Chemosensation is a fundamental sensory function, in addition to smell and taste.
In humans, the olfactory and the gustatory systems are the principal sensory systems and are responsible for smell and taste, respectively. In addition to the classical senses of taste and smell, anatomically separate systems in the mouth, nose and airways provide additional sensory input from chemical and physical stimulation, and can detect various tasteless or odorless compounds, that nevertheless contribute to “flavor”. Examples include carbon dioxide and capsaicin (the pungent compound in chilli peppers) that are potent chemical stimuli and important “flavor” compounds in foods and beverages. This fundamental sensory function is called chemosensation. Chemosensory nerve endings can be activated by physical stimuli (temperature and mechanical forces) and by a large array of chemical agents, and evoke sensations of flavor, touch, temperature and pain.

Chemosensation is mediated by somatosensory nerve endings of trigeminal, glossopharyngeal and vagus nerves.
Trigeminal nerve endings innervate the skin, covering the face, mucous membranes of the nasal and oral cavities, and cornea and conjunctiva of the eye. Glossopharyngeal and vagus nerves innervate oropharynx and respiratory tract, respectively. These nerve endings contain multiple types of chemosensory receptors, including ion channel receptors that can differentially detect external physical or chemical stimuli.

Chemicals activate chemosensory receptors via mechanisms distinct from other sensory systems, such as smell and taste.
The response threshold of chemosensory nerve fibers to chemical stimuli is generally 1-2 log units higher than olfactory thresholds for the same compounds (Bryant, B.P. and Silver, W.L., 2000 ) because they utilize different signaling mechanisms. Signaling of smell and taste involves activation of heterotrimeric G protein receptors, while activation of chemisensory receptors by chemicals involves the direct gating of ion channels (Fain, G.L. 2003). Activation of chemisensory receptors leads to changes in ionic permeability, depolarization of the sensory nerve terminals, action potential formation and afferent signaling to the brain that initiates sensations and reflexes, i.e. efferent signaling to visceral organs. For example, respiratory exposure to irritants, such as industrial chemicals, tobacco smoke, or capsaicin can induce sensations, such as urge to cough, chest tightness and dyspnea (air hunger), as well as reflexes, such as coughing.

Chemosensory nerve endings can trigger a broad range of sensations and reflexes.
Activation of chemosensory nerve fibers can trigger multiple Central Nervous System (CNS)-mediated reflexes, such as sneezing, coughing, mucus secretion, salivation, tearing, bronchospasms and respiratory depression. These are protective responses to dilute and/or expel foreign materials.
In addition to protective reflexes, activation of the same sensory nerve endings by compounds found in foods, beverages and spices, can trigger reflexes that are strongly linked to memory and can evoke feelings of pleasure and satisfaction. These sensory responses are relevant for food enjoyment and nutrition, or pleasant thermo-sensations. Examples include developed liking for the distinct sharpness or pungency of many foods that can result in craving for these foods, or pleasant sensation of cool by menthol.

Complexity of chemosensation and chemosensory mimicry.
The sensations evoked by chemical agents are very complex, and vary in their quality, temporal profile and intensity. This complexity is due to overlapping sensitivity of individual ion channels to chemical agonists, resulting in combinatorial activation of different classes of nerve endings by a single chemical. This contrasts with the olfactory system, in which hundreds of different G-protein coupled receptors can discriminate between agonists and represent them as a particular smell. Furthermore, some agonists can sensitize ion channels to other agonists, contributing to a very complex palette of chemosensory responses. For example, menthol potentiates cold sensations by sensitizing responses of sensory neurons to cold temperature (Green BG, 2004).
Complex interplay between chemical agonists and chemosensory receptors allows for “chemosensory mimicry” by chemically distinct agents. Thus, adequate mimicry of sensory receptor activation by nicotine and other smoke constituents is possible with chemically-unrelated agonists and modulators. Chemosensory receptors are activated by concentrations of compounds below those that cause actual physical changes in the respiratory tract, acting as sensors of possible irritation or damage. The proprietary composition of compounds will have smoke-mimetic chemosensory effects without delivering nicotine, toxic smoke constituents, or otherwise bioactive compounds into the body.


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