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PubMed2002

Mentholated cigarettes and smoking cessation: findings from COMMIT. Community Intervention Trial for Smoking Cessation.

OBJECTIVE: To examine the association between the use of menthol cigarettes and smoking cessation, amount smoked, and time to first cigarette in the morning. BACKGROUND: The majority of African American smokers smoke mentholated cigarettes. Some evidence suggests that African Americans may be more nicotine dependent than whites. One theory is that menthol in cigarettes is responsible for enhancing the dependence producing capacity of cigarettes; however, few studies have prospectively examined the association between menthol use and indicators of nicotine dependence. METHODS: Baseline smokers from the Community Intervention Trial for Smoking Cessation (COMMIT) completed a telephone tobacco use survey in 1988 and were re-interviewed in 1993. Use of mentholated cigarettes was assessed by self report at baseline. Indicators of dependence examined were six month cessation in 1993, amount smoked among continuing smokers in 1993, and time to first cigarette in the morning in 1988. Multivariate regression techniques were used to assess the association of baseline menthol use with these outcomes while controlling for other factors related to dependence. RESULTS: Overall, 24% of the sample smoked a mentholated brand in 1988. No consistent associations were observed for menthol use and indicators of dependence in both overall and race specific analyses. Factors significantly associated with increased menthol use were female sex, age 25-34 years, African American and Asian race/ethnicity, greater education, greater than 60 minutes to the first cigarette in the morning, two or more past quit attempts, and use of premium brand cigarettes. Canadian respondents and those who smoked 15-24 cigarettes per day had lower rates of menthol use. Use of mentholated cigarettes was not associated with quitting, amount smoked, or time to first cigarette in the morning. CONCLUSION: Future work is needed to clarify the physiological and sociocultural mechanisms involved in mentholated cigarette smoking.

Adolescent↗

PubMed2005

Shorter time to first cigarette of the day in menthol adolescent cigarette smokers.

Menthol smoking is thought to contribute to the addictiveness of smoking. Given the high prevalence of menthol smoking among youth, the aim of the current analysis was to examine differences in consumption and tobacco dependence, including smoking urgency among menthol and non-menthol adolescent smokers. Data for the current analysis were collected from telephone interviews with adolescent smokers applying to a cessation treatment study. Of 572 adolescent smokers (mean age=15.6+/-1.6 years; 55.1% female; 46.9% African American, 48.2% European American), 531 smoked menthol cigarettes and 41 smoked non-menthol as their usual brand. Analysis using Fisher's Exact (one-tailed) Test revealed that menthol smokers had a significantly shorter time to first (TTF) cigarette of the day compared to non-menthol smokers (smoking within the first 5 min of the day, 45% vs. 29%, respectively; p<0.04). Independent t tests revealed no significant difference in number of cigarettes per day (CPD) (mean=12.2+/-8.5 vs. 11.4+/-8.8; p<0.28) or Fagerstrom Test for Nicotine Dependence (FTND) scores (3.4+/-1.4 vs. 3.2+/-1.3; p<0.23). While preliminary, our findings suggest greater smoking urgency among menthol compared to non-menthol adolescent cessation-treatment seekers. Further study in a broader sample of adolescent smokers is warranted to elucidate the mechanisms underlying the effects of menthol smoking for youths.

Adolescent↗

PubMed2004

Enhanced rectal bioavailability of ibuprofen in rats by poloxamer 188 and menthol.

To improve the bioavailability of poorly water-soluble ibuprofen in the rectum with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution and pharmacokinetic study of ibuprofen delivered by the poloxamer gels composed of poloxamer 188 and menthol were then performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that four parts menthol formed eutectic mixture with six parts ibuprofen. In the presence of poloxamer, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Release mechanism showed that the release rate of ibuprofen from the poloxamer gels without menthol was independent of the time but the drug might be released from the poloxamer gels with menthol by Fickian diffusion. Furthermore, the poloxamer gel with menthol (poloxamer/menthol/ibuprofen (15%/0.25%/2.5%)) gave significantly higher initial plasma concentrations, C(max) and AUC of ibuprofen than did solid suppository, indicating that the drug from poloxamer gel could be more absorbed than that from solid one in rats. Thus, the poloxamer gel with poloxamer 188 and menthol was a more effective rectal dosage form for ibuprofen.

Administration, Rectal↗

PubMed1999

Mentholated cigarette smoking and lung-cancer risk.

PURPOSE: Menthol smoking may lead to a greater increase in lung-cancer risk than smoking of nonmentholated cigarettes. Mentholation of cigarettes adds additional carcinogenic components to cigarette smoke and increases retention times for cigarette smoke in the lungs. Only two epidemiologic studies have been conducted on menthol smoking and lung cancer, and their results are conflicting. Of note, African American males have much higher rates of lung cancer than Caucasian males despite smoking fewer cigarettes per day. Because the consumption of menthol cigarettes is much more frequent among African Americans, it is of interest to examine the possible association between menthol smoking and lung-cancer risk in this population. METHODS: We examined the association between menthol cigarette smoking and lung-cancer risk among smokers by comparing 337 incident cases of lung cancer with 478 population controls enrolled in a case-control study of lung cancer. Information on smoking history and other known and potential risk factors for lung cancer, including dietary intake, was obtained by in-person interviews. RESULTS: The adjusted odds ratios did not differ appreciably between smokers of mentholated cigarettes versus exclusive nonmentholated cigarette smokers in the overall study group of smokers. The odds ratio (OR) for 32 pack-years or more of mentholated vs. nonmentholated cigarettes was 0.90 (95% confidence interval (CI) = 0.38-2.12) in African Americans and 1.06 (95% CI = 0.47-2.36) in Caucasians, and did not differ for either ethnic group (p = 0.98). CONCLUSIONS: Our results suggest that the lung-cancer risk from smoking mentholated cigarettes resembles the risk from smoking non-mentholated cigarettes. Our data do not support the hypothesis that the increased risk of lung cancer among African Americans is due to the increased prevalence of menthol smoking.

Adult↗

PubMed1998

Identification of the L-menthol binding site in guinea-pig lung membranes.

1. L-Menthol inhibits both neurokinin A and capsaicin-induced bronchoconstriction in the guinea-pig and relaxes pre-constricted guinea-pig isolated bronchi. Structure-activity relationships have been defined for the action of (-)-menthol and related compounds on cold receptors, suggesting an action of L-menthol at a pharmacological receptor. We have performed radioligand binding studies to characterize the binding sites for [3H]-L-menthol in whole cell membranes prepared from guinea-pig lung tissue. 2. In kinetic studies. [3H]-L-menthol was found to bind rapidly and reversibly. Binding of [3H]-L-menthol to lung membranes was found to be time-dependent becoming fully associated to its site within 40 min, and half-maximum association occurred within 8 min (t1/2=8 min). [3H]-L-menthol was fully dissociated from its binding site within 8 min, (t1/2=2 min). 3. Inhibition studies presented a pharmacological profile of the 'L-menthol site'. Capsaicin, capsazepine, D-menthol, eugenol, SCH23390 and camphor were all found to displace [3H]-L-menthol binding. In contrast WS3, noradrenaline, 5-hydroxytryptamine, spiperone, flunarazine, bepridil and nicardipine were without effect. 4. We have identified a L-menthol binding site in the guinea-pig, which may represent a site common to a variety of compounds.

Animals↗

PubMed2004

Epidemiology of menthol cigarette use.

Approximately one-fourth of all cigarettes sold in the United States are mentholated. An understanding of the consequences, patterns, and correlates of menthol cigarette use can guide the development and implementation of strategies to reduce smoking prevalence and smoking-attributable morbidity and mortality. This paper summarizes the literature on the health effects of mentholated cigarettes and describes various patterns of use as indicated by consumption and survey data from the United States and other nations. The epidemiological literature on menthol cigarettes and cancer risk is inconclusive regarding whether these cigarettes confer a risk for cancer above that of nonmentholated varieties. Available data indicate that mentholated cigarettes are at least as dangerous as their nonmentholated counterparts. In addition, because mentholation improves the taste of cigarettes for a substantial segment of the smoking population and appears to mask disease symptoms, this additive may facilitate initiation or inhibit quitting. Menthol market share is high in the Philippines (60%), Cameroon (35%-40%), Hong Kong (26%), the United States (26%), and Singapore (22%). Newport has become the leading menthol brand in the United States. Surveys from four nations indicate that menthol use among adult smokers is more common among females than males. Among U.S. smokers, 68.9% of Blacks, 29.2% of Hispanics, and 22.4% of Whites reported smoking a mentholated variety. Research is needed to better explain factors that may influence menthol preference, such as marketing, risk perceptions, brand formulation, and taste preferences. Such research would guide the development of potentially more effective programs and policies.

Adolescent↗

PubMedDate not supplied

Improved solubility and in vitro dissolution of Ibuprofen from poloxamer gel using eutectic mixture with menthol.

To improve the solubility and in vitro dissolution of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution study of ibuprofen delivered by poloxamer gels composed of poloxamer 188 and menthol were performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6, followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that 4 parts of ibuprofen formed eutectic mixture with 6 parts of menthol. In the presence of poloxamer 188, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without poloxamer and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Dissolution mechanism showed that the dissolution rate of ibuprofen from the poloxamer gels without menthol was independent of the time, but the drug might be dissolved from the poloxamer gels with menthol by Fickian diffusion. Thus, the poloxamer gels developed using eutectic mixture with menthol, which gave the improved solubility and dissolution of drug, are potential candidates for ibuprofen-loaded transdermal and rectal delivery system.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

African-American menthol and nonmenthol smokers: differences in smoking and cessation experiences.

BACKGROUND: Despite smoking fewer cigarettes per day, African Americans have lower cessation rates and experience disproportionately higher rates of smoking-related health consequences. Because of their high preference for menthol cigarettes, it has been suggested that smoking menthol cigarettes may contribute to the excess smoking-related morbidity experienced by African Americans. Smoking menthol cigarettes could increase health risks from smoking if smokers of menthol cigarettes have lower cessation rates and thereby have longer duration of smoking compared to smokers of nonmentholated cigarettes. Few studies have examined associations between smoking of mentholated cigarettes and smoking cessation among African Americans. This study examined the smoking patterns of menthol cigarette smokers and their smoking cessation experiences. METHODS: A cross-sectional survey of 480 African-American smokers at an inner-city health center. Survey examined sociodemographics, smoking characteristics, and smoking cessation experiences of participants. Menthol smokers (n = 407) were compared to nonmenthol smokers (n = 73) in these characteristics. RESULTS: Menthol smokers were younger and more likely to smoke cigarettes with longer rod length, with filters, and those high in nicotine and tar. Although both groups did not differ by number of past quit attempts, time since most recent quit attempt was shorter for menthol smokers. The durations of most recent and longest-ever quit attempts were nonsignificantly shorter for menthol, compared to nonmenthol smokers. CONCLUSIONS: These data suggest that African-American menthol smokers are less successful with smoking cessation. Prospective studies are needed to confirm these findings and examine mechanisms underlying such differences.

Adolescent↗

PubMed2006

Menthol cigarettes, smoking cessation, atherosclerosis, and pulmonary function: the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: African American smokers are more likely to experience tobacco-related morbidity and mortality than European American smokers, and higher rates of menthol cigarette smoking may contribute to these disparities. METHODS: We prospectively measured cumulative exposure to menthol and nonmenthol cigarettes and smoking cessation behavior (1985-2000), coronary calcification (2000), and 10-year change in pulmonary function (1985-1995) in African American and European American smokers recruited in 1985 for the Coronary Artery Risk Development in Young Adults Study. RESULTS: We identified 1535 smokers in 1985 (972 menthol and 563 nonmenthol); 89% of African Americans preferred menthol vs 29% of European Americans (P<.001). After adjustment for ethnicity, demographics, and social factors, we found nonsignificant trends in menthol smokers toward lower cessation (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.49-1.02; P = .06) and recent quit attempt (OR, 0.77; 95% CI, 0.56-1.06; P = .11) rates and a significant increase in the risk of relapse (OR, 1.89; 95% CI, 1.17-3.05; P = .009). Per pack-year of exposure, however, we found no differences from menthol in tobacco-related coronary calcification (adjusted OR, 1.27; 95% CI, 1.01-1.60 for menthol cigarettes and 1.33; 95% CI, 1.06-1.68 for nonmenthol cigarettes per 10-pack-year increase; P = .75 for comparison) or 10-year pulmonary function decline (adjusted excess decline in forced expiratory volume in 1 second, 84 mL; 95% CI, 32-137 for menthol cigarettes and 80 mL; 95% CI, 30-129 for nonmenthol cigarettes, per 10-pack-year increase; P = .88 for comparison). CONCLUSION: Menthol and nonmenthol cigarettes seem to be equally harmful per cigarette smoked in terms of atherosclerosis and pulmonary function decline, but menthol cigarettes may be harder to quit smoking.

Adolescent↗

PubMed1994

Neural responses of thermal-sensitive lingual fibers to brief menthol stimulation.

The addition of the coolant menthol to several oral and facial products is to increase their attractiveness and commercial value. Little is, however, known about the physiological basis of menthol's sensory effects. We studied the electrophysiological responses of 45 thermal-sensitive lingual fibers to anterior tongue stimulation (10 s) with menthol in male Sprague-Dawley rats. Menthol responses were unlike the responses to cold water. Cold water (6 degrees C, 15 degrees C) elicited an immediate sustained increase in impulse frequencies of thermal-sensitive fibers adapted to room temperature water (22-24 degrees C). Inhibitory off-responses followed cold water stimulation. Depending on the concentration and time of measurement, menthol stimulation either excited, inhibited, or had no effect on impulse frequencies of thermal-sensitive fibers. Strong menthol (0.64 mM, 1.28 mM) unequivocally excited thermal-sensitive fibers with a response latency of 4-6 s. In most cases after menthol stimulation, the impulse frequencies returned to baseline; there were no off-responses. Weak menthol (0.0128 mM, 0.064 mM, 0.128 mM) inhibited impulse frequencies of 14 thermal-sensitive fibers and excited impulse frequencies of 6 fibers primarily during the first 2 s of stimulation. Menthol responses were also unlike responses to stimulation with taste solutions. Most taste solutions (30 and 100 mM NaCl, 0.3 and 1 mM quinine-HCl, 0.3 mM citric acid) significantly inhibited impulse frequencies but only during the first 2-5 s of stimulation. The effect of NaCl was biphasic with the initial inhibitory phase followed by an excitatory phase during the second 5 s of stimulation. An excitatory off-response followed quinine stimulation. While considered principally a coolant, menthol elicits a unique pattern of responses from trigeminal and taste nerve endings quite unlike those of conventional thermal and taste stimuli.

Animals↗

PubMed1996

Sensitization and desensitization to capsaicin and menthol in the oral cavity: interactions and individual differences.

It was reported in a recent study that, like capsaicin, menthol is capable of producing a desensitization to sensory irritation in the oral cavity. Whereas capsaicin is known to be able to cross-desensitize with other chemical irritants, no such information exists for menthol. To address this question, the first experiment was designed to reveal whether cross-desensitization would occur between menthol and capsaicin. After a pretest on the tongue tip in which subjects rated the intensity of irritation and cold produced by 3.5 ppm capsaicin or 0.3% l-menthol, five samples of the same stimuli were sipped and swished at 1-min intervals for 5 min. Fifteen minutes later subjects were tested on the tongue tip with either capsaicin or menthol. The results 1) confirmed self-desensitization for both chemicals, 2) demonstrated cross-desensitization of menthol by capsaicin, and 3) revealed cross-sensitization of capsaicin by menthol. This series of outcomes suggests that menthol produces much of its sensory irritation via capsaicin-sensitive pathways, but that it excites and/or desensitizes those pathways via different mechanisms than does capsaicin. Analysis of the individual data revealed large differences in sensitization, and desensitization that were significantly correlated across chemicals, which suggests the possibility that the perceptual response to repeated exposures to irritants may be idiosyncratic. Contrary to earlier findings, the first experiment also revealed apparent self- and cross-desensitization of the menthol sensation of coolness. The latter outcome was investigated in a second experiment in which the effect of capsaicin desensitization on the perception of physical as well as chemical (menthol) cooling was measured when the stimuli were presented as oral rinses. No desensitization was found for either form of stimulation, which implied the apparent desensitization of coolness in Experiment I may have been due to the difficulty of discriminating sensations of cold from sensations of chemical irritation. The overall findings are discussed in terms of the complex sensory and perceptual interactions that take place within the chemesthetic modality.

Adult↗

PubMed2006

Menthol cigarettes and indicators of tobacco dependence among adolescents.

OBJECTIVES: This study examines measures of nicotine dependence among adolescent menthol and non-menthol cigarette smokers in a nationally representative sample. METHODS: We examined rates of menthol smoking and measures of nicotine dependence among 1345 current established smokers in grades 9-12 who participated in the 2004 National Youth Tobacco Survey. Logistic regression was used to generate an adjusted odds ratio (OR) for menthol smoking for four measures of nicotine dependence, controlling for demographic characteristics and smoking patterns. RESULTS: Approximately 46% of all current established cigarette smokers were menthol smokers. Menthol smokers had 2.6 and 1.6 greater odds than non-menthol smokers for reporting that they could go for less than 1 h before feeling like they need a cigarette and that they experience cravings after not smoking for a while, respectively. CONCLUSIONS: Menthol cigarette smoking was associated with two dependence measures and may be more addictive than regular cigarettes in young smokers. Future research should continue to explore relationships between dependency and menthol use as well as the high prevalence of menthol use among adolescents.

Adolescent↗

PubMed2001

Oral irritant properties of menthol: sensitizing and desensitizing effects of repeated application and cross-desensitization to nicotine.

The irritant properties of menthol and its interactions with nicotine were investigated psychophysically in human subjects. In the first experiment, 0.3% L-menthol was applied successively to one side of the tongue 10 times at a 1-min interval (30-s interstimulus interval, ISI), and subjects rated the intensity of the perceived irritation. The intensity of irritation progressively decreased across trials, consistent with desensitization. To test for cross-desensitization of nicotine-evoked irritation by menthol, nicotine (0.6%) was applied to both sides of the tongue simultaneously, 5 min after the conclusion of menthol application. Using both a two-alternative forced choice (2-AFC) paradigm, and also by obtaining independent ratings of the irritant intensity on each side of the tongue, it was found that nicotine-evoked irritation was significantly weaker on the menthol-pretreated side. To control for a possible confounding effect of cooling, nicotine was applied bilaterally only after the cooling sensation of menthol had subsided. Nicotine-induced irritation was still significantly weaker on the menthol-pretreated side, consistent with cross-desensitization of nicotine-evoked irritation by menthol. In a final experiment, menthol was repeatedly applied to one side of the tongue at a shorter (20 s) interval (5-s ISI), and elicited a rapid increase in irritant sensation over the initial trials, consistent with sensitization, followed in subsequent trials by a progressive reduction in irritation (desensitization). After a 5-min rest period, self-desensitization was confirmed. Repeated application of menthol at the same short ISI was then resumed, and resulted in a significant mean increase in irritant intensity consistent with stimulus-induced recovery (SIR).

Adolescent↗

PubMed2000

Menthol desensitization of capsaicin irritation. Evidence of a short-term anti-nociceptive effect.

Evidence is presented of a short-term antinociceptive effect of menthol that was discovered in the course of investigating menthol's potential to sensitize the mouth to capsaicin. Previous research had shown that treating the tongue with menthol 15 min before exposure to capsaicin could enhance the irritancy of capsaicin, and we wished to learn if this effect would increase as the time between exposure to menthol and capsaicin decreased. We found instead that when capsaicin followed menthol by only 3.5 min, or when it was presented in mixture with menthol for 2-3 min, sensory irritation was reduced rather than enhanced. We examined the duration of this apparent crossdesensitization in a second experiment by varying the delay between exposure to menthol and a block of three consecutive capsaicin stimuli. Cross-desensitization tended to decline as the interstimulus interval (ISI) increased to 5 min, and even when desensitization was maximal, it was significant only for the first of the three capsaicin stimuli. In the final experiment we investigated how menthol self- and cross-desensitization can influence the perception of menthol-capsaicin mixtures. During a series of five, 90-s stimulations, self- and cross-desensitization became evident at the beginning of the second exposure, but the effect on mixture intensity again diminished rapidly as stimulation continued. We infer from these results that method can transiently desensitize capsaicin-sensitive fibers, but that exposure to capsaicin rapidly overrides the effect. The implications these findings have for menthol's potential as a topical analgesic are discussed.

Administration, Topical↗

PubMedDate not supplied

Estimation of menthol in Pan Masala samples by a spectrophotometric method.

Recently, the Prevention of Food Adulteration Act of India has fixed the level of menthol addition to Pan Masala at 0.1%, therefore good manufacturing practice (GMP) should be adopted so that the samples do not exceed 0.1% menthol (1 mg/g). The estimation of menthol in Pan Masala samples involves steam distillation followed by reaction with p-dimethyl amino benzaldehyde (DMAB) in acidic medium to give a red colour which is read at 550 nm. The sensitivity of this procedure is 75 micrograms menthol per g sample. Using this method, 130 branded and 53 non-branded samples of Pan Masala were analysed for menthol content. Almost 25% of branded samples contained less than 1 mg menthol per g while 75% of samples contained 1.1-6.5 mg menthol per g Pan Masala. Non-branded Pan Masala contained 1 mg menthol per g in only 7.6% of samples. However, 92% of samples contained 1.1-6.5 mg menthol per g, suggesting that the addition of menthol is relatively higher in non-branded Pan Masala samples than in branded ones.

Areca↗

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↗

PubMed2004

Menthol-induced Ca2+ release from presynaptic Ca2+ stores potentiates sensory synaptic transmission.

Menthol and many of its derivatives produce profound sensory and mental effects. The receptor for menthol has been cloned and named cold- and menthol-sensitive receptor-1 (CMR1) or transient receptor potential channel M8 (TRPM8) receptor. Using a dorsal root ganglion (DRG) and dorsal horn (DH) coculture system as a model for the first sensory synapse in the CNS, we studied menthol effects on sensory synaptic transmission and the underlying mechanisms. We found that menthol increased the frequency of miniature EPSCs (mEPSCs). The effects persisted under an extracellular Ca2+-free condition but were abolished by intracellular BAPTA and pretreatment with thapsigargin. Menthol-induced increases of mEPSC frequency were blocked by 2-aminoethoxydiphenylborane (2-APB) but not affected by the phospholipase C inhibitor U73122 [GenBank] or by the cADP receptor inhibitor 8-bromo-cADPR (8Br-cADPR). Double-patch recordings from DRG-DH pairs showed that menthol could potentiate evoked EPSCs (eEPSCs) and change the paired-pulse ratio of eEPSCs. A Ca2+ imaging study on DRG neurons demonstrated that menthol could directly release Ca2+ from intracellular Ca2+ stores. Menthol-induced Ca2+ release was abolished by 2-APB but not affected by U73122 [GenBank] or 8Br-cADPR. Taken together, our results indicate that menthol can act directly on presynaptic Ca2+ stores of sensory neurons to release Ca2+, resulting in a facilitation of glutamate release and a modulation of neuronal transmission at sensory synapses. Expression of TRPM8 receptor on presynaptic Ca2+ stores, a novel localization for this ligand-gated ion channel, is also strongly suggested.

Animals↗

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↗