AUTHOR=Hilfiger Louis , Triaux Zélie , Marcic Christophe , Héberlé Eléa , Emhemmed Fathi , Darbon Pascal , Marchioni Eric , Petitjean Hugues , Charlet Alexandre 

TITLE=Anti-Hyperalgesic Properties of Menthol and Pulegone

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.753873

DOI=10.3389/fphar.2021.753873

ISSN=1663-9812

ABSTRACT=<p><bold>Context:</bold> Menthol, the main monoterpene found in <italic>Mentha piperita</italic> L. (<italic>M. piperita</italic>) is known to modulate nociceptive threshold and is present in different curative preparations that reduce sensory hypersensitivities in pain conditions. While for pulegone, a menthol-like monoterpene, only a limited number of studies focus on its putative analgesic effects, pulegone is the most abundant monoterpene present in <italic>Calamintha nepeta</italic> (L.) Savi (<italic>C. nepeta</italic>), a plant of the Lamiaceae family used in traditional medicine to alleviate rheumatic disorders, which counts amongst chronic inflammatory diseases.</p><p><bold>Objectives:</bold> Here, we analyzed the monoterpenes composition of <italic>C. nepeta</italic> and <italic>M. piperita</italic>. We then compared the putative anti-hyperalgesic effects of the main monoterpenes found, menthol and pulegone, in acute inflammatory pain conditions.</p><p><bold>Methods:</bold><italic>C. nepeta</italic> and <italic>M. piperita</italic> extracts were obtained through pressurized liquid extraction and analyzed by gas chromatography-mass spectrometry. The <italic>in vitro</italic> anti-inflammatory activity of menthol or pulegone was evaluated by measuring the secretion of the tumour necrosis factor alpha (TNF α) from LPS-stimulated THP-1 cells. The <italic>in vivo</italic> anti-hyperalgesic effects of menthol and pulegone were tested on a rat inflammatory pain model.</p><p><bold>Results:</bold> Pulegone and menthol are the most abundant monoterpene found in <italic>C. nepeta</italic> (49.41%) and <italic>M. piperita</italic> (42.85%) extracts, respectively. <italic>In vitro</italic>, both pulegone and menthol act as strong anti-inflammatory molecules, with EC50 values of 1.2 ± 0.2 and 1.5 ± 0.1 mM, respectively, and exert cytotoxicity with EC50 values of 6.6 ± 0.3 and 3.5 ± 0.2 mM, respectively. <italic>In vivo</italic>, 100 mg/kg pulegone exerts a transient anti-hyperalgesic effect on both mechanical (pulegone: 274.25 ± 68.89 g, <italic>n</italic> = 8; vehicle: 160.88 ± 35.17 g, <italic>n</italic> = 8, <italic>p</italic> &lt; 0.0001), thermal heat (pulegone: 4.09 ± 0.62 s, <italic>n</italic> = 8; vehicle: 2.25 ± 0.34 s, <italic>n</italic> = 8, <italic>p</italic> &lt; 0.0001), and cold (pulegone: 2.25 ± 1.28 score, <italic>n</italic> = 8; vehicle: 4.75 ± 1.04 score, <italic>n</italic> = 8, <italic>p</italic> = 0.0003). In a similar way, 100 mg/kg menthol exerts a transient anti-hyperalgesic effect on both mechanical (mechanical: menthol: 281.63 ± 45.52 g, <italic>n</italic> = 8; vehicle: 166.25 ± 35.4 g, <italic>n</italic> = 8, <italic>p</italic> &lt; 0.0001) and thermal heat (menthol: 3.65 ± 0.88 s, <italic>n</italic> = 8; vehicle: 2.19 ± 0.26 s, <italic>n</italic> = 8, &lt;0.0001).</p><p><bold>Conclusion:</bold> Here, we show that both pulegone and menthol are anti-inflammatory and anti-hyperalgesic monoterpenes. These results might open the path towards new compound mixes to alleviate the pain sensation.</p>