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Altitude, temperature, circadian rhythms and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Henning Wackerhage, Kenneth A. Dyar, Martin Schönfelder
A key requisite for thermoregulation is that some proteins must act as biological thermometers. In our body, the TRP (transient receptor potential) ion channels have that function. In contrast to a technical thermometer, however, there is not just one TRP ion channel but a family of TRP’s that are either warm-sensitive (TRPV1–4, TRP2–5) or cold-sensitive (TRPM8, TRPA1, TRPC5) and sense everything from cold pain, to cold, warmth and heat pain. Typically, once a certain temperature is reached, the TRP ion channels open and Na+ and Ca2+ ions flow into and depolarise any neuron that expresses these TRPs. Several knockout mouse models for the TRP ion channels have been generated and suggest that together, the TRPs sense temperature (42).
Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
TRPM8 is a non-selective channel and somatic transducer for sensing temperature less than 28°C. Chemical compounds that elicit cooling sensation, such as menthol, icilin, and eucalyptol, can also activate TRPM8 channels (93–95). TRPM8 is expressed in lung epithelial cells, colon tissue, nasal mucosa, prostrate, scrotal skin, seminiferous tubules, testicles, cornea, Merkel cells, keratinocytes, and primary sensory neurons in the DRG and the TG, consistent with its predominant role in the detection of cool in mice (96,97).
Physiology of the Pain System
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Painful information is conveyed by nociceptors which detect a wide range of thermal, chemical, or mechanical perturbations through a variety of mechanisms, including bare nerve endings which either react to specific noxious stimuli or are polymodal and respond to a variety of noxious stimuli. Painful information is relayed from the skin, muscles, joints, viscera, and various neural structures. Specific transducer channels are present on the nerve ending, allowing specific chemicals to activate the receptor. For instance, the transient receptor potential vanilloid-1 (TRPV1) receptor is activated by temperatures >43°C as well as capsaicin from the chili pepper plant. In addition, then endocannabinoid anandamide may also act as an endogenous ligand.1 Transient receptor potential M member 8 (TRPM8) is activated by temperatures <25–28°C as well as menthol. The frequency at which the afferent fires is dependent upon the intensity of the stimulus.2 Importantly, the frequency of afferent firing is also dependent upon the resting potential of the axon—which can be modified.
Emerging drugs in the treatment of chronic cough
Published in Expert Opinion on Emerging Drugs, 2023
Danica Brister, Mustafaa Wahab, Moaaz Rashad, Nermin Diab, Martin Kolb, Imran Satia
Inhalational challenge studies and animal cough models indicated TRP channel antagonists might be promising targets to reduce cough frequency. However, molecules targeting TRPV1, TRPVA1, and TRPV4 have failed to show an effect on cough frequency in double-blind randomized trials in 3 separate phase 2a studies [66–68]. A novel more potent TRPA1 antagonist is in development, currently studied in a phase 2 proof of concept study in specific sub-groups of patients: UCC, RCC secondary to atopic asthma, and COPD with and without chronic bronchitis [69]. Transient receptor potential melastatin 8 (TRPM8) has been shown in animal models to contribute to cold detection in sensory nerves, and with TRPV1, is methanol sensitive [70]. In comparison with other TRP receptors which stimulate, airway TRPM8-r may inhibit cough which will be assessed in a phase 2 study exploring the efficacy of a TRPM8 agonist (AX-8) in cough management. Preliminary results reported positive findings with AX-8 40 mg PO BID in a dissolving tablet, showing improvement in cough frequency within 15 min and lasting over 4 h [71]. Corporate release suggests in a pre-specified sub-group analysis of those patients with high cough frequency, there was an improvement in 24-h cough frequency, but trial data have yet to be published or presented.
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
Transient receptor potential melastatin eight (TRPM8) channels are nonselective cationic conducting proteins, with a certain selectivity for Ca2+ permeation [59]. Initially identified as a biomarker for prostate cancer, TRPM8 receptors are highly expressed in Aδ and C fiber afferents of peripheral sensory neurons [60]. TRPM8 is also present in many other tissues, including lung, the cardiovascular system, the urogenital tract, and the central nervous system [61]. An appealing compendium on the distribution of TRPM8 channels, their importance in regulating different physiological processes and the clinical implications has recently been published [62]. These channels are gated by different physical and chemical stimuli, voltage, cold (<28°C), osmolality, and cooling natural and synthetic compounds (menthol, eucalyptol, borneol, and icilin) [59]. Some physiological lipids (phosphoinositides), hormones (testosterone), and proteins (Pirt) have also been described as endogenous modulators of TRPM8 channels [63].
Migraine pathways and the identification of novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Innocenzo Rainero, Fausto Roveta, Alessandro Vacca, Cecilia Noviello, Elisa Rubino
Several, recent GWAS have found a significant correlation between migraine incidence and SNPs located near the Transient receptor potential melastatin 8 (TRPM8) coding region [72,73]. TRPM8 belongs to transient receptor potential (TRP) superfamily, a large family of nonselective cation channels that can be activated by a wide variety of stimuli, including changes in temperature, osmolarity, and pH. Activation of TRPs allows the influx of Ca2+ and Na+, resulting in membrane depolarization as well as the activation of second messenger signaling cascades. TRP channels participate in the sensory encoding of pain under both normal and disease states. The TRPM8 gene is located at 2q37.1 region and codes for a channel protein, expressed in sensory neurons, that is activated by cold temperatures and cooling agents, such as menthol [74]. Studies in experimental animals showed that activation of TRPM8 causes migraine-like behaviors that can be blocked with TRPM8 antagonists. Pre-treatment with sumatriptan, a drug commonly used to treat migraines, prevents these migraine-like behaviors, which strongly implicates a role for TRPM8 in migraine generation. Intriguingly, activation of TRP channels can elicit CGRP release [75].