Highlights
- •Topical 10% trans-cinnamaldehyde evoked pain, neurogenic inflammation, and hyperalgesia.
- •Co-administration of 40% L-menthol alleviated several of these established sensory symptoms.
- •L-menthol's counterirritant effect likely occurs through spinal inhibition and through peripheral antagonism.
- •Transient receptor potential cation channel M8 agonists could be useful as topical anti-hyperalgesics.
Abstract
The transient receptor potential cation channel subfamily M 8 (TRPM8) agonist L-menthol
has been used traditionally for its topical counterirritant properties. Although the
use of topical L-menthol for pain is casuistically established, evidence regarding
its efficacy is negligible. This study aimed to characterize the effect of L-menthol
as a counterirritant on cutaneous pain and hyperalgesia provoked by topical application
of the transient receptor potential cation channel, subfamily A, member 1 (TRPA1)
agonist trans-cinnamaldehyde (CA). In a randomized, double-blinded study CA was applied
to a 3 × 3-cm area of the volar forearm evoking neurogenic inflammation, pain, mechanical,
and thermal hyperalgesia in 14 healthy volunteers. In different sessions, 10% CA alone
or 40% L-menthol applied simultaneously with 10% CA were administered for 20 minutes,
throughout which the subjects rated the pain intensity on a visual analogue scale
of 0 to 10. Extensive quantitative sensory testing was conducted and superficial blood
flow (neurogenic inflammation) was recorded. Administration of CA evoked spontaneous
pain, neurogenic inflammation, thermal hyperalgesia, and primary and secondary mechanical
hyperalgesia. Coadministration of topical L-menthol reduced spontaneous pain intensity
(P < .01), neurogenic inflammation (P < .01), primary mechanical hyperalgesia (P < .05), secondary mechanical hyperalgesia (P < .05), and heat hyperalgesia (P < .05), but not cold hyperalgesia. L-menthol exhibited inhibitory effects on simultaneously
established pain, hypersensitivity, and neurogenic inflammation in a human TRPA1-induced
pain model. Potent TRPM8 agonists could be useful as topical antihyperalgesics. The
study and the trial protocol is registered and approved by the local research ethics
committee under the jurisdiction of the Danish Medicines Agency number N-20130005.
The protocol also is registered at Clinicaltrials.gov under NCT02653703.
Perspective
Drugs interacting with transient receptor potential channels are of great therapeutic
potential. In the present study we established cutaneous pain and hyperalgesia using
the TRPA1 agonist CA. Subsequently, we showed that the frequently used topical counterirritant
and TRPM8 agonist, L-menthol, decreased evoked pain, hyperalgesia, and inflammation,
indicating direct and indirect antinociceptive mechanisms.
Key words
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Article info
Publication history
Published online: May 31, 2016
Accepted:
May 10,
2016
Received in revised form:
March 21,
2016
Received:
January 25,
2016
Footnotes
A grant from Aase og Ejnar Danielsens Fond funded this study. H.H.A. received support from the Danish Ministry of Higher Education and Science through an EliteForsk 2016 travel grant.
The authors have no conflicts of interest to declare.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
Identification
Copyright
© 2016 by the American Pain Society