Therapeutic Potential of TRPM8 Modulators
نویسنده
چکیده
The perception of temperature is a key tenet of sensory physiology and is critical in not only acute responses to changes in our environment, but also fundamental in regulating homeostatic mechanisms like core body temperature [1]. The somatosensory system is able to detect subtle changes in ambient temperature due to the coordinated efforts of thermosensory neurons which express temperature-sensitive members of the TRP channel family [2]. Remarkably, the range of temperatures that these channels respond to covers the entire perceived temperature spectrum, from warm to painfully hot, from pleasingly cool to excruciatingly cold. Moreover, many of these channels are receptors for ligands that elicit distinct psychophysical sensations, such as the heat associated with capsaicin and the cold felt with menthol [2]. The latter of these was influential in the discovery of the first TRP channel shown to be responsive to temperatures in the cold range (<30°C), TRPM8, a member of the melastatin TRP channel subfamily [3, 4]. In vitro, the channel is a receptor for a number of compounds which evoke the psychophysical sensation of cold (such as menthol and icilin), and is activated by temperatures that range from innocuous cool (26-15°C) to noxious cold (<15°C). Recent genetic evidence shows that TRPM8 is the predominant mammalian cold sensor and is involved in most, if not all, aspects of cold thermal transduction [5-8]. These studies demonstrated that TRPM8 mediates transduction of innocuous cool and noxious cold, hypersensitivity to cold caused by inflammation or nerve injury, and provides the analgesic effect produced by cold or chemical cooling compounds. This review highlights these findings and suggests some potential uses of both TRPM8 antagonists and agonists in the treatment of pain.
منابع مشابه
Leucettamols, Bifunctionalized Marine Sphingoids, Act as Modulators of TRPA1 and TRPM8 Channels
Leucettamols, bifunctionalized sphingoid-like compounds obtained from a marine sponge Leucetta sp., act as non-electrophilic activators of the TRPA1 channel and potent inhibitors of the icilin-mediated activation of the TRPM8 channel, while they are inactive on CB₁, CB₂ and TRPV1 receptors. Leucettamols represent the first compounds of marine origin to target TRPA1 and the first class of natura...
متن کاملShivering and tachycardic responses to external cooling in mice are substantially suppressed by TRPV1 activation but not by TRPM8 inhibition.
Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may ...
متن کاملPirt Functions as an Endogenous Regulator of TRPM8
Pirt is a membrane protein that is specifically expressed in the peripheral nervous system, where it has been shown to increase the sensitivity of the transient receptor potential vanilloid 1 channel and modulate its role in heat pain. The broad expression of Pirt among dorsal root ganglion neurons suggests it may modulate other transient receptor potentials, such as the menthol and cooling sen...
متن کاملProstate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function.
In recent years, the transient receptor potential melastatin member 8 (TRPM8) channel has emerged as a promising prognostic marker and putative therapeutic target in prostate cancer (PCa). However, the mechanisms of prostate-specific regulation and functional evolution of TRPM8 during PCa progression remain unclear. Here we show, for the first time to our knowledge, that only secretory mature d...
متن کاملTryptamine-Based Derivatives as Transient Receptor Potential Melastatin Type 8 (TRPM8) Channel Modulators.
Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acti...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2010