Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons.

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 GABA_A receptors. Here, we examined the actions of menthol on GABA_A 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 GABA_A receptor-mediated phasic IPSCs and tonic currents. Key Results Menthol (150-750 μM) produced a concentration-dependent prolongation of spontaneous GABA_A 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 GABA_A receptor antagonists, picrotoxin (100 μM), bicuculline (30 μM) and Zn²⁺ (100 μM), but unaffected by gabazine (10 μM) and a GABA_C receptor antagonist, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA; 50 μM). In addition, menthol potentiated currents induced by the extrasynaptic GABA_A receptor agonist THIP/gaboxadol (10 μM). Conclusions and Implications These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABA_A receptors in native PAG neurons. The development of agents that potentiate GABA_A-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABA_A-related pharmacotherapies. [ABSTRACT FROM AUTHOR]