Menthol blocks dihydropyridine‐insensitive Ca<sup>2+</sup> channels and induces neurite outgrowth in human neuroblastoma cells

Sidell, Neil; Verity, M. Anthony; Nord, Edward P.

doi:10.1002/jcp.1041420226

Cited by 35 publications

(14 citation statements)

References 23 publications

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“…However, neither cyclohexanol, a highly lipid soluble cyclic alcohol from which menthol is derived, nor menthone, in which the hydroxy group of menthol is replaced with a keto group, produced any alteration in bioelectric properties, suggesting that the stimulation of Cl secretion may be specific for menthol. This specificity has also been reported in dihydropyridine-insensitive Ca2+ channels in human neuroblastoma cells (Sidell et al, 1990).…”

Section: Discussionsupporting

confidence: 74%

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium

Chiyotani

Tamaoki

Takeuchi

et al. 1994

British J Pharmacology

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1 To investigate the effect of menthol on airway epithelial ion transport function, we studied the bioelectrical properties of canine cultured tracheal epithelium by Ussing's short-circuit technique in vitro. 2 Addition of menthol (10-3 M) to the mucosal but not the submucosal solution increased the shortcircuit current (ISC) from 6.2 ± 0.9 to 14.0 ± 2.2 jIA cm-2 (P <0.001), and this effect was accompanied by increases in transepithelial potential difference and conductance. The response was dose-dependent, with the maximal increase from the baseline value and the concentration required to produce a half-maximal effect (EC50) being 6.4 ± 0.9 jA cm-2 (P<0.001) and 40 jM, respectively. 3 Other cyclic alcohols, including menthone and cyclohexanol, had no effect on the electrical properties.4 The menthol-induced increase in ISC was not altered by pretreatment of the cells with amiloride, indomethacin, or propranolol but was abolished by diphenylamine-2-carboxylate, furosemide or substitution of Cl with iodide in the medium. 5 Menthol (l0-M) increased cytosolic levels of free calcium ([Ca2+]i) from 98 ± 12 to 340 ± 49 nM (P<0.01) in fura-2-loaded tracheal epithelium but did not affect the intracellular adenosine 3',5'-cyclic monophosphate content. 6 These results suggest that menthol stimulates Cl secretion across airway epithelium, probably through a Ca2+-dependent mechanism, and might thus influence mucociliary transport in the respiratory tract.

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Section: Discussionsupporting

confidence: 74%

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium

Chiyotani

Tamaoki

Takeuchi

et al. 1994

British J Pharmacology

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“…In addition to activating TRPM8 channels, these concentrations are sufficient or by far exceed the concentrations needed to exert pharmacological effects on other targets implicated as mediators of menthol-induced analgesia, including voltage-dependent Ca 2+ channels, GABA A -receptors, sodium channels, peripheral nicotinic acetyl choline receptors or serotonin-gated ion channels [11; 19; 22; 24; 49; 52; 63; 67]. The role of these alternative targets in L-menthol-induced analgesia should have been unmasked in Trpm8−/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies suggest that menthol analgesia is mediated by TRP channel-independent mechanisms. Menthol was found to inhibit neuronal voltage-dependent Ca 2+ channels [49; 52]. Menthol was shown to activate GABA A -receptors, which may induce central inhibition of nociception [11; 63; 67].…”

Section: Introductionmentioning

confidence: 99%

TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain

Liu¹,

Liu²,

Balakrishna³

et al. 2013

Pain

235

231

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Menthol, the cooling natural product of peppermint, is widely used in medicinal preparations for the relief of acute and inflammatory pain in sports injuries, arthritis and other painful conditions. Menthol induces the sensation of cooling by activating TRPM8, an ion channel in cold-sensitive peripheral sensory neurons. Recent studies identified additional targets of menthol, including the irritant receptor, TRPA1, voltage-gated ion channels and neurotransmitter receptors. It remains unclear which of these targets contribute to menthol-induced analgesia, or to the irritating side effects associated with menthol therapy. Here, we use genetic and pharmacological approaches in mice to probe the role of TRPM8 in analgesia induced by L-menthol, the predominant analgesic menthol isomer in medicinal preparations. L-menthol effectively diminished pain behavior elicited by chemical stimuli (capsaicin, acrolein, acetic acid), noxious heat and inflammation (complete Freund's adjuvant). Genetic deletion of TRPM8 completely abolished analgesia by L-menthol in all these models, while other analgesics (acetaminophen) remained effective. Loss of L-menthol-induced analgesia was recapitulated in mice treated with a selective TRPM8 inhibitor, AMG2850. Selective activation of TRPM8 with WS-12, a menthol derivative we characterized as a specific TRPM8 agonist in cultured sensory neurons and in vivo, also induced TRPM8-dependent analgesia of acute and inflammatory pain. L-menthol and WS-12 induced analgesia was blocked by naloxone, suggesting activation of endogenous opioid-dependent analgesic pathways. Our data show that TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. In contrast to menthol, selective TRPM8 agonists may produce analgesia more effectively with diminished side effects.

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“…In LA-N-5 cells, brief application of menthol inhibited the depolarization-induced Ca 2+ influx though both dihydropyridine-sensitive and -insensitive L-type Ca 2+ channels with IC 50 value of 0.25 mM (Sidell et al, 1990). Ca 2+ increases induced by high K + were suppressed by menthol in Leech neurons (Dierkes et al, 1997), chick retinal neurons and synaptosomes (Hawthorn et al, 1988).…”

Section: Effects Of Menthol On Ion Channelsmentioning

confidence: 99%

Cellular and Molecular Targets of Menthol Actions

et al. 2017

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Menthol belongs to monoterpene class of a structurally diverse group of phytochemicals found in plant-derived essential oils. Menthol is widely used in pharmaceuticals, confectionary, oral hygiene products, pesticides, cosmetics, and as a flavoring agent. In addition, menthol is known to have antioxidant, anti-inflammatory, and analgesic effects. Recently, there has been renewed awareness in comprehending the biological and pharmacological effects of menthol. TRP channels have been demonstrated to mediate the cooling actions of menthol. There has been new evidence demonstrating that menthol can significantly influence the functional characteristics of a number of different kinds of ligand and voltage-gated ion channels, indicating that at least some of the biological and pharmacological effects of menthol can be mediated by alterations in cellular excitability. In this article, we examine the results of earlier studies on the actions of menthol with voltage and ligand-gated ion channels.

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Menthol blocks dihydropyridine‐insensitive Ca²⁺ channels and induces neurite outgrowth in human neuroblastoma cells

Cited by 35 publications

References 23 publications

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium

TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain

Cellular and Molecular Targets of Menthol Actions

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Menthol blocks dihydropyridine‐insensitive Ca2+ channels and induces neurite outgrowth in human neuroblastoma cells

Cited by 35 publications

References 23 publications

Stimulation by menthol of Cl secretion via a Ca2+‐dependent mechanism in canine airway epithelium

Stimulation by menthol of Cl secretion via a Ca2+‐dependent mechanism in canine airway epithelium

TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain

Cellular and Molecular Targets of Menthol Actions

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Menthol blocks dihydropyridine‐insensitive Ca²⁺ channels and induces neurite outgrowth in human neuroblastoma cells

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium

Stimulation by menthol of Cl secretion via a Ca²⁺‐dependent mechanism in canine airway epithelium