Menthol enhances phasic and tonic GABA_A 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.