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 Zn 2+ (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.