Why the Terpene Menthol works on the TRPM8 Receptor to help reduce pain

Menthol might be the most medically researched, commonly known plant terpene to date. Most of the studies conducted are based on improving human health. Thanks to positive results in that area, menthol appears in many over-the-counter products, in addition to being used in topical analgesics and essential oils.

Perceived benefits and uses of menthol include:

• Antibacterial
• Fever-Reducer
• Headache Relief
• Numbing
• Protects From Cancer Treatment Side Effects
• Relieves Joint Pain
• Reduces Acne
• Stimulates Hair Growth
• Treating Asthma

But how does Menthol interact with the human body and how does this interaction produce some of the benefits/uses above – in particular, its effectiveness as a topical analgesic?

The brief excerpt below (from the book TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades)helps to explain one of the reasons why Menthol has the effect that it does on the human body with regards to helping reduce pain associated with certain conditions.

Chapter 13 TRPM8: The Cold and Menthol Receptor

Author

David D. McKemy

Affiliations

University of Southern California

INTRODUCTION

Our sensory systems are able to detect subtle changes in ambient temperature, due to the coordinated efforts of thermosensory neurons. At the level of the primary afferent nerve, the site at which thermal stimuli are converted into neuronal activity, temperature-sensitive members of the TRP channel family are found. 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. 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. This chapter focuses on TRPM8, describing what was known about cold signaling before the channel was cloned, how TRPM8 was identified as a cold sensor, and what advances have been made in our understanding of the molecular logic for cold sensation since its identification.

COLD SENSING AND MENTHOL

The perception of nonpainful, cool temperatures is reported to occur when the skin is cooled as little as 1°C from normal body temperature. However, once temperatures approach 15°C, the perception of cold pain is felt, with qualities described as burning, aching, and prickling. In the early to mid-twentieth century, a number of laboratories began to observe cold-induced electrical impulses when recording from mammalian sensory nerves. These peripheral cold receptors, both Aδ- and C-fibers, have thermal thresholds (i.e., the temperature at which nerve impulses are generated) for cold activation between 30–20°C, temperatures considered to be innocuously cool. Further cooling to temperatures below what is considered noxious (<15°C) was also shown to excite a small percentage of nociceptors (20–30 percent), while cooling to <0°C was reported to activate all fibers. Thus, there is significant diversity in the types of neurons that respond to cold, as well as an expansive range of cold activation thresholds. Moreover, no defined mechanism for cold sensing was described.

Most cold-sensitive neurons are also sensitive to the ubiquitous cooling compound menthol, a cyclic terpene alcohol found in mint leaves.

It is well known that moderate concentrations of menthol induce a pleasant cool sensation, such as that felt when using menthol-containing products such as candy and vapo-rubs. However, when present at higher doses menthol can be noxious, causing burning, irritation, and pain. In seminal studies conducted by Hensel and Zotterman in the 1950s, menthol elicited its “cool” sensation by increasing the threshold temperature for activation of cold receptors. Indeed, the researchers hypothesized that menthol exerted its actions on “an enzyme” that was involved in the activation of these nerves. Surprisingly, it took more than 50 years for Hensel and Zotterman’s hypothesis to be validated.

TRP ion channels were first described in Drosophila melanogaster in 1989 and in mammals several years later. In 1997, TRPV1, a member of the TRP channel superfamily (now with more than 60 members in vertebrates and invertebrates but not in bacteria and plants), was described to respond to the pungent ingredients of hot pepper, then named capsaicin receptor. Ever since we have witnessed an explosion of activity in this field of scientific inquiry for obvious reasons. TRP ion channels are critical elements in signal transduction of cellular signaling cascades and of neurosensory processes, which are involved in all five senses.

This book, TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades presents 31 chapters written by researchers who have made these key discoveries, such as Dr. Lutz Birnbaumer who discovered mammalian TRP channels, and who continues to conduct TRP ion channel research at the cutting edge of this hyperdynamic area. Because of the burgeoning nature of the field, this book does not represent an all-comprehensive view on TRP channel biology. However, it does shed light on selected topics of outstanding interest in the TRP arena, such as signal transduction in axonal pathfinding, and vascular, renal, auditory, and nociceptive functioning, to name a few, and the spotlight is cast by an international cast of outstanding chapter authors.

For full references or more info on the chapter, please see:https://www.ncbi.nlm.nih.gov/books/NBK5238/

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