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PubMed1988

The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations.

The activities of menthol and peppermint oil were determined in guinea-pig ileal smooth muscle, in rat and guinea-pig atrial and papillary muscle, in rat brain synaptosomes and in chick retinal neurones by pharmacological 45Ca2+ uptake and radioligand binding assays. Menthol is a major constituent of peppermint oil and is approximately twice as potent as peppermint oil as an inhibitor of K+ depolarization-induced and electrically stimulated responses in ileum and electrically stimulated atrial and papillary muscles. IC50 values in the ileal preparation ranged from 7.7 to 28.1 micrograms ml-1 and in the cardiac preparations from 10.1 to 68.5 micrograms ml-1. Similar potencies were demonstrated against K+ depolarization-induced 45Ca2+ uptake in synaptosomes and against K+ depolarization and Bay K 8644-induced uptake in chick retinal neurons. IC50 values for menthol inhibition of K+ and Bay K 8644 responses in the retinal neurons were 1.1 x 10(-4) M (17.2 micrograms ml-1) and 1.75 x 10(-4) M (26.6 micrograms ml-1), respectively, and for peppermint oil were 20.3 and 41.7 micrograms ml-1 respectively. Both menthol and peppermint oil inhibited specific [3H]nitrendipine and [3H]PN 200-110 binding to smooth and cardiac muscle and neuronal preparations with potencies comparable to, but slightly lower than, those measured in the pharmacological and 45Ca2+ uptake experiments. Binding of menthol and peppermint oil, studied at 78 micrograms ml-1, was competitive against [3H]nitrendipine in both smooth muscle and synaptosome preparations. The data indicate that both menthol and peppermint oil exert Ca2+ channel blocking properties which may underlie their use in irritable bowel syndrome. Ca2+ channel antagonism may not be the only pharmacological effect of menthol and peppermint oil contributing to intestinal smooth muscle relaxation.

Animals↗
PubMed2002

A cold- and menthol-activated current in rat dorsal root ganglion neurones: properties and role in cold transduction.

Skin temperature is sensed by peripheral thermoreceptors. Using the neuronal soma in primary culture as a model of the receptor terminal, we have investigated the mechanisms of cold transduction in thermoreceptive neurones from rat dorsal root ganglia. Cold-sensitive neurones were pre-selected by screening for an increase in [Ca(2+)](i) on cooling; 49 % of them were also excited by 0.5 microM capsaicin. Action potentials and voltage-gated currents of cold-sensitive neurones were clearly distinct from those of cold-insensitive neurones. All cold-sensitive neurones expressed an inward current activated by cold and sensitised by (-)-menthol, which was absent from cold-insensitive neurones. This current was carried mainly by Na(+) ions and caused a depolarisation on cooling accompanied by action potentials, inducing voltage-gated Ca(2+) entry; a minor fraction of Ca(2+) entry was voltage-independent. Application of (-)-menthol shifted the threshold temperatures of the cold-induced depolarisation and the inward current to the same extent, indicating that the cold- and menthol-activated current normally sets the threshold temperature for depolarisation during cooling. The action of menthol was stereospecific, with the (+)-isomer being a less effective agonist than the (-)-isomer. Extracellular Ca(2+) modulated the cold- and menthol-activated current in a similar way to its action on intact cold receptors: lowered [Ca(2+)](o) sensitised the current, while raised [Ca(2+)](o) antagonised the menthol-induced sensitisation. During long cooling pulses the current showed adaptation, which depended on extracellular Ca(2+) and was mediated by a rise in [Ca(2+)](i). This adaptation consisted of a shift in the temperature sensitivity of the channel. In capsaicin-sensitive neurones, capsaicin application caused a profound depression of the cold-activated current. Inclusion of nerve growth factor in the culture medium shifted the threshold of the cold-activated current towards warmer temperatures. The current was blocked by 50 microM capsazepine and 100 microM SKF 96365. We conclude that the cold- and menthol-activated current is the major mechanism responsible for cold-induced depolarisation in DRG neurones, and largely accounts for the known transduction properties of intact cold receptors.

Action Potentials↗
PubMed1991

Upper airway cooling and l-menthol reduce ventilation in the guinea pig.

Cooling of the upper airway, which stimulates specific cold receptors and inhibits laryngeal mechanoreceptors, reduces respiratory activity in unanesthetized humans and anesthetized animals. This study shows that laryngeal cooling affects the pattern of breathing in the guinea pig and assesses the potential role of cold receptors in this response by using a specific stimulant of cold receptors (l-menthol). The response to airflows (30 ml/s, 10-s duration) through the isolated upper airway was studied in 23 anesthetized (urethan, 1 g/kg ip) guinea pigs breathing through a tracheostomy. Respiratory airflow, tidal volume, laryngeal temperature, and esophageal pressure were recorded before the challenges (control), during cold airflows (25 degrees C, 55% relative humidity), and during warm airflows (37 degrees C, saturated) with or without the addition of l-menthol. Whereas warm air trials had no effect, cold air trials, which lowered laryngeal but not nasal temperature, reduced ventilation (VE) to 85% of control, mainly by prolonging expiratory time (TE, 145% of control), an effect abolished by laryngeal anesthesia. Addition of l-menthol to the warm airflow caused a greater reduction in VE (41% of control) by prolonging TE (1,028% of control). Nasal anesthesia markedly reduced the apneogenic effect of l-menthol but did not affect the response to cold air trials. In conclusion, both cooling of the larynx and l-menthol in the laryngeal lumen reduce ventilation. Exposure of the nasal cavity to l-menthol markedly enhances this ventilatory inhibition; considering the stimulatory effect of l-menthol on cold receptors, these results suggest a predominant role of nasal cold receptors in this response.

Anesthesia, Local↗
PubMed1992

The sensory effects of l-menthol on human skin.

Psychophysical measurements were made of the sensory effects of l-menthol applied topically to the forearm under controlled thermal conditions. In the first experiment, subjects judged the intensity and quality of sensations produced by warming or cooling the skin in the presence of menthol or the vehicle. During cooling, menthol intensified cutaneous sensations and increased reports of burning. During warming, menthol intensified sensations transiently at low temperatures and weakened them lastingly at higher temperatures; the frequency of reports of burning varied with intensity. A second experiment tested the hypothesis that menthol would lower the threshold for warmth and raise the threshold for heat pain. No change in either threshold was observed. The primary sensory effects of l-menthol on hairy skin are therefore to heighten the perception of cooling and to attenuate the perception of moderate warming. In contrast with other common chemical irritants, menthol's pungent qualities appear to be enhanced by cooling and suppressed by warming; this suggests that its sensory irritancy may be attributable to the stimulation of a population of high-threshold cold fibers or cold-sensitive nociceptors.

Adult↗
PubMedDate not supplied

The role of Ca2+ in (-)-menthol-induced human promyelocytic leukemia HL-60 cell death.

A human promyelocytic leukemia HL-60 cell line was selected to examine the effect of (-)-Menthol on cell death. Based on the results from morphological changes and the percentage of viable cells in HL-60 cells after treatment with various concentrations of (-)-Menthol, it was shown that (-)-Menthol induced cell death through necrosis, not apoptosis. No cell cycle arrest was found in HL-60 cells examined by flow cytometry analysis. Also, the DNA gel electrophoresis method showed that (-)-Menthol did not induce apoptosis in HL-60 cells. However, it was found that (-)-Menthol induced the production of Ca2+ in these examined cells, dose-dependently. When HL-60 cells were pretreated with the chelator (BAPTA) of Ca2+ for 3 hours before addition of (-)-Menthol to the culture, a decrease of Ca2+ production was observed. Under the same conditions, the percentage of viable HL-60 cells was increased. Apparently Ca2+ production is associated with the induction of (-)-Menthol-induced cell death.

Acetylation↗
PubMedDate not supplied

Determination of menthol in honey by gas chromatography.

A gas chromatographic method was developed for the determination of L-menthol in honey at levels as low as 0.1 ppm. The method includes steam distillation and hexane extraction with an internal standard (2,6-dimethylphenol). Beehives treated to control Acarapis woodi over 21 days with 30-60 g L-menthol contained L-menthol residues in honey and beeswax. L-Menthol was found only in treated portions of the hive and not later transferred to added honey supers. The highest levels of residues in honey (18 ppm) and beeswax (2790 ppm) were found when pure L-menthol was adsorbed into foam strips placed on top of the hives. L-Menthol residues in honey were not reduced by storage in open containers at room temperature for up to 55 days. Untrained panelists could not detect L-menthol in honey until the levels approached 36 ppm.

Chromatography, Gas↗
PubMed2004

Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay.

1. TRPM8 (CMR1) is a Ca(2+)-permeable channel, which can be activated by low temperatures, menthol, eucalyptol and icilin. It belongs to the transient receptor potential (TRP) family, and therefore is related to vanilloid receptor type-1 (VR1, TRPV1). We tested whether substances which are structurally related to menthol, or which produce a cooling sensation, could activate TRPM8, and compared the responses of TRPM8 and VR1 to these ligands. 2. The effects of 70 odorants and menthol-related substances on recombinant mouse TRPM8 (mTRPM8), expressed in HEK293 cells, were examined using a FLIPR assay. In all, 10 substances (linalool, geraniol, hydroxycitronellal, WS-3, WS-23, FrescolatMGA, FrescolatML, PMD38, CoolactP and Cooling Agent 10) were found to be agonists. 3. The EC(50) values of the agonists defined their relative potencies: icilin (0.2+/-0.1 microM)>FrescolatML (3.3+/-1.5 microM) > WS-3 (3.7+/-1.7 microM) >(-)menthol (4.1+/-1.3 microM) >frescolatMAG (4.8+/-1.1 microM) > cooling agent 10 (6+/-2.2 microM) >(+)menthol (14.4+/-1.3 microM) > PMD38 (31+/-1.1 microM) > WS-23 (44+/-7.3 microM) > Coolact P (66+/-20 microM) > geraniol (5.9+/-1.6 mM) > linalool (6.7+/-2.0 mM) > eucalyptol (7.7+/-2.0 mM) > hydroxycitronellal (19.6+/-2.2 mM). 4. Known VR1 antagonists (BCTC, thio-BCTC and capsazepine) were also able to block the response of TRPM8 to menthol (IC(50): 0.8+/-1.0, 3.5+/-1.1 and 18+/-1.1 microM, respectively). 5. The Ca(2+) response of hVR1-transfected HEK293 cells to the endogenous VR1 agonist N-arachidonoyl-dopamine was potentiated by low pH. In contrast, menthol- and icilin-activated TRPM8 currents were suppressed by low pH. 6. In conclusion, in the present study, we identified 10 new agonists and three antagonists of TRPM8. We found that, in contrast to VR1, TRPM8 is inhibited rather than potentiated by protons.

Animals↗
PubMed1990

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

Voltage-gated Ca2+ channels were identified in LA-N-5 human neuroblastoma cells using the Ca2+ sensitive fluorescent probe, fura-2. Using a variety of "classical" Ca2+ channel blockers, we have demonstrated the presence of both dihydropyridine (DHP)-sensitive and -insensitive channel types that can be activated by depolarization of the cells with either high K+ or gramicidin in the bathing solution. Brief exposure of LA-N-5 cells to menthol blunted the depolarization-induced Ca2+ influx though both DHP-sensitive and DHP-insensitive channels. This effect is concentration dependent (50% maximal blocking effect with 0.25 mM menthol), rapid in onset, and readily reversible. The specificity of the Ca2(+)-channel blocking effect of menthol was demonstrated in parallel studies using compounds with similar structures: menthone blocked Ca2+ channels with about half the potency of menthol, while cyclohexanol was without effect. Addition of either menthol or menthone to LA-N-5 cultures induced neurite outgrowth, cellular clustering, and reduction of cell growth in a dose-dependent fashion that correlated with the ability of these compounds to inhibit the DHP-insensitive Ca2+ influx. Cyclohexanol had no biologic activity. Taken together, the parallel potency for blockade of DHP-insensitive Ca2+ influx with the biologic activity of menthol suggests a role for certain types of Ca2+ channels in triggering growth and morphologic changes in LA-N-5 cells.

Acetylcholinesterase↗
PubMed2000

Role of cold receptors and menthol in thirst, the drive to breathe and arousal.

Menthol is widely used in candy, chewing gum, toothpastes, cigarettes and common cold medications. Menthol has been shown to stimulate cold receptors in the mouth and nose. The present paper puts forward the hypothesis that menthol, by its effects on oral and nasal cold receptors, may influence thirst, the drive to breathe, and arousal. The satisfying effects of menthol on thirst and breathing, together with an effect on arousal, may explain the popularity of menthol and account for the very large amount of menthol-containing products that are consumed each day.

Arousal↗
PubMed2005

(-)-Menthol biosynthesis and molecular genetics.

(-)-Menthol is the most familiar of the monoterpenes as both a pure natural product and as the principal and characteristic constituent of the essential oil of peppermint (Mentha x piperita). In this paper, we review the biosynthesis and molecular genetics of (-)-menthol production in peppermint. In Mentha species, essential oil biosynthesis and storage is restricted to the peltate glandular trichomes (oil glands) on the aerial surfaces of the plant. A mechanical method for the isolation of metabolically functional oil glands, has provided a system for precursor feeding studies to elucidate pathway steps, as well as a highly enriched source of the relevant biosynthetic enzymes and of their corresponding transcripts with which cDNA libraries have been constructed to permit cloning and characterization of key structural genes. The biosynthesis of (-)-menthol from primary metabolism requires eight enzymatic steps, and involves the formation and subsequent cyclization of the universal monoterpene precursor geranyl diphosphate to the parent olefin (-)-(4S)-limonene as the first committed reaction of the sequence. Following hydroxylation at C3, a series of four redox transformations and an isomerization occur in a general "allylic oxidation-conjugate reduction" scheme that installs three chiral centers on the substituted cyclohexanoid ring to yield (-)-(1R, 3R, 4S)-menthol. The properties of each enzyme and gene of menthol biosynthesis are described, as are their probable evolutionary origins in primary metabolism. The organization of menthol biosynthesis is complex in involving four subcellular compartments, and regulation of the pathway appears to reside largely at the level of gene expression. Genetic engineering to up-regulate a flux-limiting step and down-regulate a side route reaction has led to improvement in the composition and yield of peppermint oil.

Genetic Engineering↗
PubMed2004

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects.

OBJECTIVES: The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people. METHODS: Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2nd, 5th and 7th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry. RESULTS: Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC0-24, Cmax, t(max), dehydrofelodipine/felodipine AUC0-24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments. CONCLUSIONS: We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.

Adult↗
PubMed1995

Tongue adaptation temperature influences lingual nerve responses to thermal and menthol stimulation.

Menthol, a tangible substance present in many orally administered products, can produce a powerful influence on the perceived intensity of subsequent thermal stimulation in humans as well as the response magnitudes of thermally sensitive neurons in rats. However, there are no prior studies examining the influence of adaptation temperature on perceived intensity and/or response magnitudes of thermally sensitive neurons to subsequent menthol stimulation. We identified 32 thermally sensitive neurons that increased their discharge rate to a gradual temperature decrement beginning from 35 degrees C and dropping to 10 degrees C at 1 degree C/s. Based on their response threshold, time-to-peak, and range of sensitivity, these thermally sensitive lingual neurons were found to be divisible into two distinct groups. Group 1 neurons (n = 21) responded best to the upper cool range (34-15 degrees C) of the temperature decrement, whereas Group 2 neurons (n = 11) responded to the lower cold range (32-10 degrees C) of the temperature decrement. Our Group 1 and Group 2 neurons may be analogous to low threshold and high threshold cold receptors identified previously in primates. We also examined the responses of lingual neurons to 0%, 25%, 50% and 75% dilution's of a stock menthol concentration (1.28 mM) at 25 and 35 degrees C adaptation temperatures. Menthol responses across all concentrations were far larger after adaptation to 35 degrees C compared to 25 degrees C. Furthermore, only during 35 degrees C adaptation did responses to menthol stimulation persist during the ensuing 20 s after menthol off-set and water on-set.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1996

Nasal receptors responding to cold and l-menthol airflow in the guinea pig.

The aim of this study was to demonstrate the presence of nasal 'cold' receptors, through recordings of action potentials from the ethmoidal nerve (EN), in guinea pigs and to characterize their responsiveness to l-menthol and capsaicin. Constant flows (400 ml/min) of room air (20 degrees C), warm air (45 degrees C), room air containing l-menthol, and cold air (-5 degrees C) were directed into the nasal cavity in the inspiratory direction via a nasopharyngeal catheter in the anesthetized guinea pigs breathing spontaneously through a tracheostomy. The ethmoidal afferent activity was increased by cold air, and to a greater extent by l-menthol but hardly by warm air. After topical anesthesia of the nasal cavity with 2% lidocaine, cold air and l-menthol no longer stimulated the EN. L-menthol noticeably stimulated the EN even after repeated capsaicin instillation into the nose, but these values were lower than those following the l-menthol stimulus before the 1st capsaicin treatment. These results suggest that the ethmoidal nerve in guinea pigs has cold-sensitive receptors which consist of both small myelinated fibers and C-fiber endings.

Action Potentials↗
PubMed1986

Calcium channel current inactivation is selectively modulated by menthol.

The effect of menthol on Ca channel current inactivation was studied in identified Helix neurons. External application of menthol accelerated the Ca-dependent rapid phase of inactivation. Menthol restored a fast inactivation phase after the Ca-dependent inactivation had been removed by strongly buffering changes in intracellular free Ca or by using Ba ions as current carriers. The menthol-induced inactivation was unchanged by variations in intracellular free Ca. A sensitizing effect of menthol on Ca-dependent inactivation appeared unlikely. Instead the results indicate a modulating action of menthol on Ca inactivation.

Animals↗
PubMed2006

Thermal and nociceptive sensations from menthol and their suppression by dynamic contact.

It was recently found that cooling the skin to temperatures as mild as 25-30 degrees C can induce nociceptive sensations (burning, stinging or pricking) that are strongly suppressed by dynamic contact between the thermode and skin (contact suppression). Here we investigated whether nociceptive sensations produced by menthol can be similarly suppressed. In the first experiment subjects rated the intensity of cold and burning/stinging/pricking sensations before and after application of 10% l-menthol to the forearm. Ratings were compared at resting skin temperature ( approximately 33 degrees C) and at 28, 24, or 20 degrees C during static or dynamic contact cooling via a Peltier thermode. At resting skin temperature, menthol produced cold and nociceptive sensations, both of which were suppressed by dynamic contact. When the skin was cooled during static contact, menthol increased nociceptive sensations but not cold sensations; when the skin was cooled during dynamic contact, cold sensations were again unchanged while nociceptive sensations were suppressed. A second experiment tested whether contact suppression of menthol's cold and nociceptive sensations at resting skin temperature was caused by slight deviations of thermode temperature above skin temperature. The results showed that suppression occurred even when the thermode was slightly cooler (-0.5 degrees C) than the skin. These findings support other evidence that the menthol-sensitive channel, TRPM8, plays a role in cold nociception, and raise new questions about how dynamic tactile stimulation may modify perception of nonpainful cold stimulation.

Adolescent↗
PubMed2006

More than cool: promiscuous relationships of menthol and other sensory compounds.

Several temperature-activated transient receptor potential (thermoTRP) ion channels are the molecular receptors of natural compounds that evoke thermal and pain sensations. Menthol, popularly known for its cooling effect, activates TRPM8--a cold-activated thermoTRP ion channel. However, human physiological studies demonstrate a paradoxical role of menthol in modulation of warm sensation, and here, we show that menthol also activates heat-activated TRPV3. We further show that menthol inhibits TRPA1, potentially explaining the use of menthol as an analgesic. Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, respectively) also modulate other thermoTRPs. Therefore, we find that many "sensory compounds" presumed to be specific have a promiscuous relationship with thermoTRPs.

Animals↗
PubMed2006

Psychophysical study of the effects of topical application of menthol in healthy volunteers.

Cold hyperalgesia is a major clinical phenomenon, but validated experimental models are still lacking for humans. Topical menthol application has recently been proposed as a possible model for the study of cold pain. We characterized the psychophysical effects of 30% l-menthol in ethanol on glabrous skin in 39 healthy subjects, using a double-blind, randomized, crossover design, with ethanol as a control. Psychophysical testing included an assessment of pain thresholds and detection of mechanical, cold, and heat stimuli, and of the sensations induced by suprathreshold stimuli. Most subjects (90%) perceived a cooling sensation with menthol. Menthol decreased cold pain thresholds and enhanced pain responses to suprathreshold noxious cold stimuli, without affecting responses to other stimuli. Menthol therefore has selective effects on noxious cold processing. No subject displayed signs of skin irritation or redness. These data suggest that 30% menthol application may be a useful experimental model for studies of cold hyperalgesia in humans. The absence of local skin reactions also makes this test potentially suitable for use in patients.

Administration, Topical↗
PubMed2002

Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol.

BACKGROUND AND OBJECTIVE: Thymol is a naturally occurring phenol derivative used in anaesthetic practice as a stabilizer and preservative of halothane, usually at a concentration of 0.01%. Although analgesic effects have long been described for thymol and its structural homologue menthol, a molecular basis for these effects is still lacking. We studied the blocking effects of thymol and menthol on voltage-activated sodium currents in vitro as possible molecular target sites. METHODS: Whole cell sodium inward currents via heterologously (HEK293 cells) expressed rat neuronal (rat type IIA) and human skeletal muscle (hSkM1) sodium channels were recorded in the absence and presence of definite concentrations of either thymol or menthol. RESULTS: When depolarizing pulses to 0 mV were started from a holding potential of -70 mV, half-maximum blocking concentrations (IC50) for the skeletal muscle and the neuronal sodium channel were 104 and 149 mumol for thymol and 376 and 571 mumol for menthol. The blocking potency of both compounds increased at depolarized holding potentials with the fraction of inactivated channels. The estimated dissociation constant Kd for thymol and menthol from the inactivated state was 22 and 106 mumol for the neuronal and 23 and 97 mumol for the skeletal muscle sodium channel, respectively. CONCLUSIONS: The results suggest that antinociceptive and local anaesthetic effects of thymol and menthol might be mediated via blockade of voltage-operated sodium channels with the phenol derivative thymol being as potent as the local anaesthetic lidocaine.

Analgesics↗