Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/ F2RL1 and TRPM8

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Abstract

Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the PAR2 gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the TRPM8 gene. Carriers of the minor A allele of the rs2243057 polymorphism of PAR2 and minor C allele of the rs12992084 polymorphism of TRPM8 exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both PAR2 and TRPM8 are involved in individual differences in cold pain sensitivity.

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TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury.

Koichi Obata, Hirokazu Katsura, Toshiyuki Mizushima … (2005)

Cold hyperalgesia is a well-documented symptom of inflammatory and neuropathic pain; however, the underlying mechanisms of this enhanced sensitivity to cold are poorly understood. A subset of transient receptor potential (TRP) channels mediates thermosensation and is expressed in sensory tissues, such as nociceptors and skin. Here we report that the pharmacological blockade of TRPA1 in primary sensory neurons reversed cold hyperalgesia caused by inflammation and nerve injury. Inflammation and nerve injury increased TRPA1, but not TRPM8, expression in tyrosine kinase A-expressing dorsal root ganglion (DRG) neurons. Intrathecal administration of anti-nerve growth factor (anti-NGF), p38 MAPK inhibitor, or TRPA1 antisense oligodeoxynucleotide decreased the induction of TRPA1 and suppressed inflammation- and nerve injury-induced cold hyperalgesia. Conversely, intrathecal injection of NGF, but not glial cell line-derived neurotrophic factor, increased TRPA1 in DRG neurons through the p38 MAPK pathway. Together, these results demonstrate that an NGF-induced TRPA1 increase in sensory neurons via p38 activation is necessary for cold hyperalgesia. Thus, blocking TRPA1 in sensory neurons might provide a fruitful strategy for treating cold hyperalgesia caused by inflammation and nerve damage.

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Regulation of Pain and Itch by TRP Channels

Wolfgang Liedtke, Yong Chen, Sven-Eric Jordt … (2018)

Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily (TRPV1, TRPV3, and TRPV4), and finally members of the melastatin group (TRPM2, TRPM3, and TRPM8). Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory compounds targeting specific pain/itch-TRPs so that physiological protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1-modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accomplished via simple dosing strategies, and also by incorporating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

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TRPA1 contributes to cold hypersensitivity.

Patrick Earley, N Hayward, Clifford Woolf … (2010)

TRPA1 is a nonselective cation channel expressed by nociceptors. Although it is widely accepted that TRPA1 serves as a broad irritancy receptor for a variety of reactive chemicals, its role in cold sensation remains controversial. Here, we demonstrate that mild cooling markedly increases agonist-evoked rat TRPA1 currents. In the absence of an agonist, even noxious cold only increases current amplitude slightly. These results suggest that TRPA1 is a key mediator of cold hypersensitivity in pathological conditions in which reactive oxygen species and proinflammatory activators of the channel are present, but likely plays a comparatively minor role in acute cold sensation. Supporting this, cold hypersensitivity can be induced in wild-type but not Trpa1(-/-) mice by subcutaneous administration of a TRPA1 agonist. Furthermore, the selective TRPA1 antagonist HC-030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide] reduces cold hypersensitivity in rodent models of inflammatory and neuropathic pain.

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Journal

Journal ID (nlm-ta): Mol Pain

Journal ID (iso-abbrev): Mol Pain

Journal ID (publisher-id): MPX

Journal ID (hwp): spmpx

Title: Molecular Pain

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Electronic): 1744-8069

Publication date (Electronic): 25 March 2021

Publication date Collection: 2021

Volume: 17

Electronic Location Identifier: 17448069211002009

Affiliations

[1 ]Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

[2 ]Department of Oral Health and Clinical Science, Tokyo Dental College, Tokyo, Japan

[3 ]Department of Dental Anesthesiology, Tokyo Dental College, Tokyo, Japan

Author notes

[*]Kazutaka Ikeda, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Email: ikeda-kz@ 123456igakuken.or.jp

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Kazutaka Ikeda https://orcid.org/0000-0001-8342-0278

Article

Publisher ID: 10.1177_17448069211002009

DOI: 10.1177/17448069211002009

PMC ID: 8822448

PubMed ID: 33765896

SO-VID: e9d97351-80ff-47c9-becf-0cb0b6c55175

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Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 26 January 2021

Date revision received : 26 January 2021

Date accepted : 22 February 2021

Funding

Funded by: Japan Society for the Promotion of Science, FundRef https://doi.org/10.13039/501100001691;

Award ID: 17H04324

Award ID: 17K08970

Award ID: 17K09052

Award ID: 20K07774

Award ID: 20K09259

Award ID: JP16H06276 (AdAMS)

Funded by: Japan Agency for Medical Research and Development, FundRef https://doi.org/10.13039/100009619;

Award ID: JP19ek0610011

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cover-date January-December 2021

typesetter ts2

ScienceOpen disciplines: Molecular medicine

Keywords: par2,trpm8,cold-induced pain test,cold pain sensitivity,single-nucleotide polymorphism

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ScienceOpen disciplines: Molecular medicine

Keywords: par2, trpm8, cold-induced pain test, cold pain sensitivity, single-nucleotide polymorphism

Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2/ F2RL1 and TRPM8

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Most cited references 36

TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury.

Regulation of Pain and Itch by TRP Channels

TRPA1 contributes to cold hypersensitivity.

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