Central mechanisms of menthol-induced analgesia.

Abstract

Menthol is one of the most commonly used chemicals in our daily life, not only because of its fresh flavor and cooling feeling but also because of its medical benefit. Previous studies have suggested that menthol produces analgesic action in acute and neuropathic pain through peripheral mechanisms. However, the central actions and mechanisms of menthol remain unclear. Here, we report that menthol has direct effects on the spinal cord. Menthol decreased both ipsilateral and contralateral pain hypersensitivity induced by complete Freund's adjuvant in a dose-dependent manner. Menthol also reduced both first and second phases of formalin-induced spontaneous nocifensive behavior. We then identified the potential central mechanisms underlying the analgesic effect of menthol. In cultured dorsal horn neurons, menthol induced inward and outward currents in a dose-dependent manner. The menthol-activated current was mediated by Cl(-) and blocked by bicuculline, suggesting that menthol activates γ-aminobutyric acid type A receptors. In addition, menthol blocked voltage-gated sodium channels and voltage-gated calcium channels in a voltage-, state-, and use-dependent manner. Furthermore, menthol reduced repetitive firing and action potential amplitude, decreased neuronal excitability, and blocked spontaneous synaptic transmission of cultured superficial dorsal horn neurons. Liquid chromatography/tandem mass spectrometry analysis of brain menthol levels indicated that menthol was rapidly concentrated in the brain when administered systemically. Our results indicate that menthol produces its central analgesic action on inflammatory pain probably via the blockage of voltage-gated Na(+) and Ca(2+) channels. These data provide molecular and cellular mechanisms by which menthol decreases neuronal excitability, therefore contributing to menthol-induced central analgesia.

• Authors: Rong Pan, Yuzhen Tian, Ruby Gao, Haitao Li, Xianguo Zhao, James E Barrett, Huijuan Hu
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 343 Issue 3 Pg. 661-72 (Dec 2012) ISSN: 1521-0103 [Electronic] United States
• PMID: 22951274 (Publication Type: Journal Article)

Chemical References

• Calcium Channel Blockers
• Calcium Channels
• GABA-A Receptor Agonists
• Receptors, GABA-A
• Voltage-Gated Sodium Channel Blockers
• Voltage-Gated Sodium Channels
• Menthol

Topics

• Action Potentials (drug effects)
• Analgesia (methods)
• Animals
• Behavior, Animal (drug effects)
• Brain (drug effects, metabolism)
• Calcium Channel Blockers (pharmacokinetics, pharmacology, therapeutic use)
• Calcium Channels (metabolism)
• Cells, Cultured
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• GABA-A Receptor Agonists (pharmacology, therapeutic use)
• Male
• Mass Spectrometry
• Menthol (pharmacokinetics, pharmacology, therapeutic use)
• Mice
• Mice, Inbred Strains
• Neuralgia (drug therapy, metabolism, psychology)
• Pain Measurement
• Pain Threshold (drug effects, psychology)
• Posterior Horn Cells (drug effects, metabolism)
• Receptors, GABA-A (metabolism)
• Voltage-Gated Sodium Channel Blockers (pharmacokinetics, pharmacology, therapeutic use)
• Voltage-Gated Sodium Channels (metabolism)