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At least 19 recordsLinked to original sources
PubMed1990

Determination of menthol and menthol glucuronide in human urine by gas chromatography using an enzyme-sensitive internal standard and flame ionization detection.

The rate of peppermint oil absorption and excretion, following peroral administration, was determined by measuring urinary levels of menthol glucuronide. Menthol, a major component of peppermint oil, was liberated from its glucuronide metabolite by treating raw urine with beta-D-glucuronidase (Patella vulgata). Phenyl glucuronide was employed as an enzyme-sensitive internal standard. Menthol and phenol were recovered by ethyl acetate extraction and quantitated by capillary gas chromatography using flame ionization detection. Standard curves were linear between 25 and 250 micrograms/ml with a detection limit (signal-to-noise ratio = 2) of 0.25 microgram/ml. Assay precision was shown to be +/- 1.2% relative standard deviation.

Chromatography, Gas↗
PubMed1989

Menthol cigarette smoking and oesophageal cancer.

Oesophageal cancer incidence and mortality among American blacks is over three times the rate for whites. Between 1950 and 1977 the age-adjusted oesophageal cancer mortality rate approximately doubled in non-whites while remaining virtually unchanged in whites. Between World War II and the 1970s menthol cigarette sales dramatically increased, roughly paralleling the increase in oesophageal cancer among blacks. The present study uses existing data from a large hospital-based case-control study to test whether menthol cigarette smoking is related to oesophageal cancer. Oesophageal cancer cases were current smokers. Controls were matched to the cases on age (+/- 5 years) and sex, had conditions thought not to be related to tobacco use, and were also current smokers. Tabular analyses showed no change in risk for males ever-smoking menthol versus those never smoking menthol cigarettes. For women, however, there was an increased risk. Results of logistic regression analyses performed to account for potential confounding factors showed a marginally significant (P = 0.08) decrease in risk among male short term (less than 10 years) menthol smokers versus male never-menthol smokers (OR = 0.50, 95% Cl: 0.23-1.07) but no increased risk for menthol smoking of longer duration. Duration of menthol smoking fitted as a continuous variable showed no increased risk (P = 0.9) after accounting for non-menthol cigarette smoking duration (about 2% per year increase, P = 0.02). For females, the logistic analysis produced a marginally significant (P = 0.07) increased risk for longer menthol use (OR = 2.30, 95% Cl: 0.93-5.72).(ABSTRACT TRUNCATED AT 250 WORDS)

Black or African American↗
PubMed1987

Effect of menthol on two types of Ca currents in cultured sensory neurons of vertebrates.

The effect of menthol on voltage-dependent Ca currents was investigated in cultured dorsal root ganglion cells from chick and rat embryos. Bath application of menthol (0.1-1 mM) had different effects on the various Ca currents present in these neurons. Below -20 mV, the low threshold Ca currents were reduced in amplitude in a dose-dependent manner by menthol with little changes of their activation kinetics. In contrast to this, the time course of inactivation of the high-threshold Ca currents, activated above -20 mV from a holding potential of -80 mV, was drastically accelerated by external menthol. The action of menthol was unchanged with more positive holding potentials (-50 mV). Thus, a proposed third type of Ca current with transient activation and complete deactivation below -50 mV was either not present or not affected by menthol. Menthol exerted its action only when applied from the outside. Its effect was completely reversible within 15-20 min of wash-out. Our findings are consistent with the idea that menthol acts on two types of Ca channels coexisting on the membrane of cultured sensory neurons. Menthol blocks currents through the low voltage-activated Ca channel, and facilitates inactivation gating of the classical high voltage-activated Ca channel.

Animals↗
PubMed1988

The effects of D and L isomers of menthol upon nasal sensation of airflow.

Objective and subjective measurements of nasal airflow were made before and after inhalation of Vanilla, D-Menthol and L-Menthol separately. Despite the fact that the menthol isomers were mirror images of one another, only L-Menthol produced the sensation of increased nasal airway patency. No objective change in resistance was found after inhaling either D-Menthol, L-Menthol or the vanilla control. These findings demonstrate that L-Menthol exerts a specific action upon nasal sensory nerve endings, which are responsible for the subjective appreciation of nasal airflow.

Adult↗
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↗
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↗
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↗
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↗
PubMedDate not supplied

Studies on the metabolism of l-menthol in rats.

Metabolism of l-menthol in rats was investigated both in vivo and in vitro. Metabolites isolated and characterized from the urine of rats after oral administration (800 mg/kg of body weight/day) of l-menthol were the following: p-menthane-3,8-diol (II), p-menthane-3,9-diol (III), 3,8-oxy-p-menthane-7-carboxylic acid (IV), and 3,8-dihyroxy-p-menthane-7-carboxylic acid (V). In vivo, the major urinary metabolites were compounds II and V. Repeated oral administration (800 mg/kg of body weight/day) of l-menthol to rats for 3 days resulted in the increase of both liver microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity by nearly 80%. Further treatment (for 7 days total) reduced their levels considerably, although the levels were still higher than the control values. Both cytochrome b5 and NADH-cytochrome c reductase levels were not changed during the 7 days of treatment. Rat liver microsomes readily converted l-menthol to p-menthane-3,8-diol (II) in the presence of NADPH and O2. This activity was significantly higher in microsomes obtained from phenobarbital (PB)-induced rats than from control microsomal preparations, whereas 3-methylcholanthrene (3-MC)-induced microsomes failed to convert l-menthol to compound II in the presence of NADPH and O2. l-Menthol elicited a type I spectrum with control (Ks = 60.6 microM) and PB-induced (Ks = 32.3 microM) microsomes whereas with 3MC-induced microsomes it produced a reverse type I spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2025

Structural Basis of Cold and Menthol Sensing by TRPM8.

The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific "cold spot". These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.

Journal Article↗
PubMed1991

Effect of l-menthol on laryngeal receptors.

We have studied the effect of l-menthol on laryngeal receptors. Experiments have been conducted in 11 anesthetized dogs that breathed through a tracheostomy. We have recorded the activity of 23 laryngeal cold receptors and 19 mechanoreceptors. Constant flows of air, 15-50 ml/s (low) and 100-150 ml/s (high), passing for 10 s through the isolated upper airway in the expiratory direction, lowered laryngeal temperature and activated the cold receptors. This cold-induced discharge promptly ceased upon withdrawal of the airflow. Addition of l-menthol to the airflow evoked, for a similar decrease in temperature, a greater peak activation of the cold receptors than airflow alone (low flows 164%, high flows 111%); statistical significance was reached only for the lower flow. This activity outlasted the cessation of airflow by 30-120 s, even at a time when laryngeal temperature had returned to control (low flow 237%, high flow 307% of similar trials with airflow alone). Four laryngeal cold receptors were also tested with l-menthol added to a warm, humidified airflow that did not change laryngeal temperature; all of them were stimulated with a long-lasting discharge. Nine cold receptors were also tested with d-neomenthol and d-isomenthol; both isomers stimulated the receptors. None of the 19 mechano-receptors tested was affected by l-menthol. We conclude that l-menthol constitutes a specific stimulant of laryngeal cold receptors and could provide a useful tool for the study of their reflex effects.

Action Potentials↗
PubMed1992

Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin.

The effect of l-menthol on the skin permeability of mannitol, cortisone or indomethacin was examined by an in vitro penetration technique with hairless mouse skin. The donor solution was prepared with phosphate buffered saline, ethanol:buffered saline (20:80, v/v) or ethanol:buffered saline (20:80, v/v) containing 1% (w/v) l-menthol. Although ethanol showed little enhancing effect, l-menthol in an aqueous ethanol vehicle at pH 7.4 increased the permeability coefficients of mannitol and indomethacin by about 100 times that of the control (an aqueous vehicle) and increased that of cortisone by about 10 times. l-Menthol, however, scarcely enhanced the penetration of indomethacin at pH 3.0, the majority of the species being in unionized form. These results suggested that the menthol-ethanol-aqueous system enhanced skin permeability through a direct effect on the polar and/or lipid pathways, while the thermodynamic activity of the penetrant molecule in the delivery vehicle might also influence the effectiveness of the penetration enhancer.

Administration, Cutaneous↗
PubMed1991

Use of mentholated cigarettes and lung cancer risk.

Black males have higher age-adjusted lung cancer incidence rates compared to white males, and blacks of both sexes have higher rates of increase in lung cancer incidence over past decades. The majority of black smokers smoke mentholated cigarettes. These observations prompted us to assess the effect of smoking mentholated cigarettes on lung cancer risk, using data from a hospital-based case-control study of tobacco-related cancers. Analysis was restricted to current cigarette smokers and was carried out on 588 male lung cancer cases and 914 male control patients and on 456 female lung cancer cases and 410 female controls interviewed between 1985 and 1990. The prevalence of menthol usage did not differ between cases and controls of either sex. No significant association was observed between either short-term (1-14 years) or long-term (15+ years) menthol use and lung cancer in logistic regression analyses adjusting for covariates. For specific histological types of lung cancer there was no indication of an association with menthol usage.

Adult↗
PubMed1992

Menthol in the upper airway depresses ventilation in newborn dogs.

Upper airway cooling depresses ventilation in the newborn dog. Since airway cooling stimulates laryngeal cold receptors and inhibits laryngeal mechanoreceptors, the type of afferent ending responsible for this reflex cannot be easily identified. l-menthol, a specific stimulant of cold receptors in the absence of any cooling, has been used to ascertain the discrete role of upper airway cold receptors in this ventilatory depression. Experiments were carried out in 8 anesthetized 7-14-day-old dogs breathing through a tracheostomy with the upper airway functionally isolated. Constant flows of warm air (37 degrees C), with and without addition of l-menthol, and cold air (25 degrees C) were delivered through the upper airway in the expiratory direction. As compared to warm air trials, cold air and warm air + l-menthol trials greatly reduced ventilation (57.5 +/- 10.7% and 52.8 +/- 11.7% of control, respectively; P less than 0.01) mostly due to a prolongation of Te (291.2 +/- 106.4% and 339.2 +/- 90.0%, respectively, P less than 0.01). Section of the superior laryngeal nerve abolished the response to cold air. However, a residual depressive effect of l-menthol was still present in 3 of 5 animals and was abolished by nasal anesthesia, suggesting the involvement of nasal cold receptors. The results suggest that in the newborn dog stimulation of laryngeal cold receptors, without any concurrent inhibition of laryngeal mechanoreceptors, is a sufficient stimulus to cause respiratory depression.

Animals↗
PubMed1990

The effects of oral administration of (-)-menthol on nasal resistance to airflow and nasal sensation of airflow in subjects suffering from nasal congestion associated with the common cold.

The effects of oral administration of a lozenge containing 11 mg (-)-menthol on nasal resistance to airflow (NAR) and nasal sensation of airflow in 62 subjects suffering from nasal congestion associated with naturally acquired common cold infection have been studied. NAR was measured by posterior rhinomanometry and nasal sensation of airflow by means of a visual analogue scale (VAS). The effects of the lozenge were compared with a candy placebo lozenge in a double blind randomized trial. NAR showed a significant increase (P less than 0.05) in both the menthol and placebo groups over the 2 h experiment with no difference between the groups at any time. The VAS scores showed significant changes of subjective improvement in nasal sensation of airflow (P less than 0.001) in the menthol-treated group 10 min after dosing whereas the placebo group showed no change. It is concluded that dosing with 11 mg menthol in subjects with common cold has no effect on NAR as measured by posterior rhinomanometry but causes a marked change in nasal sensation of airflow with a subjective sensation of nasal decongestion.

Administration, Oral↗
PubMed1989

Mentholated cigarette use among multiphasic examinees, 1979-86.

Mentholated cigarette use was studied in relation to age and race in 29,037 current smokers who were Kaiser Permanente Medical Care Program members. The percentages of mentholated cigarette users were much higher in Blacks and Asians than in Whites, especially in the younger age groups. A marked inverse relationship between mentholated cigarette use and age was present in Blacks and Asians; mentholated cigarette use showed little difference with age in Whites.

Adolescent↗
PubMed1990

Effects of menthol on peripheral nerve and cortical unit responses to thermal stimulation of the oral cavity in the rat.

Neurophysiological responses were recorded in individual fibers of the lingual and chorda tympani nerves and in single cortical neurons in the rat in response to a battery of tactile, thermal and chemical stimuli applied to the oral cavity. Two categories of thermally sensitive units were identified. Chorda tympani fibers and one type of cortical unit ('Type I') were activated by cold water stimulation but were unaffected by warm water or menthol. In contrast, lingual fibers and a different category of cortical units ('Type II') were extremely sensitive to menthol exposure. These units were cold water sensitive, however, this sensitivity was suppressed following menthol presentation.

Action Potentials↗