Linalool inhalation in mice leads to brain accumulation and metabolite-driven neuronal activation

Multiple chemical sensitivity is a disorder characterized by a range of adverse health symptoms occurring after exposure to various environmental chemicals, yet its underlying mechanisms remain unclear. In particular, exposure to fragrance substances is difficult to avoid completely in daily life, and this issue is increasingly recognized as a public and social concern. In this study, we focused on linalool, a typical fragrance, and examined its direct effects on the brain rather than on olfactory perception. Inhalation exposure to linalool resulted in its detection in the mouse brain along with the metabolites, cis- and trans-furanoid linalool oxide. These findings suggest that linalool can be transferred to the brain and metabolized into its oxidized form. Investigations involving various human cytochrome P450 proteins indicated that CYP3A4 is highly active in producing linalool oxide from linalool. Inhalation exposure to linalool also led to an increase in heart rate. We further demonstrated that linalool oxide, but not linalool, directly activated neurons in the amygdala of the mouse brain, an area associated with negative emotions. These results indicate that linalool may act directly on the nervous system independently of the mediation of olfactory information.