TRPA1 Channels Mediate Cold Temperature Sensing in Mammalian Vagal Sensory Neurons: Pharmacological and Genetic Evidence

Fajardo, Otto; Meseguer, Víctor; Belmonte, Carlos; Viana, Félix

doi:10.1523/jneurosci.1696-08.2008

Cited by 147 publications

(134 citation statements)

References 71 publications

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“…Although as was noted above, TRPA1 appears to function exclusively as a pain receptor within the somatosensory system, there is evidence that in airway epithelia, TRPA1 receptors of the vagus nerve are sensitive to cooling to temperatures as mild as 24°C. 51 The latter finding raises the possibility that stimulation of TRPA1 by nicotine 23 may contribute to the rise in Coolness/Cold that we observed up to a nicotine concentration of 18 mg/ml.…”

Section: Discussionmentioning

confidence: 67%

Sensory Effects of Menthol and Nicotine in an E-Cigarette

Rosbrook

Green

2016

NICTOB

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Introduction: Despite the longstanding use and popularity of menthol as a flavorant in tobacco products, its sensory interactions with inhaled nicotine have never been measured independently of the other irritants in tobacco smoke. We therefore measured the perception of menthol in an E-cigarette with the primary goal of assessing its analgesic effect on the sensory irritation produced by inhaled nicotine. Methods: Adult cigarette smokers sampled aerosolized E-liquids containing five different concentrations of nicotine with 0%, 0.5%, or 3.5% l-menthol, as well as two commercial menthol flavors with and without nicotine. For each of the E-liquids participants used a labeled magnitude scale to rate the Overall Sensation intensity, Coolness/Cold, and Irritation/Harshness they experienced, and a Labeled Hedonic Scale to indicate how much they liked/disliked the overall flavor. Results: The main findings were that (1) perceived Irritation/Harshness was unaffected by a low (0.5%) menthol concentration, whereas a high menthol concentration (3.5%) led to higher perceived Irritation/Harshness at low nicotine concentrations but to lower Irritation/Harshness at the highest nicotine concentration (24 mg/ml); (2) a commercial Menthol-Mint flavor produced similar results; (3) nicotine tended to enhance rather than suppress sensations of Coolness/Cold; and (4) menthol tended to slightly increase liking independently of nicotine concentration. Conclusion: In addition to adding a sensation of coolness, menthol can reduce perceived airway irritation and harshness produced by inhalation when nicotine concentration is high, and contributes to the sensory impact of E-liquids when nicotine concentration is low. Implications: The evidence presented here indicates that menthol can potentially improve the appeal of E-cigarettes not only via its coolness and minty flavor, but also by reducing the harshness from high concentrations of nicotine. As the first direct demonstration of an analgesic effect of menthol on inhaled nicotine in humans, these data also have implications for the role of menthol flavors in other inhaled tobacco products.

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Section: Discussionmentioning

confidence: 67%

Sensory Effects of Menthol and Nicotine in an E-Cigarette

Rosbrook

Green

2016

NICTOB

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“…Thus, most low-threshold CS neurons were activated and/or sensitized by menthol. Furthermore, these cold responses were blocked by BCTC, an effective TRPM8 channel blocker with sensitizing actions on TRPA1 (Madrid et al, 2006;Fajardo et al, 2008). The majority of studies, including phenotypic analysis of TRPM8 knock-out mice, agree with this view (McKemy, 2005;Reid, 2005;Daniels and McKemy, 2007).…”

Section: Discussionmentioning

confidence: 73%

“…2C). The other six were sensitive to AITC, menthol, and capsaicin, a phenotype characteristic of polymodal nociceptors probably expressing TRPA1 channels (Jordt et al, 2004;Fajardo et al, 2008). Interestingly, we noted that cooling inhibited the responses to menthol and AITC in these neurons (Fig.…”

Section: Trpa1 Channels Are Not the Main Determinants Of Cold Detectimentioning

confidence: 67%

“…These results suggest that TRPA1 ion channels of trigeminal ganglion neurons are not important for cold detection within a wide range of cold temperatures, in contrast with visceral neurons in which this channel appears to be the main determinant of cold sensitivity (Fajardo et al 2008). Karashima et al (2007), a fraction (56%) of AITCsensitive neurons was also activated by menthol (n ϭ 66) (Fig.…”

Section: Trpa1 Channels Are Not the Main Determinants Of Cold Detectimentioning

confidence: 86%

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Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

Madrid¹,

Peña²,

et al. 2009

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Molecular determinants of threshold differences among cold thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I KD , a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and I TRPM8 , a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of I KD . In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent I KD . Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of I KD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of I KD blockade were observed in TRPA1 Ϫ/Ϫ mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low-and high-threshold cold thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.

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“…Certain ion channels exhibit dramatic temperature sensitivity in gating over physiologically relevant ranges (Q 10 = 10-30). Mammalian ion channels with such high Q 10 values include particular two-pore K + channels (3), the voltage-gated proton channel (4), transient receptor potential cation channel subfamily V members 1-3 (TRPV1-3) (5-7), transient receptor potential menthol receptor 8 (TRPM8) (8), and in some reports, TRP cation channel subfamily A member 1 (TRPA1) (9,10). There is no a priori requirement for cold encoding by high Q 10 channels-action potential firing rates are affected perforce by temperature, even if driven solely by conventional Na V and K V channels-but high Q 10 channels are likely suspects in encoding temperature changes.…”

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confidence: 99%

Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system

Zimmermann

Lennerz

Hein³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

207

168

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Detection and adaptation to cold temperature is crucial to survival. Cold sensing in the innocuous range of cold (>10-15°C) in the mammalian peripheral nervous system is thought to rely primarily on transient receptor potential (TRP) ion channels, most notably the menthol receptor, TRPM8. Here we report that TRP cation channel, subfamily C member 5 (TRPC5), but not TRPC1/TRPC5 heteromeric channels, are highly cold sensitive in the temperature range 37-25°C. We found that TRPC5 is present in mouse and human sensory neurons of dorsal root ganglia, a substantial number of peripheral nerves including intraepithelial endings, and in the dorsal lamina of the spinal cord that receives sensory input from the skin, consistent with a potential TRPC5 function as an innocuous cold transducer in nociceptive and thermosensory nerve endings. Although deletion of TRPC5 in 129S1/SvImJ mice resulted in no temperature-sensitive behavioral changes, TRPM8 and/or other menthol-sensitive channels appear to underpin a much larger component of noxious cold sensing after TRPC5 deletion and a shift in mechanosensitive C-fiber subtypes. These findings demonstrate that highly cold-sensitive TRPC5 channels are a molecular component for detection and regional adaptation to cold temperatures in the peripheral nervous system that is distinct from noxious cold sensing.pain | single-fiber | thermo-transient receptor potential | nociception | temperature sensing N ociceptors and thermoreceptive neurons, such as cold and heat receptors, innervate the skin and deep tissues. The cell bodies of sensory nerve endings are clustered in ganglia located in the vertebral column and cranium. Their projections extend to the skin where they arborize in terminals embedded between keratinocytes. Although nociceptors are polymodal and respond to stimuli (cold, heat, pressure, and noxious chemicals) that are capable of producing tissue damage and pain (1), cold receptors are unimodal and specialized to detect cool and cold temperatures (2). Transient receptor potential (TRP) ion channels are principal transducers of thermal stimuli that depolarize nerve terminals to the action potential threshold. Action potentials then relay the sensory information to integrative centers in the spinal cord and brain.All proteins are temperature sensitive, but most ion channels exhibit two-to threefold increases in gating with a 10°C change in temperature (Q 10 = 2-3). Certain ion channels exhibit dramatic temperature sensitivity in gating over physiologically relevant ranges (Q 10 = 10-30). Mammalian ion channels with such high Q 10 values include particular two-pore K + channels (3), the voltage-gated proton channel (4), transient receptor potential cation channel subfamily V members 1-3 (TRPV1-3) (5-7), transient receptor potential menthol receptor 8 (TRPM8) (8), and in some reports, TRP cation channel subfamily A member 1 (TRPA1) (9, 10). There is no a priori requirement for cold encoding by high Q 10 channels-action potential firing rates are affected perforce by temperature,...

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TRPA1 Channels Mediate Cold Temperature Sensing in Mammalian Vagal Sensory Neurons: Pharmacological and Genetic Evidence

Cited by 147 publications

References 71 publications

Sensory Effects of Menthol and Nicotine in an E-Cigarette

Sensory Effects of Menthol and Nicotine in an E-Cigarette

Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

Transient receptor potential cation channel, subfamily C, member 5 (TRPC5) is a cold-transducer in the peripheral nervous system

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