Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene

Kaimoto, Taeko; Hatakeyama, Yukari; Takahashi, Kenji; Imagawa, Toshiaki; Tominaga, Makoto; Ohta, Toshio

doi:10.1002/ejp.840

Cited by 35 publications

(24 citation statements)

References 50 publications

(81 reference statements)

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“…Male mice were placed in cages for 30 min before experiments. Twenty microliters of limonene (5 μmol/paw) was injected into the hind paw to elicit TRPA1‐dependent nocifensive behaviors (Kaimoto et al, ). The numbers of times each mouse licked and flicked the injected paw were counted for 10 min after the limonene injection.…”

Section: Methodsmentioning

confidence: 99%

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Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons

Nishizawa

Takahashi

Oguma

et al. 2017

J of Neuroscience Research

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T-type Ca channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca concentration ([Ca ] ), which were suppressed by selective T-type Ca channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T-type Ca channel. The magnitude of 15K-induced [Ca ] increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1 mouse sensory neurons. TRPA1 blockers diminished the [Ca ] responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca ] increases even in AITC-sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca ] increase regardless of the sensitivity to capsaicin. [Ca ] responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca , we hypothesize that Ca entered via T-type Ca channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca channel may be a potential target for TRPA1-related pain.

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Section: Methodsmentioning

confidence: 99%

“…Male mice were placed in cages for 30 min before experiments. Twenty microliters of limonene (5 lmol/paw) was injected into the hind paw to elicit TRPA1-dependent nocifensive behaviors (Kaimoto et al, 2016).…”

Section: Behavioral Experimentsmentioning

confidence: 99%

Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons

Nishizawa

Takahashi

Oguma

et al. 2017

J of Neuroscience Research

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“…Furthermore, pharmacological inhibition of TRPA1 recapitulated the response in wild-type mice. Common e-cig flavoring agents, including cinnamaldehyde (cinnamon), cannabidiol (cannabis oil), linalool (floral/spicy flavor), menthol (mint), eugenol (clove), limonene (citrus), gingerol (ginger), and ethyl vanillin (vanilla) are potent TRPA1 agonists [123–128]; These data further illustrate a potential role for TRPA1 in the pathogenesis of asthma and bring into question the safety of repeated inhalation of e-cig flavoring agents that are known TRPA1 agonists.…”

Section: E-liquid Components and Their Effects On The Lungmentioning

confidence: 99%

Electronic Cigarettes: Their Constituents and Potential Links to Asthma

Clapp

Jaspers

2017

Curr Allergy Asthma Rep

153

141

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Purpose of Review Vaping is gaining popularity in the USA, particularly among teens and young adults. While e-cigs are commonly represented as safer alternatives to tobacco cigarettes, little is known regarding the health effects of their short- or long-term use, especially in individuals with pre-existing respiratory diseases such as asthma. Flavored e-cig liquids (e-liquids) and e-cig aerosols contain airway irritants and toxicants that have been implicated in the pathogenesis and worsening of lung diseases. In this review, we will summarize existing data on potential health effects of components present in e-cig aerosols, such as propylene glycol, vegetable glycerin, nicotine, and flavorings, and discuss their relevance in the context of asthma. Recent Findings Recent survey data indicate that adolescents with asthma had a higher prevalence of current e-cig use (12.4%) compared to their non-asthmatics peers (10.2%) and conveyed positive beliefs about tobacco products, especially e-cigs. Similarly, a study conducted among high school students from Ontario, Canada, indicated a greater likelihood of e-cig use in asthmatics as compared to their non-asthmatic peers. Availability of different flavorings is often cited as the main reason among youth/adolescents for trying e-cigs or switching from cigarettes to e-cigs. Occupational inhalation of some common food-safe flavoring agents is reported to cause occupational asthma and worsen asthmatic symptoms. Moreover, workplace inhalation exposures to the flavoring agent diacetyl have caused irreversible obstructive airway disease in healthy workers. Additionally, recent studies report that thermal decomposition of propylene glycol (PG) and vegetable glycerin (VG), the base constituents of e-liquids, produces reactive carbonyls, including acrolein, formaldehyde, and acetaldehyde, which have known respiratory toxicities. Furthermore, recent nicotine studies in rodents reveal that prenatal nicotine exposures lead to epigenetic reprogramming in the offspring, abnormal lung development, and multigenerational transmission of asthmatic-like symptoms. Summary Comparisons of the toxicity and health effects of e-cigs and conventional cigarettes often focus on toxicants known to be present in cigarette smoke (CS) (i.e., formaldehyde, nitrosamines, etc.), as well as smoking-associated clinical endpoints, such as cancer, bronchitis, and chronic obstructive pulmonary disease (COPD). However, this approach disregards potential toxicity of components unique to flavored e-cigs, such as PG, VG, and the many different flavoring chemicals, which likely induce respiratory effects not usually observed in cigarette smokers.

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“…Desensitization of TRPA1-Mediated Anethole Responses. TRPA1 agonists such as AITC, limonene, and eugenol often show bimodal activity on TRPA1 channels such that repetitive applications desensitize the channels (Chung et al, 2014;Kaimoto et al, 2016;Kistner et al, 2016). Similarly, the dose-response experiment shown in Fig.…”

Section: Fo Selectively Activates Mouse and Human Trpa1mentioning

confidence: 88%

trans-Anethole of Fennel Oil is a Selective and Nonelectrophilic Agonist of the TRPA1 Ion Channel

et al. 2019

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Transient receptor potential (TRP) cation channels are molecular targets of various natural products. TRPA1, a member of TRP channel family, is specifically activated by natural products such as allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), and allicin (garlic). In this study, we demonstrated that TRPA1 is also a target of trans-anethole in fennel oil (FO) and fennel seed extract. Similar to FO, trans-anethole selectively elicited calcium influx in TRPA1-expressing mouse sensory neurons of the dorsal root and trigeminal ganglia. These FOand anethole-induced calcium responses were blocked by a selective TRPA1 channel antagonist, HC-030031. Moreover, both FO and trans-anethole induced calcium influx and transmembrane currents in HEK293 cells stably overexpressing human TRPA1 channels, but not in regular HEK293 cells. Mutation of the amino acids S873 and T874 binding site of human TRPA1 significantly attenuated channel activation by trans-anethole, whereas pretreating with glutathione, a nucleophile, did not. Conversely, activation of TRPA1 by the electrophile allyl isothiocyanate was abolished by glutathione, but was ostensibly unaffected by mutation of the ST binding site. Finally, it was found that trans-anethole was capable of desensitizing TRPA1, and unlike allyl isothiocyanate, it failed to induce nocifensive behaviors in mice. We conclude that trans-anethole is a selective, nonelectrophilic, and seemingly less-irritating agonist of TRPA1.

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Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene

Cited by 35 publications

References 50 publications

Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons

Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons

Electronic Cigarettes: Their Constituents and Potential Links to Asthma

trans-Anethole of Fennel Oil is a Selective and Nonelectrophilic Agonist of the TRPA1 Ion Channel

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Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene

Cited by 35 publications

References 50 publications

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T‐type Ca2+ channel in mouse sensory neurons

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T‐type Ca2+ channel in mouse sensory neurons

Electronic Cigarettes: Their Constituents and Potential Links to Asthma

trans-Anethole of Fennel Oil is a Selective and Nonelectrophilic Agonist of the TRPA1 Ion Channel

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Product

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Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons

Possible involvement of transient receptor potential ankyrin 1 in Ca²⁺ signaling via T‐type Ca²⁺ channel in mouse sensory neurons