α-Pinene, a Major Constituent of Pine Tree Oils, Enhances Non-Rapid Eye Movement Sleep in Mice through GABA_A-benzodiazepine Receptors

Abstract

α-Pinene is a major monoterpene of the pine tree essential oils. It has been reported that α-pinene shows anxiolytic and hypnotic effects upon inhaled administration. However, hypnotic effect by oral supplementation and the molecular mechanism of α-pinene have not been determined yet. By combining in vivo sleep behavior, ex vivo electrophysiological recording from brain slices, and in silico molecular modeling, we demonstrate that (-)-α-pinene shows sleep enhancing property through a direct binding to GABA-benzodiazepine (BZD) receptors by acting as a partial modulator at the BZD binding site. The effect of (-)-α-pinene on sleep-wake profiles was evaluated by recording electroencephalogram and electromyogram. The molecular mechanism of (-)-α-pinene was investigated by electrophysiology and molecular docking study. (-)-α-pinene significantly increased the duration of non-rapid eye movement sleep (NREMS) and reduced the sleep latency by oral administration without affecting duration of rapid eye movement sleep and delta activity. (-)-α-pinene potentiated the GABA receptor-mediated synaptic response by increasing the decay time constant of sIPSCs in hippocampal CA1 pyramidal neurons. These effects of (-)-α-pinene on sleep and inhibitory synaptic response were mimicked by zolpidem, acting as a modulator for GABA-BZD receptors, and fully antagonized by flumazenil, an antagonist for GABA-BZD receptor. (-)-α-pinene was found to bind to aromatic residues of α1- and -γ2 subunits of GABA-BZD receptors in the molecular model. We conclude that (-)-α-pinene enhances the quantity of NREMS without affecting the intensity of NREMS by prolonging GABAergic synaptic transmission, acting as a partial modulator of GABA-BZD receptors and directly binding to the BZD binding site of GABA receptor.

The effect of central administration of alpha‐pinene on capsaicin‐induced dental pulp nociception

“…), has a specific binding site on aromatic residues of α1‐ and γ2‐subunits of GABA A ‐benzodiazepine receptors (Yang et al . ). Furthermore, the authors revealed that oral administration of α‐pinene enhanced the duration of nonrapid eye movement sleep, predominantly via the activation of GABA A receptors.…”

“…Moreover, it has been reported that α‐pinene induces hypnotic activity via interaction with GABA A receptors (Yang et al . ).…”

Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases

“…In addition, α-pinene was shown to induce cell cycle arrest and anti-tumor activity by controlling miR-221 [123], expending their functions on microRNA regulation. Moreover, 3-carene as well as α-pinene were shown to function as positive modulators for benzodiazepine (BZD)-receptors, exerting a sleep-enhancing effect upon oral administration [122,124], supporting the beneficial effects of forest bathing for patients with sleep disorders or anxiety.…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…Alpha-pinene is considered a natural compound present not only in Cannabis sativa but also in essential oils of many aromatic plants, such as Lavender angustifolia, Rosmarinus officinalis, and coniferous trees [149]. Alpha-pinene is a bicyclo[3.1.1]hept-2-ene that contains a reactive 4-membered ring structure and exhibits antioxidant, antimicrobial, anti-tumor, hypnotic, and anxiolytic activities [83,120,[150][151][152]. There are different biological properties described to α-pinene, as well as essential oils containing this compound have been used to treat several diseases [153], although no affinity towards CBRs have been described [154].…”

“…Alpha-pinene has been extensively investigated in the last years for its medicinal properties that include sedative, hypnotic, and anxiolytic [152,155]. In this context, Yang and colleagues demonstrated that α-pinene interacts with GABA A /benzodiazepine receptors prolonging its synaptic transmission, significantly increasing the duration of non-rapid eye movement sleep (NREMS), and reducing sleep latency [151]. The beneficial effects of α-pinene are also extended to convulsions [80,81], ischemic stroke [82], and schizophrenia [156].…”