Menthol shares general anesthetic activity and sites of action on the GABAA receptor with the intravenous agent, propofol

Watt, Erin E.; Betts, Brooke A.; Kotey, Francesca O.; Humbert, Danielle J.; Griffith, Theanne N.; Kelly, Elizabeth; Veneskey, Kelley C.; Gill, Nikhila; Rowan, Kathleen C.; Jenkins, Andrew; Hall, Alex R.

doi:10.1016/j.ejphar.2008.06.003

Cited by 82 publications

(96 citation statements)

References 29 publications

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“…We found that menthol induced Cl Ϫ -mediated currents, which was blocked by bicuculline, a GABA A receptor antagonist, indicating that menthol directly activates GABA A receptors. This finding is consistent with results from previous studies implicating menthol as a GABA A receptor modulator (Watt et al, 2008;Zhang et al, 2008).…”

Section: Discussionsupporting

confidence: 83%

Central Mechanisms of Menthol-Induced Analgesia

Rong

Tian

Gao

et al. 2012

J Pharmacol Exp Ther

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Menthol is one of the most commonly used chemicals in our daily life, not only because of its fresh flavor and cooling feeling but also because of its medical benefit. Previous studies have suggested that menthol produces analgesic action in acute and neuropathic pain through peripheral mechanisms. However, the central actions and mechanisms of menthol remain unclear. Here, we report that menthol has direct effects on the spinal cord. Menthol decreased both ipsilateral and contralateral pain hypersensitivity induced by complete Freund's adjuvant in a dose-dependent manner. Menthol also reduced both first and second phases of formalin-induced spontaneous nocifensive behavior. We then identified the potential central mechanisms underlying the analgesic effect of menthol. In cultured dorsal horn neurons, menthol induced inward and outward currents in a dose-dependent manner. The menthol-activated current was mediated by Cl Ϫ and blocked by bicuculline, suggesting that menthol activates ␥-aminobutyric acid type A receptors. In addition, menthol blocked voltage-gated sodium channels and voltage-gated calcium channels in a voltage-, state-, and usedependent manner. Furthermore, menthol reduced repetitive firing and action potential amplitude, decreased neuronal excitability, and blocked spontaneous synaptic transmission of cultured superficial dorsal horn neurons. Liquid chromatography/tandem mass spectrometry analysis of brain menthol levels indicated that menthol was rapidly concentrated in the brain when administered systemically. Our results indicate that menthol produces its central analgesic action on inflammatory pain probably via the blockage of voltage-gated Na ϩ and Ca 2ϩ channels. These data provide molecular and cellular mechanisms by which menthol decreases neuronal excitability, therefore contributing to menthol-induced central analgesia.

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Section: Discussionsupporting

confidence: 83%

Central Mechanisms of Menthol-Induced Analgesia

Rong

Tian

Gao

et al. 2012

J Pharmacol Exp Ther

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“…The two types, dand l-menthol are with respect to local anesthetic activity [25]. D-menthol was a moderately potent anesthetic [21], whereas only l-menthol induced analgesia in mice [25]. In the present experiment, both types of menthol induced surgical anesthesia with no difference in percentages of responses, latency, or recovery time at different concentrations.…”

Section: Discussionmentioning

confidence: 55%

“…In addition, menthol is known to be a potent positive modulator of the -aminobutyric acid type A (GABA A ) receptor [20] and acts as a potent positive allosteric modulator of GABA A receptors via sites similar to propofol, an intravenous anesthetic agent [21]. These finding suggest a possibility that menthol has an anesthetic effect on fish as well as sea cucumber and prawns [3,4].…”

Section: Introductionmentioning

confidence: 83%

Menthol Induces Surgical Anesthesia and Rapid Movement in Fishes

Kasai¹,

Hososhima²,

Yun-Fei³

2014

TONEURJ

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Abstract:To determine whether fishes respond to menthol, Japanese medaka Oryzias latipes, goldfish Carassius auratus, and zebrafish Danio rerio were exposed to various types of menthol receptors agonists and the behavioral responses to these drugs were observed. Waterbone application of dl-menthol (0.5 mM) induced surgical anesthesia in 100% of medaka, 90% of goldfish, and 100% of zebrafish. The percentage of response increased dose-dependently from 0.2 mM to 0.5 mM. There were no differences in either percentage or latency of the response in surgical anesthesia among dl-, d-, and l-types of menthol. A high (3.0 mM) concentration of any of the three types of menthol induced rapid movement followed by the anesthetic response. Rapid movement was observed with allyl isothiocyanate, a cold nociceptor agonist, but not with icilin, a cold receptor agonist, in medaka and goldfish. Both allyl isothiocyanate and icilin failed to induce surgical anesthesia. To determine the involvement of -aminobutyric acid (GABA) system in menthol-induced surgical anesthesia, the effect of the receptors antagonist for the GABA A was tested. Pretreatment with a specific GABA A receptor antagonist prolonged the latency of the anesthetic response to menthol, but not to cold-water stimulation, in medaka and goldfish. These results demonstrate that menthol can play a role in the induction of surgical anesthesia in fishes, related at least in part to the activation of GABA A receptors, and of rapid movement possibly via cold nociceptors.

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“…13 Brain tissue contains quite a lot of GABA A receptors, mainly in the cerebral cortex, thalamus and hippocampus, but even in the striatum, caudal nucleus and cerebellum. 14 The results of the present study, indicate that regions showing decreased cerebral glucose metabolism correlate with those areas that are known to have the most GABA A receptors.…”

Section: Discussionmentioning

confidence: 99%

Imaging the Effects of Propofol on Human Cerebral Glucose Metabolism Using Positron Emission Tomography

et al. 2008

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The effects of propofol on glucose metabolism in different cerebral regions were observed, using positron emission tomography (PET) technology, to determine a possible cerebral target region. Seven healthy volunteers were injected with 18 F-fluorodeoxyglucose developing agent for PET scanning whilst awake (control group T1), during sedation (induced by 1.5 µg/ml propofol administered by target controlled injection [TCI], group T2) and when unconsciousness (induced by 2.5 µg/ml propofol administered by TCI, group T3). Whole brain glucose metabolism was reduced during propofol anaesthesia; this was initially observed in the cortical areas at the lower dose of propofol (group T2) but extended to the subcortical regions, especially the thalamus and hippocampus, at the higher dose (group T3). This suggests that these regions of the brain might be important targets that are susceptible to propofol.

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Menthol shares general anesthetic activity and sites of action on the GABAA receptor with the intravenous agent, propofol

Cited by 82 publications

References 29 publications

Central Mechanisms of Menthol-Induced Analgesia

Central Mechanisms of Menthol-Induced Analgesia

Menthol Induces Surgical Anesthesia and Rapid Movement in Fishes

Imaging the Effects of Propofol on Human Cerebral Glucose Metabolism Using Positron Emission Tomography

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