Cold receptors

TRPM8 is also known as TRP-P8 or the cold receptor. TRP Channels... 

Menthol is a mild anesthetic and anti-irritant. It causes a cool sensation on the skin, by activating the peripheral cold receptors. It is used in cigarettes, and in topical creams for the relief of sore muscles. It also is used in cough drops, aftershave lotions, inhalers, and cooling gels. 

Braun, H.A., Schaefer, K., Voigt, K., and Huber, M.T. Temperature encoding in peripheral cold receptors oscillations, resonances, chaos and noise. Nova Acta Leopoldina 2003, 88 293-318. 

Bulsara, A., and Gammeitoni, L Tuning in to noise. Phys. Today 1996,1996 39-45. Longtin, A., and Hinzer, K. Encoding with bursting, subthreshold oscillations, and noise in mammalian cold receptors. Neural Comput 1996,8 215-255. Mosekilde, E., Sosnovtseva, O.V., Postnov, D., Braun, H.A., and Huber, M.T. Noise-activated and noise-induced rhythms in neural systems. Nonlin Stud 2004,11 449-467. 

L. Discharge pattern analysis suggests existence of a low-threshold calcium channel in cold receptors. Experientia 1991,47 47-50. 

Schafer, K., Braun, H.A., and Isenberg, C. Effect of menthol on cold receptor activity. Analysis of receptor processes. 

Menthol is widely used in pharmaceuticals, confectionery, and toiletry products as a flavoring agent or odor enhancer. In addition to its characteristic peppermint flavor, /-menthol, which occurs naturally, also exerts a cooling or refreshing sensation that is exploited in many topical preparations. Unlike mannitol, which exerts a similar effect due to a negative heat of solution, /-menthol interacts directly with the body s coldness receptors. d-Menthol has no cooling effect, while racemic menthol exerts an effect approximately half that of /-menthol. 

The compound to the left below, 2-methyl-2-propanol, often called t-butyl alcohol, is an octane booster for unleaded gasoline. The other compound, menthol, affects the cold receptors on the tongue so as to produce a cool taste when added to foods and medicines. Which of these two compounds would you expect to be more soluble in water ... 

D. Julius, Identification of a cold receptor reveals a general role for TRP channels in thermosensation, Nature 2002, 416, 52-58. 

All eight isomers possess characteristic minty odours. The reason for the importance of /-menthol is its ability to interact, not only with odour receptors, but also with the receptors which sense cold. The presence of menthol will induce cold receptors to respond as if they had sensed a drop in temperature. This physiologically induced sensation of cold is used in many products from foodstuffs, such as confectionery, chewing gum, through oral care products such as toothpaste to cosmetic preparations such as shaving products. There is therefore a large market for menthol and, since not all of it can be met from natural mint oils, a demand for synthetic material. Consequently, there has been a lot of work on the synthesis of menthol and all of the synthetic routes considered must take stereochemistry into account as /-menthol is always the preferred target. 

Proudfoot CJ, Garry EM, Cottrell DP, Rosie R, Anderson H, Robertson DC, Fleetwood-Walker SM, Mitchell R (2006) Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. CurrBiol 16(16) 1591-605... 

McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416 52-58 McLeod RL, Bolser DC, Jia Y, Parra LE, Mutter JC, Wang X, Tulshian DB, Egan RW, Hey JA (2002) Antitussive effect of nociceptin/orphanin FQ in experimental cough models. Pulm Pharmacol Ther 15 213-216... 

Humans have at their disposal thermoreceptors, as part of the peripheral nervous system in the skin, in the cornea, on the tongue and in the bladder. One can differentiate warm and cold receptors, which allow, quite precisely, for the detection of small temperature differences, without being able to estimate the absolute temperatiu e with nearly the same acciuacy. In the hypothalamus, the temperature signals are processed, compared with the body s normal tem-peratme, and the actual body temperature is correspondingly regulated. Small temperature differences feel pleasant or unpleasant. Temperatures, which are potentially harmful to the body, mostly those below 0 °C or above 45 °C, cause a feeling of pain. 

It was only in 2002 that two research groups, working independently of each other, were able to describe the first cold receptor as a Transient Receptor Poten-... 

Brauchi S, Orio P, Latorre R (2004) Clues to understanding cold sensation Thermodynamics and electrophysiological analysis of the cold receptor TRPM8.1549 15499. 

Along with other ion channel modulators, menthol is recognized as a potential novel therapy for the treatment of chronic cough (Morice et al., 2004). It is not clear whether the antitussive activity of menthol is due solely to its stimulation of airway cold receptors it may also involve pulmonary C- bers (a percentage of which also express TRPM8) or there may be a sped c interaction with the neuronal cough re ex. 

Thus, it has been demonstrated that menthol is not a nasal decongestant. However, it is useful in therapy since stimulation of the cold receptors causes a subjective sensation of nasal decongestion and so relieves the feeling of a blocked nose. In commercial preparations that include menthol, a true decongestant such as oxymetazoline hydrochloride is often present. 

In 1992, Sloan et al. conducted breath-hold experiments with 20 healthy volunteers. The ingestion of a lozenge containing 11 mg of menthol signi cantly increased the hold time, indicating a depression of the ventilatory drive. It was later postulated by Eccles (2000) that in addition to chemoreceptors detecting oxygen and carbon dioxide in the blood, cold receptors in the respiratory tract may also modulate the drive to breathe. 

In cases of asthma, the bene cial effects of menthol seem to be mainly due to its bronchodilatory activity on smooth muscle interaction with cold receptors and the respiratory drive may also play an important role. 

Cineole interacts with TRPM8, the cool sensitive thermoreceptor that is primarily affected by menthol. In comparison to menthol, the effect of 1,8 cineole on TRPM8 (as measured by Ca in ux kinetics) is much slower and declines more rapidly (Behrendt et al., 2004). In a similar manner to menthol, the antitussive activity of 1,8-cineole may be due in part to its stimulation of airway cold receptors. 

Burgess, K. R Whitelaw, W. A. 1988. Effects of nasal cold receptors on patterns of breathing, 64 371-376. 

Eccles, R. 2000. Role of cold receptors and menthol in thirst, the drive to breathe and arousal. Aggcfite. 34 29-35. 

Thermoreceptors of the mucous membranes may also be subjected to irritation by chemicals. They react, e.g., to pepper, paprika, carbon dioxide, and alcohol. Menthol and peppermint act on cold receptors. The thermoreceptors transmit their stimulation to the temperature control center and thus trigger further regulatory processes like being cold and shivering, goose pimples, contractions of blood vessels, or closeness with sweating and dilatation of blood vessels. 

---