, M., Sassano, M. F., Tarran, R. and Gray, M. A. (2021) Acute cigarette smoke or extract exposure rapidly activates TRPA1-mediated calcium influx in primary human airway smooth muscle cells. Sci. Rep. 11, 9643.
    Pubmed KoreaMed CrossRef
  64. Lin, W., Ogura, T., Margolskee, R. F., Finger, T. E. and Restrepo, D. (2008) TRPM5-expressing solitary chemosensory cells respond to odorous irritants. J. Neurophysiol. 99, 1451-1460.
    Pubmed CrossRef
  65. Lin, Y. S., Hsu, C. C., Bien, M. Y., Hsu, H. C., Weng, H. T. and Kou, Y. R. (2010) Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats. J. Appl. Physiol. (1985) 108, 1293-1303.
    Pubmed CrossRef
  66. Ling, Y. H., Chen, S. P., Fann, C. S., Wang, S. J. and Wang, Y. F. (2019) TRPM8 genetic variant is associated with chronic migraine and allodynia. J. Headache Pain 20, 115.
    Pubmed KoreaMed CrossRef
  67. Liu, H., Liu, Q., Hua, L. and Pan, J. (2018) Inhibition of transient receptor potential melastatin 8 alleviates airway inflammation and remodeling in a murine model of asthma with cold air stimulus. Acta Biochim. Biophys. Sin. (Shanghai) 50, 499-506.
    Pubmed CrossRef
  68. Liu, S. C., Lu, H. H., Cheng, L. H., Chu, Y. H., Lee, F. P., Wu, C. C. and Wang, H. W. (2015) Identification of the cold receptor TRPM8 in the nasal mucosa. Am. J. Rhinol. Allergy 29, e112-e116.
    Pubmed CrossRef
  69. Lübbert, M., Kyereme, J., Schöbel, N., Beltrán, L., Wetzel, C. H. and Hatt, H. (2013) Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons. PLoS One 8, e77998.
    Pubmed KoreaMed CrossRef
  70. Lu, Z., Li, C. M., Qiao, Y., Yan, Y. and Yang, X. (2008) Effect of inhaled formaldehyde on learning and memory of mice. Indoor Air 18, 77-83.
    Pubmed CrossRef
  71. Lundberg, J. M. and Saria, A. (1983) Capsaicin-induced desensitization of airway mucosa to cigarette smoke, mechanical and chemical irritants. Nature 302, 251-253.
    Pubmed CrossRef
  72. Macpherson, L. J., Dubin, A. E., Evans, M. J., Marr, F., Schultz, P. G., Cravatt, B. F. and Patapoutian, A. (2007) Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445, 541-545.
    Pubmed CrossRef
  73. Macpherson, L. J., Geierstanger, B. H., Viswanath, V., Bandell, M., Eid, S. R., Hwang, S. and Patapoutian, A. (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr. Biol. 15, 929-934.
    Pubmed CrossRef
  74. Matsunami, H. and Buck, L. B. (1997) A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90, 775-784.
    Pubmed CrossRef
  75. Matta, J. A., Cornett, P. M., Miyares, R. L., Abe, K., Sahibzada, N. and Ahern, G. P. (2008) General anesthetics activate a nociceptive ion channel to enhance pain and inflammation. Proc. Natl. Acad. Sci. U. S. A. 105, 8784-8789.
    Pubmed KoreaMed CrossRef
  76. McNamara, C. R., Mandel-Brehm, J., Bautista, D. M., Siemens, J., Deranian, K. L., Zhao, M., Hayward, N. J., Chong, J. A., Julius, D., Moran, M. M. and Fanger, C. M. (2007) TRPA1 mediates formalin-induced pain. Proc. Natl. Acad. Sci. U. S. A. 104, 13525-13530.
    Pubmed KoreaMed CrossRef
  77. Miller, K. W., Richards, C. D., Roth, S. H. and Urban, B. W. (2002) Molecular and basic mechanisms of anaesthesia. Br. J. Anaesth. 89, 1-2.
  78. Mori, Y., Tanaka-Kagawa, T., Tahara, M., Kawakami, T., Aoki, A., Okamoto, Y., Isobe, T., Ohkawara, S., Hanioka, N., Azuma, K., Sakai, S. and Jinno, H. (2023) Species differences in activation of TRPA1 by resin additive-related chemicals relevant to indoor air quality. J. Toxicol. Sci. 48, 37-45.
    Pubmed CrossRef
  79. Mutoh, T., Taki, Y. and Tsubone, H. (2013) Desflurane but not sevoflurane augments laryngeal C-fiber inputs to nucleus tractus solitarii neurons by activating transient receptor potential-A1. Life Sci. 92, 821-828.
    Pubmed CrossRef
  80. Mutoh, T. and Tsubone, H. (2003) Hypersensitivity of laryngeal C-fibers induced by volatile anesthetics in young guinea pigs. Am. J. Respir. Crit. Care Med. 167, 557-562.
    Pubmed CrossRef
  81. Mutoh, T., Tsubone, H., Nishimura, R. and Sasaki, N. (1998) Responses of laryngeal capsaicin-sensitive receptors to volatile anesthetics in anesthetized dogs. Respir. Physiol. 111, 113-125.
    Pubmed CrossRef
  82. Nair, V., Tran, M., Behar, R. Z., Zhai, S., Cui, X., Phandthong, R., Wang, Y., Pan, S., Luo, W., Pankow, J. F., Volz, D. C. and Talbot, P. (2020) Menthol in electronic cigarettes: a contributor to respiratory disease? Toxicol. Appl. Pharmacol. 407, 115238.
    Pubmed KoreaMed CrossRef
  83. Nassenstein, C., Kwong, K., Taylor-Clark, T., Kollarik, M., Macglashan, D. M., Braun, A. and Undem, B. J. (2008) Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J. Physiol. 586, 1595-1604.
    Pubmed KoreaMed CrossRef
  84. Nassini, R., Materazzi, S., Vriens, J., Prenen, J., Benemei, S., De Siena, G., la Marca, G., Andrè, E., Preti, D., Avonto, C., Sadofsky, L., Di Marzo, V., De Petrocellis, L., Dussor, G., Porreca, F., Taglialatela-Scafati, O., Appendino, G., Nilius, B. and Geppetti, P. (2012) The 'headache tree' via umbellulone and TRPA1 activates the trigeminovascular system. Brain 135, 376-390.
    Pubmed CrossRef
  85. Ni, Y., Zhang, G. and Kokot, S. (2005) Simultaneous spectrophotometric determination of maltol, ethyl maltol, vanillin and ethyl vanillin in foods by multivariate calibration and artificial neural networks. Food Chem. 89, 465-473.
    CrossRef
  86. Nilius, B. and Owsianik, G. (2011) The transient receptor potential family of ion channels. Genome Biol. 12, 218.
    Pubmed KoreaMed CrossRef
  87. Ogawa, N., Kurokawa, T., Fujiwara, K., Polat, O. K., Badr, H., Takahashi, N. and Mori, Y. (2016) Functional and structural divergence in human TRPV1 channel subunits by oxidative cysteine modification. J. Biol. Chem. 291, 4197-4210.
    Pubmed KoreaMed CrossRef
  88. Patapoutian, A., Peier, A. M., Story, G. M. and Viswanath, V. (2003) ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat. Rev. Neurosci. 4, 529-539.
    Pubmed CrossRef
  89. Peier, A. M., Moqrich, A., Hergarden, A. C., Reeve, A. J., Andersson, D. A., Story, G. M., Earley, T. J., Dragoni, I., McIntyre, P., Bevan, S. and Patapoutian, A. (2002) A TRP channel that senses cold stimuli and menthol. Cell 108, 705-715.
    Pubmed CrossRef
  90. Perez, C. M., Hazari, M. S. and Farraj, A. K. (2015) Role of autonomic reflex arcs in cardiovascular responses to air pollution exposure. Cardiovasc. Toxicol. 15, 69-78.
    Pubmed KoreaMed CrossRef
  91. Pires, P. W. and Earley, S. (2018) Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke. Elife 7, e35316.
    Pubmed KoreaMed CrossRef
  92. Reiter, J., Levina, N., van der Linden, M., Gruhlke, M., Martin, C. and Slusarenko, A. J. (2017) Diallylthiosulfinate (allicin), a volatile antimicrobial from garlic (Allium sativum), kills human lung pathogenic bacteria, including MDR strains, as a vapor. Molecules 22, 1711.
    Pubmed KoreaMed CrossRef
  93. Salthammer, T. (2016) Very volatile organic compounds: an understudied class of indoor air pollutants. Indoor Air 26, 25-38.
    Pubmed CrossRef
  94. Saunders, C. J., Li, W. Y., Patel, T. D., Muday, J. A. and Silver, W. L. (2013) Dissecting the role of TRPV1 in detecting multiple trigeminal irritants in three behavioral assays for sensory irritation. F1000Res. 2, 74.
    Pubmed KoreaMed CrossRef
  95. Saviuc, C. M., Drumea, V., Olariu, L., Chifiriuc, M. C., Bezirtzoglou, E. and Lazăr, V. (2015) Essential oils with microbicidal and antibiofilm activity. Curr. Pharm. Biotechnol. 16, 137-151.
    Pubmed CrossRef
  96. Sawada, Y., Hosokawa, H., Matsumura, K. and Kobayashi, S. (2008) Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur. J. Neurosci. 27, 1131-1142.
    Pubmed CrossRef
  97. Schaefer, E. A., Stohr, S., Meister, M., Aigner, A., Gudermann, T. and Buech, T. R. (2013) Stimulation of the chemosensory TRPA1 cation channel by volatile toxic substances promotes cell survival of small cell lung cancer cells. Biochem. Pharmacol. 85, 426-438.
    Pubmed CrossRef
  98. Silver, W. L., Clapp, T. R., Stone, L. M. and Kinnamon, S. C. (2006) TRPV1 receptors and nasal trigeminal chemesthesis. Chem. Senses 31, 807-812.
    Pubmed CrossRef
  99. Soares, G., Bhattacharya, T., Chakrabarti, T., Tagde, P. and Cavalu, S. (2021) Exploring pharmacological mechanisms of essential oils on the central nervous system. Plants (Basel) 11, 21.
    Pubmed KoreaMed CrossRef
  100. Soffritti, M., Belpoggi, F., Lambertin, L., Lauriola, M., Padovani, M. and Maltoni, C. (2002) Results of long-term experimental studies on the carcinogenicity of formaldehyde and acetaldehyde in rats. Ann. N. Y. Acad. Sci. 982, 87-105.
    Pubmed CrossRef
  101. Takahashi, N., Kuwaki, T., Kiyonaka, S., Numata, T., Kozai, D., Mizuno, Y., Yamamoto, S., Naito, S., Knevels, E., Carmeliet, P., Oga, T., Kaneko, S., Suga, S., Nokami, T., Yoshida, J. and Mori, Y. (2011) TRPA1 underlies a sensing mechanism for O2. Nat. Chem. Biol. 7, 701-711.
    Pubmed CrossRef
  102. Talavera, K., Gees, M., Karashima, Y., Meseguer, V. M., Vanoirbeek, J. A., Damann, N., Everaerts, W., Benoit, M., Janssens, A., Vennekens, R., Viana, F., Nemery, B., Nilius, B. and Voets, T. (2009) Nicotine activates the chemosensory cation channel TRPA1. Nat. Neurosci. 12, 1293-1299.
    Pubmed CrossRef
  103. Taylor-Clark, T. E. and Undem, B. J. (2010) Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J. Physiol. 588, 423-433.
    Pubmed KoreaMed CrossRef
  104. Ton, H. T., Phan, T. X. and Ahern, G. P. (2020) Inhibition of ligand-gated TRPA1 by general anesthetics. Mol. Pharmacol. 98, 185-191.
    Pubmed KoreaMed CrossRef
  105. Tsubone, H., Sant'Ambrogio, G., Anderson, J. W. and Orani, G. P. (1991) Laryngeal afferent activity and reflexes in the guinea pig. Respir. Physiol. 86, 215-231.
    Pubmed CrossRef
  106. van Swinderen, B., Saifee, O., Shebester, L., Roberson, R., Nonet, M. L. and Crowder, C. M. (1999) A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 96, 2479-2484.
    Pubmed KoreaMed CrossRef
  107. Vanden Abeele, F., Kondratskyi, A., Dubois, C., Shapovalov, G., Gkika, D., Busserolles, J., Shuba, Y., Skryma, R. and Prevarskaya, N. (2013) Complex modulation of the cold receptor TRPM8 by volatile anaesthetics and its role in complications of general anaesthesia. J. Cell Sci. 126, 4479-4489.
    Pubmed CrossRef
  108. Vanden Abeele, F., Lotteau, S., Ducreux, S., Dubois, C., Monnier, N., Hanna, A., Gkika, D., Romestaing, C., Noyer, L., Flourakis, M., Tessier, N., Al-Mawla, R., Chouabe, C., Lefai, E., Lunardi, J., Hamilton, S., Fauré, J., Van Coppenolle, F. and Prevarskaya, N. (2019) TRPV1 variants impair intracellular Ca(2+) signaling and may confer susceptibility to malignant hyperthermia. Genet. Med. 21, 441-450.
    Pubmed KoreaMed CrossRef
  109. Vannier, B., Peyton, M., Boulay, G., Brown, D., Qin, N., Jiang, M., Zhu, X. and Birnbaumer, L. (1999) Mouse trp2, the homologue of the human trpc2 pseudogene, encodes mTrp2, a store depletion-activated capacitative Ca2+ entry channel. Proc. Natl. Acad. Sci. U. S. A. 96, 2060-2064.
    Pubmed KoreaMed CrossRef
  110. Wakamori, M., Ikemoto, Y. and Akaike, N. (1991) Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat. J. Neurophysiol. 66, 2014-2021.
    Pubmed CrossRef
  111. Wang, C., Fujita, T., Yasuda, H. and Kumamoto, E. (2022) Spontaneous excitatory transmission enhancement produced by linalool and its isomer geraniol in rat spinal substantia gelatinosa neurons - involvement of transient receptor potential channels. Phytomed. Plus 2, 100155.
    CrossRef
  112. Wang, H. and Siemens, J. (2015) TRP ion channels in thermosensation, thermoregulation and metabolism. Temperature (Austin) 2, 178-187.
    Pubmed KoreaMed CrossRef
  113. Weng, W. H., Hsu, C. C., Chiang, L. L., Lin, Y. J., Lin, Y. S. and Su, C. L. (2013) Role of TRPV1 and P2X receptors in the activation of lung vagal C-fiber afferents by inhaled cigarette smoke in rats. Mol. Med. Rep. 7, 1300-1304.
    Pubmed CrossRef
  114. Win-Shwe, T. T., Fujimaki, H., Arashidani, K. and Kunugita, N. (2013) Indoor volatile organic compounds and chemical sensitivity reactions. Clin. Dev. Immunol. 2013, 623812.
    Pubmed KoreaMed CrossRef
  115. Wu, Y., Duan, J., Li, B., Liu, H. and Chen, M. (2020) Exposure to formaldehyde at low temperatures aggravates allergic asthma involved in transient receptor potential ion channel. Environ. Toxicol. Pharmacol. 80, 103469.
    Pubmed CrossRef
  116. Xu, H., Delling, M., Jun, J. C. and Clapham, D. E. (2006) Oregano, thyme and clove-derived flavors and skin sensitizers activate specific TRP channels. Nat. Neurosci. 9, 628-635.
    Pubmed CrossRef
  117. Yamakura, T. and Harris, R. A. (2000) Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology 93, 1095-1101.
    Pubmed CrossRef
  118. Yoon, M., Ryu, M. H., Huff, R. D., Belvisi, M. G., Smith, J. and Carlsten, C. (2022) Effect of traffic-related air pollution on cough in adults with polymorphisms in several cough-related genes. Respir. Res. 23, 113.
    Pubmed KoreaMed CrossRef
  119. Yu, G. Y., Song, X. F., Liu, Y. and Sun, Z. W. (2014) Inhaled formaldehyde induces bone marrow toxicity via oxidative stress in exposed mice. Asian Pac. J. Cancer Prev. 15, 5253-5257.
    Pubmed CrossRef
  120. Zhang, P., Yang, C. and Delay, R. J. (2010) Odors activate dual pathways, a TRPC2 and a AA-dependent pathway, in mouse vomeronasal neurons. Am. J. Physiol. Cell Physiol. 298, C1253-C1264.
    Pubmed KoreaMed CrossRef
  121. Zhong, J., Pollastro, F., Prenen, J., Zhu, Z., Appendino, G. and Nilius, B. (2011) Ligustilide: a novel TRPA1 modulator. Pflugers Arch. 462, 841-849.
    Pubmed CrossRef
  122. Zhou, C., Liang, P., Liu, J., Zhang, W., Liao, D., Chen, Y., Chen, X. and Li, T. (2014) Emulsified isoflurane enhances thermal transient receptor potential vanilloid-1 channel activation-mediated sensory/nociceptive blockade by QX-314. Anesthesiology 121, 280-289.
    Pubmed CrossRef
  123. Zhou, Y. and Rui, L. (2010) Chapter Six - Major urinary protein regulation of chemical communication and nutrient metabolism. In: Vitamins & Hormones (G. Litwack, Ed.), pp. 151-163. Academic Press.
    Pubmed CrossRef


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