Menthol shares general anesthetic activity and sites of action on the GABA(A) receptor with the intravenous agent, propofol.

Menthol and related compounds were investigated for modulation of recombinant human gamma-aminobutyric acid type A (GABA(A), alpha(1)beta(2)gamma(2s)) receptor currents expressed in Xenopus oocytes. Sub-maximal (EC(20)) GABA currents were typically enhanced by co-applications of 3-300 microM (+)-menthol (e.g. by approximately 2-fold at 50 microM) > isopulegol > isomenthol> alpha-terpineol >> cyclohexanol. We studied menthol's actions on GABA(A) receptors compared to sedatives (benzodiazepines) and intravenous anesthetics (barbiturates, steroids, etomidate and propofol). Flumazenil (a benzodiazepine antagonist) did not inhibit menthol enhancements while currents directly activated by 50 microM propofol were significantly inhibited (by 26+/-3%) by 50 microM (+)-menthol. GABA(A) receptors containing beta(2) subunits with either a point mutation in a methionine residue to a tryptophan at the 286 position (in transmembrane domain 3, TM-3) or a tyrosine to a tryptophan at the 444 position (TM-4) are insensitive to modulation by propofol. Enhancements of GABA EC(20) currents by menthol were equally abolished in GABA(A) alpha(1)beta(2)(M286W)gamma(2s) and alpha(1)beta(2)(Y444W)gamma(2s) receptors while positive modulations by benzodiazepines, barbiturates and steroids were unaffected. Menthol may therefore exert its actions on GABA(A) receptors via sites distinct from benzodiazepines, steroids and barbiturates, and via sites important for modulation by propofol. Finally, using an in vivo tadpole assay, addition of (+)-menthol resulted in a loss of righting reflex with an EC(50) of 23.5+/-4.7 microM (approximately10-fold less potent anesthesia than propofol). Thus, menthol and analogs share general anesthetic action with propofol, possibly via action at similar sites on the GABA(A) receptor.

[1]  E. Clercq.  2001 ASPET Otto Krayer Award Lecture. Molecular targets for antiviral agents. , 2001 .

[2]  Hiroyasu Ito,et al.  Ambulation-promoting effect of peppermint oil and identification of its active constituents , 2001, Pharmacology Biochemistry and Behavior.

[3]  C. Ghelardini,et al.  Local Anaesthetic Activity of (+)- and (-)-Menthol , 2001, Planta medica.

[4]  R. Mckernan,et al.  Which GABAA-receptor subtypes really occur in the brain? , 1996, Trends in Neurosciences.

[5]  C. Ghelardini,et al.  Menthol: a natural analgesic compound , 2002, Neuroscience Letters.

[6]  J. Casida,et al.  Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Mohammadi,et al.  Structural requirements of phenol derivatives for direct activation of chloride currents via GABA(A) receptors. , 2001, European journal of pharmacology.

[8]  J. Carstensen,et al.  Short term toxicity study in rats dosed with pulegone and menthol. , 1983, Toxicology letters.

[9]  R. Eccles.  Role of cold receptors and menthol in thirst, the drive to breathe and arousal , 2000, Appetite.

[10]  G. Johnston,et al.  (+)- And (−)-borneol: efficacious positive modulators of GABA action at human recombinant α1β2γ2L GABAA receptors , 2005 .

[11]  N L Harrison,et al.  Propofol and other intravenous anesthetics have sites of action on the gamma-aminobutyric acid type A receptor distinct from that for isoflurane. , 1998, Molecular pharmacology.

[12]  W. R. Lieb,et al.  Molecular and cellular mechanisms of general anaesthesia , 1994, Nature.

[13]  D. Sattelle,et al.  Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABAA receptors and a homo‐oligomeric GABA receptor from Drosophila melanogaster , 2003, British journal of pharmacology.

[14]  E A Barnard,et al.  International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. , 1998, Pharmacological reviews.

[15]  A. Hall,et al.  Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids. , 2004, European journal of pharmacology.

[16]  J. Gu,et al.  Menthol-Induced Ca2+ Release from Presynaptic Ca2+ Stores Potentiates Sensory Synaptic Transmission , 2004, The Journal of Neuroscience.

[17]  H. Aoshima,et al.  Potentiation of GABAA receptors expressed in Xenopus oocytes by perfume and phytoncid. , 1999, Bioscience, biotechnology, and biochemistry.

[18]  T. Hales,et al.  The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones , 1991, British journal of pharmacology.

[19]  N. Harrison,et al.  General anaesthetic actions on ligand-gated ion channels , 1999, Cellular and Molecular Life Sciences CMLS.

[20]  Kyong-Tai Kim,et al.  Inhibition of acetylcholine-mediated effects by borneol. , 2003, Biochemical pharmacology.

[21]  A. Jenkins,et al.  A Conserved Tyrosine in the β2 Subunit M4 Segment Is a Determinant of γ-Aminobutyric Acid Type A Receptor Sensitivity to Propofol , 2007 .

[22]  N. Harrison,et al.  Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics , 2001, Neuropharmacology.

[23]  P. Tonner,et al.  Inhibition of Nitric Oxide Synthase Decreases Anesthetic Requirements of Intravenous Anesthetics in Xenopus laevis , 1997, Anesthesiology.

[24]  H. Downes,et al.  Contrasting effects of anesthetics in tadpole bioassays. , 1996, The Journal of pharmacology and experimental therapeutics.

[25]  R. Dengler,et al.  Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. , 2002, European journal of anaesthesiology.

[26]  J. Faber,et al.  Normal table of Xenopus laevis (Daudin). A systematical and chronological survey of the development from the fertilized egg till the end of metamorphosis. , 1956 .

[27]  The Effects of Isoflurane on Desensitized Wild-Type and &agr;1(S270H) γ-Aminobutyric Acid Type A Receptors , 2004 .

[28]  T. Park,et al.  Noncompetitive inhibition by camphor of nicotinic acetylcholine receptors. , 2001, Biochemical pharmacology.

[29]  Andrew Jenkins,et al.  Additive Effects of Sevoflurane and Propofol on &ggr;-Aminobutyric Acid Receptor Function , 2006, Anesthesiology.

[30]  A. Jenkins,et al.  Stereoselective Effects of Etomidate Optical Isomers on Gamma‐aminobutyric Acid Type A Receptors and Animals , 1998, Anesthesiology.

[31]  E. Overton.  Studien über die Narkose : zugleich ein Beitrag zur allgemeinen Pharmakologie , 1901 .

[32]  Waud Dr.  ON BIOLOGICAL ASSAYS INVOLVING QUANTAL RESPONSES , 1972 .

[33]  W. Sieghart,et al.  A novel positive allosteric modulator of the GABAA receptor: the action of (+)‐ROD188 , 2000, British journal of pharmacology.

[34]  D. McKemy,et al.  Identification of a cold receptor reveals a general role for TRP channels in thermosensation , 2002, Nature.

[35]  N L Harrison,et al.  General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility. , 2001, The Journal of pharmacology and experimental therapeutics.

[36]  A J Hopfinger,et al.  4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor. , 2002, Journal of medicinal chemistry.