Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors

Abstract

The a3b4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves. The nAChR subtype transduces the irritant effects of nicotine in tobacco smoke and, in certain brain areas, may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human a3b4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca 21 imaging, 86 Rb 1 efflux, and voltage-clamp measurements. Coapplication of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. These effects increased with agonist concentration. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Notably, menthol acted in a voltageindependent manner and reduced the mean open time of single channels without affecting their conductance, arguing against a simple channel-blocking effect. Further, menthol slowed or prevented the recovery of nAChRs from desensitization, indicating that it probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [ 3 H]epibatidine. Taken together, these data indicate that menthol promotes desensitization of a3b4 nAChRs by an allosteric action.

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats

“…Together with the negative results obtained from the test using a selective TRPM8 antagonist RQ-00203078, it is confident to conclude that the occasion-setting effect of menthol for nicotine seeking does not involve the classic menthol receptors, the TRPM8 ion channels (Peier et al, 2002) located at the peripheral sensory nerve terminals. In light of increasing evidence showing that menthol can exert its actionn on neurotransmitter receptors such as the nicotinic acetylcholine receptors, r-aminobutyric acid receptors, and serotonin receptors in the central nervous system (Ashoor et al, 2013a; Ashoor et al, 2013b; Lau et al, 2014; Ton et al, 2015), it is suggested that menthol may act directly at central neurotransmitter receptors in the present experimental preparation. Future studies are warranted to elucidate the central-mediated mechanisms via which menthol sustains nicotine-seeking behavior.…”

Little Cigars vs 3R4F Cigarette: Physical Properties and HPHC Yields

“…Menthol reduces the tobacco smoke’s harshness 59 and was found to inhibit nicotine metabolism which enhances nicotine delivery and increases exposure. 60,61 As these data are only from one little cigar, more work is needed to understand mentholation levels and nicotine delivery across a variety of mentholated little cigars.…”

Allosteric modulation of nicotinic acetylcholine receptors

“…These include psychoactive drugs such as mecamylamine and phencyclidine [105][106][107][108][109], philanthotoxin [110], general anaesthetics [111], antidepressants [112][113][114], monoterpines such as camphor, menthol and propofol [115][116][117][118][119], aminoglycoside antibiotics [120] antipsychotics [121], the fluorophore crystal violet [122]; zinc [99,123] and some detergents [124]. Several endogenous ligands have also been reported to have negative allosteric effects on nAChRs.…”