Chemesthesis - the chemical sense

Eating experience is a mix of sensations: taste, smell, touch or texture and even vision. Somatosensory systems have also an important role in the way we perceive food. All of us have experienced the hot sensation of chilli pepper or the cold sensation of menthol in a chewing gum. These chemical stimuli activate the somatosensory receptors, which transduce temperature and pain. This phenomenon is known as chemesthesis - referring to a “chemical sense” - in which exogenous chemical agonists (in this case present in food) switch on these nerves resulting in cooling, freshness, pungency, burning, stinging or tingling (1).

Chemesthetic sensations can be stimulated not only in mucosal surfaces but anywhere on the body’s surface due to the fact that the skin and the nervous system are strongly related. Nevertheless, since mucous membranes lack the barrier function of cornified skin, they are generally more sensitive to chemical stimuli (2). Somatosensory nerves innervate the skin and the mucous membranes present in the eyes, oral and nasal cavities; when their receptors are activated, sensations such as temperature, pain, touch or texture, arise (1).


These receptors are proteins forming transient receptor potential (TRP) channels, which allow ions to flow into nerve cells while giving a signal (3). They are polymodal channels found in the cell membrane and often activated by chemical compounds, usually hydrophobic molecules that readily enter and permeate the plasma membrane. The activation of temperature-sensitive ion channelled by a ligand provides a molecular explanation for chemesthesis, where a certain chemical compound mimics a physical stimulus.


Mammalian TRP ion channels detect a broad range of temperatures and each of them mediate a different thermal zone. As mentioned before, many of them are also activated by plant-derived ligands, stimulating distinct sensations of temperatures such as warmth or cooling. (4)


Chilli pepper is usually associated with a burning sensation due to the chemical compound capsaicin. This substance excites nociceptive nerve fibers, related to pain perception and very sensitive to noxious heat. (1) Capsaicin is a naturally occurring irritant compound and its initial neuronal excitation is followed by a long-lasting period of desensitization, in which those excited neurons are no longer responsive to a broad range of stimuli. The desensitization process can be exploited for its therapeutic potential and; in fact many capsaicin-containing creams have been used to relieve painful conditions.

Nevertheless, its use has limitations due to its side effects: burning sensation and its accumulation in skin together with erythema reactions. Moreover, skin carcinogenesis has been reported in mice treated with a tumor promoter (such as sunlight) due to long-term topical applications of capsaicin. (5)



Atopic and sensitive skin itchiness is mainly mediated by the capsaicin receptor TRPV1 expressed in skin cells. TRPV1 subtype channel is a temperature sensor and mediator of cutaneous inflammation and itch. To improve the calming profile of capsaicin, innovative neurocosmetic ingredients are being developed. Recently, the biotech company AntalGenics developed Calmapsin, an active ingredient targeting neuronal receptor TRPV1 and designed based on the chemical structure of the natural compound capsaicin. It reduces the 99.6% of the capsaicin receptor’s activity and so does the itching signalling in sensitive and atopic skin. Positively, and in contrast to capsaicin, it elicits desensitization but without any burning sensation. (6)

In contrast, menthol is the primary chemesthetic agent in peppermint and is known to stimulate thermoreceptors of lingual nerves evoking sensations of cooling in the oral cavity. Its freshness is very useful in products such as chewing gums, toothpastes and mouthwashes. This coolness effect is not only experienced in the mouth, but also can be observed in the skin, when used for example in topical analgesic creams. Menthol sensitizes those receptors in response to small changes in temperature and enhances nerve activity at temperatures below body temperature (<25ºC), whereas it reduces nerve responses to high temperatures (>40ºC). (1)


In the following figure it can be observed the chemosensitive responses of neurons to capsaicin (100 nM) and warm temperature (A) or menthol (100 μM) and cold temperature (B). The graphic shows how capsaicin and high temperature elicit a very similar neuronal response, and the same happens with menthol and low temperature. (8)

Adapted from Viana, F. 2011 (8)

Apart from the activation of thermoreceptors, other chemesthetic sensations are detected by the somatosensory receptors. For example, it is well known the stinging or tingling of carbonated beverages in the nose and mouth; the pungent sensation in the back of the throat elicited by the oleocanthal in high-quality extra virgin olive oil; the pungent bite of non-volatile vanillyl amides in ginger (3); or even the tear-induction of cut onions. (2)


Chemesthesis is not only relevant to food enjoyment but also it is an important aspect of human sensory physiology in terms of thermoregulation and mechanisms of itch and pain. Since its discovery, much progress has been made in finding how our sensory system detects and responds to different chemicals in a unique sensation and which are the responsible receptors and channels. In the near future, it will be interesting to see how modulating those receptors we can target diverse therapeutic areas in which TRP channels are involved, including pain, itch or even cough, asthma and headache. (8)

References

1- Slack, J. P. Molecular Pharmacology of Chemesthesis. Chemosens. Transduct. Detect. Odors, Tast. Other Chemostimuli 375–391 (2016). https://doi.org/10.1016/B978-0-12-801694-7.00021-4

2- Chemesthesis https://en.wikipedia.org/wiki/Chemesthesis (Last visit on May 22, 2020)

3- Chemistry World – A matter of taste? https://www.chemistryworld.com/opinion/why-pain-is-part-of-making-food-delicious/2500210.article (Last visit on May 22, 2020)

4- Roper SD. TRPs in taste and chemesthesis. Handb Exp Pharmacol. 2014; 223:827‐871. doi:10.1007/978-3-319-05161-1_5

5- Bode AM, Dong Z. The two faces of capsaicin. Cancer Res. 2011;71(8):2809‐2814. https://doi.org/10.1158/0008-5472.can-10-3756

6- Cosmetics Business – Antalgenics launches Calmapsin, an innovative neurocosmetic ingredient for sensitive skin https://www.cosmeticsbusiness.com/news/article_page/Antalgenics_launches_Calmapsin_a_innovative_neurocosmetic_ingredient_for_sensitive/164707 (Last visit on May 23, 2020)

7- Youtube - Calmapsin® a new and innovative neurocosmeceutical ingredient designed for sensitive skin https://www.youtube.com/watch?v=a4CTrj29ppg (Last visit on May 23, 2020)

8- Viana, F. Chemosensory properties of the trigeminal system. ACS Chem. Neurosci. 2, 38–50 (2011).

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