Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 5:15:1006908.
doi: 10.3389/fnmol.2022.1006908. eCollection 2022.

The distinctive role of menthol in pain and analgesia: Mechanisms, practices, and advances

Ziping Li  1 , Haoyue Zhang  1   2 , Yigang Wang  1   2 , Yize Li  2 , Qing Li  2 , Linlin Zhang  2
Affiliations
Review

The distinctive role of menthol in pain and analgesia: Mechanisms, practices, and advances

Ziping Li et al. Front Mol Neurosci. .

Abstract

Menthol is an important flavoring additive that triggers a cooling sensation. Under physiological condition, low to moderate concentrations of menthol activate transient receptor potential cation channel subfamily M member 8 (TRPM8) in the primary nociceptors, such as dorsal root ganglion (DRG) and trigeminal ganglion, generating a cooling sensation, whereas menthol at higher concentration could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization. In addition, the paradoxical irritating properties of high concentrations of menthol is associated with its activation of transient receptor potential cation channel subfamily A member 1 (TRPA1). Under pathological situation, menthol activates TRPM8 to attenuate mechanical allodynia and thermal hyperalgesia following nerve injury or chemical stimuli. Recent reports have recapitulated the requirement of central group II/III metabotropic glutamate receptors (mGluR) with endogenous κ-opioid signaling pathways for menthol analgesia. Additionally, blockage of sodium channels and calcium influx is a determinant step after menthol exposure, suggesting the possibility of menthol for pain management. In this review, we will also discuss and summarize the advances in menthol-related drugs for pathological pain treatment in clinical trials, especially in neuropathic pain, musculoskeletal pain, cancer pain and postoperative pain, with the aim to find the promising therapeutic candidates for the resolution of pain to better manage patients with pain in clinics.

Keywords: analgesia; menthol; opioid receptor; pain; transient receptor potential channel.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The possible mechanisms of menthol action on the DRG or trigeminal ganglion via TRPM8 and TRPA1. The effects of menthol are concentration dependent. Low to moderate concentrations of menthol activate TRPM8 in the DRG and trigeminal ganglion to produce a cooling sensation; at higher concentration, menthol could induce cold allodynia, and cold hyperalgesia mediated by TRPM8 sensitization; following nerve injury or chemical stimuli, menthol activates TRPM8 to mediate relief of mechanical allodynia and thermal hyperalgesia. Its analgesic effect is also dependent on the activation of central group II/III mGluR with endogenous κ-opioid signaling pathways. In addition, the thermal and mechanical allodynia of high concentrations of menthol is associated with its activation of TRPA1. Created with BioRender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Airaksinen O. V., Kyrklund N., Latvala K., Kouri J. P., Grönblad M., Kolari P. (2003). Efficacy of cold gel for soft tissue injuries: A prospective randomized double-blinded trial. Am. J. Sports Med. 31 680–684. 10.1177/03635465030310050801 - DOI - PubMed
    1. Altis K., Schmidtko A., Angioni C., Kuczka K., Schmidt H., Geisslinger G., et al. (2009). Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 147 116–121. 10.1016/j.pain.2009.08.018 - DOI - PubMed
    1. Amato A., Liotta R., Mulè F. (2014). Effects of menthol on circular smooth muscle of human colon: Analysis of the mechanism of action. Eur. J. Pharmacol. 740 295–301. 10.1016/j.ejphar.2014.07.018 - DOI - PubMed
    1. Andersen H. H., Gazerani P., Arendt-Nielsen L. (2016). High-concentration L-menthol exhibits counter-irritancy to neurogenic inflammation, thermal and mechanical hyperalgesia caused by trans-cinnamaldehyde. J. Pain 17 919–929. 10.1016/j.jpain.2016.05.004 - DOI - PubMed
    1. Andersen H. H., Melholt C., Hilborg S. D., Jerwiarz A., Randers A., Simoni A., et al. (2017). Antipruritic effect of cold-induced and transient receptor potential-agonist-induced counter-irritation on histaminergic itch in humans. Acta Derm. Venereol. 97 63–67. 10.2340/00015555-2447 - DOI - PubMed

LinkOut - more resources

  NODES
Note 2
twitter 2