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      Linalool odor‐induced analgesia is triggered by TRPA1-independent pathway in mice

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          Abstract

          We had recently reported that linalool odor exposure induced significant analgesic effects in mice and that the effects were disappeared in olfactory-deprived mice in which the olfactory epithelium was damaged, thus indicating that the effects were triggered by chemical senses evoked by linalool odor exposure. However, the peripheral neuronal mechanisms, including linalool receptors that contribute toward triggering the linalool odor-induced analgesia, still remain unexplored. In vitro studies have shown that the transient receptor potential ankyrin 1 (TRPA1) responded to linalool, thus raising the possibility that TRPA1 expressed on the trigeminal nerve terminal detects linalool odor inhaled into the nostril and triggers the analgesic effects. To address this hypothesis, we measured the behavioral pain threshold for noxious mechanical stimulation in TRPA1-deficient mice. In contrast to our expectation, we found a significant increase in the threshold after linalool odor exposure in TRPA1-deficient mice, indicating the analgesic effects of linalool odor even in TRPA1-deficient mice. Furthermore, intranasal application of TRPA1 selective antagonist did not alter the analgesic effect of linalool odor. These results showed that the linalool odor-induced analgesia was triggered by a TRPA1-independent pathway in mice.

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          The capsaicin receptor: a heat-activated ion channel in the pain pathway.

          Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
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            A capsaicin-receptor homologue with a high threshold for noxious heat.

            Pain-producing heat is detected by several classes of nociceptive sensory neuron that differ in their thermal response thresholds. The cloned capsaicin receptor, also known as the vanilloid receptor subtype 1 (VR1), is a heat-gated ion channel that has been proposed to mediate responses of small-diameter sensory neurons to moderate (43 degrees C) thermal stimuli. VR1 is also activated by protons, indicating that it may participate in the detection of noxious thermal and chemical stimuli in vivo. Here we identify a structurally related receptor, VRL-1, that does not respond to capsaicin, acid or moderate heat. Instead, VRL-1 is activated by high temperatures, with a threshold of approximately 52 degrees C. Within sensory ganglia, VRL-1 is most prominently expressed by a subset of medium- to large-diameter neurons, making it a candidate receptor for transducing high-threshold heat responses in this class of cells. VRL-1 transcripts are not restricted to the sensory nervous system, indicating that this channel may be activated by stimuli other than heat. We propose that responses to noxious heat involve these related, but distinct, ion-channel subtypes that together detect a range of stimulus intensities.
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              Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors.

              The transient receptor potential (TRP) superfamily of cation channels contains four temperature-sensitive channels, named TRPV1-4, that are activated by heat stimuli from warm to that in the noxious range. Recently, two other members of this superfamily, TRPA1 and TRPM8, have been cloned and characterized as possible candidates for cold transducers in primary afferent neurons. Using in situ hybridization histochemistry and immunohistochemistry, we characterized the precise distribution of TRPA1, TRPM8, and TRPV1 mRNAs in the rat dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons. In the DRG, TRPM8 mRNA was not expressed in the TRPV1-expressing neuronal population, whereas TRPA1 mRNA was only seen in some neurons in this population. Both A-fiber and C-fiber neurons expressed TRPM8, whereas TRPV1 was almost exclusively seen in C-fiber neurons. All TRPM8-expressing neurons also expressed TrkA, whereas the expression of TRPV1 and TRPA1 was independent of TrkA expression. None of these three TRP channels were coexpressed with TrkB or TrkC. The TRPM8-expressing neurons were more abundant in the TG compared with the DRG, especially in the mandibular nerve region innervating the tongue. Our data suggest heterogeneity of TRPM8 and TRPA1 expression by subpopulations of primary afferent neurons, which may result in the difference of cold-sensitive primary afferent neurons in sensitivity to chemicals such as menthol and capsaicin and nerve growth factor. Copyright (c) 2005 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                danny@m3.kufm.kagoshima-u.ac.jp
                Journal
                Behav Brain Funct
                Behav Brain Funct
                Behavioral and Brain Functions : BBF
                BioMed Central (London )
                1744-9081
                26 April 2021
                26 April 2021
                2021
                : 17
                : 3
                Affiliations
                [1 ]GRID grid.258333.c, ISNI 0000 0001 1167 1801, Department of Physiology, Graduate School of Medical and Dental Sciences, , Kagoshima University, ; 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
                [2 ]GRID grid.258333.c, ISNI 0000 0001 1167 1801, Department of Dental Anesthesiology, Graduate School of Medical and Dental Sciences, , Kagoshima University, ; 8-35-1 Sakuragaoka, Kagoshima, 890-8544 Japan
                Author information
                http://orcid.org/0000-0001-8267-6626
                Article
                176
                10.1186/s12993-021-00176-y
                8077846
                33902628
                cb738443-b7be-4ff8-9f70-a8ee84680c20
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 6 December 2020
                : 19 April 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: KAKENHI 26670290
                Funded by: FundRef http://dx.doi.org/10.13039/501100004330, Smoking Research Foundation;
                Award ID: Smoking Research Foundation
                Award Recipient :
                Categories
                Short Paper
                Custom metadata
                © The Author(s) 2021

                Neurology
                linalool,analgesia,trpa1,trpa1-deficient mice,trpa1-selective antagonist
                Neurology
                linalool, analgesia, trpa1, trpa1-deficient mice, trpa1-selective antagonist

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