Menthol Enhances Phasic and Tonic GABAA Receptor-Mediated Currents in Midbrain Periqueductal Grey Neurons

Journal of Pharmacology DOI:10.1111/bph.12602

Benjamin K Lau1 *, Shafinaz Karim1,2*, Ann K Goodchild2 , Christopher W Vaughan1 and Geoffrey M Drew1 1 Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, Australia, and 2 Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW, Australia

Correspondence Dr Benjamin K Lau, Pain Management Research Institute, Level 13 Kolling Building, Kolling Institute of Medical Research, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia. E-mail:

*These authors contributed equally to this work.

Accepted 19 January 2014

BACKGROUND AND PURPOSE Menthol, a naturally occurring compound in the essential oil of mint leaves, is used for its medicinal, sensory and fragrant properties. Menthol acts via transient receptor potential (TRPM8 and TRPA1) channels and as a positive allosteric modulator of recombinant GABAA receptors. Here, we examined the actions of menthol on GABAA receptor-mediated currents in intact midbrain slices.

EXPERIMENTAL APPROACH Whole-cell voltage-clamp recordings were made from periaqueductal grey (PAG) neurons in midbrain slices from rats to determine the effects of menthol on GABAA receptor-mediated phasic IPSCs and tonic currents. KEY RESULTS Menthol (150–750 μM) produced a concentration-dependent prolongation of spontaneous GABAA receptor-mediated IPSCs, but not non-NMDA receptor-mediated EPSCs throughout the PAG. Menthol actions were unaffected by TRPM8 and TRPA1 antagonists, tetrodotoxin and the benzodiazepine antagonist, flumazenil. Menthol also enhanced a tonic current, which was sensitive to the GABAA receptor antagonists, picrotoxin (100 μM), bicuculline (30 μM) and Zn2+ (100 μM), but unaffected by gabazine (10 μM) and a GABAC receptor antagonist, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA; 50 μM). In addition, menthol potentiated currents induced by the extrasynaptic GABAA receptor agonist THIP/gaboxadol (10 μM).

CONCLUSIONS AND IMPLICATIONS These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies. Abbreviations CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; THIP, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride, gaboxadol; TPMPA, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate; TTX, tetrodotoxin BJP British