TRP channels and receptors: how plant molecules communicate with our sensory systems

Why do plants interact with our bodies?

For millennia, plants have been part of the traditional pharmacopoeias of very different populations. Spices, aromatic plants, barks, roots, resins, and fruits have been used to alter the perception of pain, aid digestion, stimulate or calm the body, treat skin conditions, or relieve respiratory disorders.

A fundamental question of modern pharmacognosy is therefore: why do so many plant molecules produce recognizable effects in the human body?

One possible answer comes from evolutionary biology. Many specialized metabolites produced by plants were not necessarily selected "to cure" humans. They may have had, and continue to have, ecological functions such as defense against herbivores, protection from microorganisms, communication with other organisms, or attraction of beneficial species. The enormous diversity of plant metabolites can, in fact, also be interpreted in light of the evolutionary interactions between plants, herbivores, microorganisms, and the environment.

However, when a plant molecule interacts with a human protein, that same relationship can take on a pharmacological meaning.

A particularly interesting example is represented by TRP receptors, an acronym for Transient Receptor Potential.

TRP receptors: biological sensors of the environment

TRPs are a large family of membrane ion channels. When activated, they primarily allow the passage of cations, including calcium and sodium, rapidly altering the electrical and biochemical activity of the cell.

They are not simply "pain receptors". TRPs participate in a wide variety of sensory and homeostatic functions: temperature, touch, mechanical stimuli, pain, taste, smell, hearing, osmolarity, and the perception of numerous chemicals. Many are also polymodal receptors, meaning they are capable of integrating different stimuli.

Their importance is precisely linked to their ability to transform an environmental stimulus into a cellular signal.

In simple terms:

stimulus → opening of the TRP channel → entry of ions → modification of cellular activity → nervous or physiological response

This property explains why plant molecules capable of modulating TRPs have become of great interest to pharmacology and phytotherapy.

A review specifically dedicated to phytochemicals and TRPs highlighted how numerous plant substances interact with these proteins and how such interaction can provide a molecular explanation for some effects traditionally attributed to plants. However, the same authors emphasize the importance of considering dose, bioavailability, metabolism, local and systemic effects, and possible adverse events.

TRPs as an "alarm" system

From an evolutionary point of view, the function of TRPs is particularly interesting.

An organism must be able to quickly recognize an environment that is too hot or too cold, an irritating substance, a mechanical variation, a potentially toxic molecule, or tissue damage.

For this reason, some TRPs can be considered true biological hazard sensors.

This function also helps explain why some plants have a spicy, pungent, cool, irritating, or aromatic taste. These sensations are not simply properties "of taste": they may be the result of the activation of specific ion channels present in nerve endings and other tissues.

Chili pepper, for example, does not produce a true sensation of heat by increasing the temperature of the mouth. Capsaicin activates TRPV1 and induces a nerve signal that the brain interprets as heat and burning.

Mint, on the other hand, produces a sensation of cold through the activation of TRPM8.

The result is striking: a plant molecule can alter our perception of the environment without necessarily physically altering that environment.

TRPV1: the heat and capsaicin receptor

Among the most studied TRPs is TRPV1, initially identified as the molecular receptor for capsaicin.

TRPV1 is expressed mainly in sensory nerve fibers involved in nociception and responds to various stimuli, including high temperatures, tissue conditions associated with inflammation, and numerous chemical molecules.

Capsaicin from chili pepper is one of its best-known agonists. Piperine from black pepper, gingerols and shogaols from ginger, and eugenol from cloves can also modulate TRPV1.

The activation of TRPV1 increases the flow of calcium and sodium through the cell membrane and determines a neuronal response.

In an initial phase, this can translate into:

• a burning sensation;
• pain;
• vasodilation;
• release of neuropeptides;
• neurogenic inflammation.

But repeated and sufficiently intense stimulation can produce a completely different phenomenon: desensitization of nerve endings.

This is one of the principles that make capsaicin interesting in the field of analgesia.

From the burning sensation to pain reduction

The most fascinating characteristic of TRPV1 is therefore the possibility of obtaining a biphasic response.

An initial exposure to capsaicin can increase the sensation of pain; repeated or pharmacologically controlled exposure can instead reduce the ability of nociceptive fibers to transmit pain.

This mechanism has found clinical application especially in the topical therapy of neuropathic pain.

A systematic review of clinical studies found a benefit of topical capsaicin in neuropathic pain, while a 2024 meta-analysis including eight randomized studies and 498 patients with osteoarthritis highlighted a significant reduction in pain intensity compared to placebo. However, the studies also showed an increase in local events, especially burning at the application site.

This is a fundamental point for correctly interpreting phytopharmacology: the activation of a receptor does not automatically equate to a therapeutic effect. The response depends on the molecule, the concentration, the duration of exposure, the tissue, and the pathophysiological state.

Pepper, ginger and chili pepper: a family of pungent signals

The link between aromatic plants and TRPV1 is particularly evident when examining some commonly used spices.

Capsaicin from Capsicum activates TRPV1.

Piperine from Piper nigrum can activate the same channel.

Gingerols and shogaols from Zingiber officinale can interact with TRPV1; some ginger compounds can also modulate TRPA1.

This observation may help explain why many cultures have traditionally used spicy and aromatic spices not only as food, but also in preparations intended to support digestive well-being or to locally treat painful conditions.

This does not mean, of course, that the traditional effect is automatically proven to be therapeutic. It means that today we can formulate testable pharmacological hypotheses.

TRPA1: the sensor for irritating substances

Another key player is TRPA1, which is frequently expressed alongside TRPV1 in sensory fibers.

TRPA1 responds to numerous reactive molecules found in the environment and in food. These include several compounds of plant origin, including isothiocyanates from Brassicaceae, cinnamaldehyde from cinnamon, eugenol, and other aromatic molecules.

TRPA1 participates in the perception of pungency, nociception, itching, and neurogenic inflammation.

It is therefore another point of convergence between phytochemistry and sensory physiology.

Its activation can have different effects depending on the context. It can contribute to the perception of an irritating stimulus, but TRPA1 modulation is also studied for its potential analgesic, anti-inflammatory, and metabolic implications. Research on natural compounds highlights a complex interaction between TRPA1, TRPV1, and other sensory channels.

TRPM8: when a plant produces the sensation of cold

If TRPV1 represents one of the main sensors of noxious heat, TRPM8 is one of the main cold sensors.

Its most famous plant ligand is menthol, found mainly in mint.

Applying menthol to the skin does not actually lower the tissue temperature in proportion to the perceived sensation. It is the nervous system that interprets the activation of TRPM8 as a cooling sensation.

But TRPM8 is not just a thermal sensor. Its activation can modulate nociception.

Genetic and pharmacological experiments have shown that menthol-induced analgesia in several experimental models depends largely on TRPM8.

Clinical data are also interesting, although they are still less extensive than those available for capsaicin. In a proof-of-concept study on patients with neuropathic pain related to cancer treatments, the topical application of 1% menthol was associated with pain improvement in a large part of the evaluable patients. However, this is a preliminary study and is not sufficient on its own to establish definitive clinical efficacy.

Menthol also shows an important characteristic: at high concentrations it can become irritating and contribute to cold allodynia or hyperalgesia, also through interaction with other channels such as TRPA1.

Once again, the same principle emerges: dose and biological context determine the response.

TRPV3: temperature, skin and hair follicle

The TRP family does not only concern neurons.

TRPV3, for example, is expressed in keratinocytes and other skin cells and is involved in the perception of relatively moderate temperatures, skin homeostasis, and hair follicle biology.

This greatly expands the concept of a sensory receptor.

A receptor born to contribute to the perception of a stimulus can also be expressed in cells that do not directly generate a conscious sensation, participating in local tissue regulation processes.

Research on skin TRPs is indeed studying their involvement in the epidermal barrier, inflammation, itching, hair follicles, and cell differentiation.

TRPs are not only pain receptors

One of the most important aspects of contemporary research is moving beyond the idea that TRPs are simply "pain receptors".

Their distribution and functions are much broader.

Thermosensation

TRPV1, TRPV3, TRPV4, TRPM8, TRPA1, and other channels contribute to the conversion of temperature variations into nerve signals. The so-called thermo-TRPs constitute a sophisticated system for recognizing temperatures within different ranges.

Mechanosensation

Some members of the TRP family participate in the perception of mechanical forces, pressure, stretch, and cellular movement. The precise role of some channels is still a subject of research, because in several cases it is not completely clear whether the channel directly perceives the force or acts downstream of other mechanical sensors.

Chemosensation and Chemesthesis

Chemesthesis is the perception of chemical stimuli that produce sensations such as burning, tingling, coolness, or irritation.

Capsaicin, menthol, piperine, cinnamaldehyde, isothiocyanates, and eugenol are examples of molecules capable of interacting with TRP sensory systems.

Pain

TRPV1, TRPA1, and TRPM8 participate in nociception and the modulation of pain sensitivity. Their activity can be influenced by temperature, inflammatory mediators, and endogenous and exogenous molecules.

Taste and Smell

The function of TRPs also extends to the systems that process gustatory and olfactory stimuli. In this case, they do not always represent the primary receptor of the stimulus, but can contribute to the integration and modulation of the sensory signal.

Hearing

Some members of the TRP family are involved in ear mechanotransduction processes and the physiology of auditory structures. The picture is particularly complex and varies considerably between invertebrates and vertebrates.

From the mouth to the gut: TRPs as metabolic sensors

The presence of TRPs in tissues not classically considered "sensory" opens an even more interesting perspective.

These channels are also present in the gastrointestinal tract and may participate in detecting substances contained in food.

In this context, a plant molecule does not necessarily need to reach high concentrations in the blood to produce a biological response. It can interact locally with epithelial cells, nerve endings, or other cells present in the mucosa.

The stimulation of some intestinal TRPs can influence motility, secretions, satiety, and neuroendocrine communication. More recent research is also exploring the role of TRP chemosensation in the regulation of feeding and metabolism.

This perspective is particularly important because it suggests that the biological effect of a phytochemical may begin at the point of contact with the organism, even before its eventual systemic distribution.

The idea of "acupharmacology"

From this observation arises an interesting concept for understanding some actions of plants: the possibility that a molecule can produce a pharmacological response through interaction with receptors localized on the surface of the skin and mucosa.

It would therefore not always be necessary to imagine that an active principle must be absorbed, reach the bloodstream, and arrive at a target organ to produce a response.

A molecule can generate a local signal that is subsequently transformed by the organism into a nervous, vascular, secretory, or immune response.

This concept does not replace traditional pharmacokinetics, but can represent a useful interpretive model for some activities of plant substances.

The distinction is important: local action and systemic action are not synonyms, and their relevance depends on the substance and the mode of use.

Why are spices and aromatic plants so interesting?

Observing the plants most frequently associated with TRPs, a fascinating fact emerges.

Many belong to the category of spices and strongly aromatic plants:

Chili pepper → capsaicin → TRPV1

Black pepper → piperine → TRPV1

Ginger → gingerols and shogaols → TRPV1/TRPA1

Mint → menthol → TRPM8

Cinnamon → cinnamaldehyde → TRPA1

Clove → eugenol → multiple TRPs

Brassicaceae → isothiocyanates → especially TRPA1

These plants have in common a high richness of specialized metabolites capable of interacting with sensory systems.

Research on natural compounds indeed suggests that some phytochemicals, especially aromatic and volatile molecules, can modulate more than one TRP channel simultaneously. This helps explain why a single plant can produce a complex sensation, composed of heat, coolness, pungency, irritation, and subsequent attenuation of sensitivity.

The evolutionary perspective: a possible "conversation" between plants and animals

The most suggestive fact, however, is not merely pharmacological.

TRPs belong to a deeply conserved family of proteins in the animal kingdom involved in adaptation to the environment. Plant metabolites, on the other hand, are the result of millions of years of plant evolution and their interactions with herbivores, insects, microorganisms, and other organisms.

It is therefore possible to observe the relationship between plant and animal as a kind of molecular dialogue built by evolution.

The plant produces a molecule.

The animal possesses a sensor capable of recognizing it.

Recognition produces a response.

That response can drive the animal away from the plant, modify its behavior, or, in certain circumstances, be exploited by humans to achieve a desired biological effect.

It is important not to turn this hypothesis into a simplistic explanation. Not all plant molecules have evolved to interact with human TRPs, and not all therapeutic effects of plants can be traced back to these channels.

Coevolution, however, offers an interpretive framework, while experimental pharmacology and clinical studies must establish whether that interaction actually has therapeutic significance.

From biological mechanism to medicine: beware of confusing evidence

The growing interest in TRPs does not mean that every plant that modulates a TRP can be considered a treatment.

There are at least four levels of evidence:

molecular interaction, when a substance demonstrates that it activates or inhibits a channel;

cellular evidence, when activation produces a response in cells or neurons;

preclinical evidence, when the effect is observed in animal models;

clinical evidence, when the effect is demonstrated in humans through controlled studies.

The transition from one level to the next is not automatic.

The same molecule can have different effects in vitro and in the body. Furthermore, a plant often contains dozens or hundreds of metabolites, with mutual interactions that can modify absorption, metabolism, pharmacological activity, and tolerability.

For this reason, a review on TRPs and phytochemicals explicitly highlights the need to consider the actual quantities present in the preparation, bioavailability, metabolism, excretion, and differences between local and systemic effects.

A new way of reading phytotherapy

The study of TRP receptors does not show that plants are "designed" for humans.

It suggests something more interesting: plants and animals share a long evolutionary history in which molecules have served as tools for communication, defense, adaptation, and environmental perception.

Some of these plant signals can be recognized by our sensory systems and transformed into physiological responses.

Chili pepper makes us perceive heat.

Mint makes us perceive cold.

Pepper produces pungency.

Ginger stimulates sensory systems associated with spiciness.

Cinnamon and other aromatic compounds activate systems capable of recognizing irritating substances.

These are not just neurobiological curiosities. These interactions are helping to identify new pharmacological targets for pain, inflammation, sensory disorders, and some metabolic disorders.

Research on TRPs thus reveals one of the most fascinating characteristics of plant pharmacology: a seemingly simple sensation — heat, cold, burning, tingling — can be the expression of a precise molecular event.

And it is precisely through these molecular events that we can begin to understand, with greater scientific rigor, why some plants have accompanied traditional medicine for centuries and why they continue to represent a source of molecules of pharmacological interest.

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