GABA- and Glycine-Mimetic Responses of Linalool on the Substantia Gelatinosa of the Trigeminal Subnucleus Caudalis in Juvenile Mice: Pain Management through Linalool-Mediated Inhibitory Neurotransmission

Abstract

Linalool, a major odorous constituent in essential oils extracted from lavender, is known to have a wide range of physiological effects on humans including pain management. The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) is involved in transmission of orofacial nociceptive responses through thin myelinated A[Formula: see text] and unmyelinated C primary afferent fibers. Up to date, the orofacial antinociceptive mechanism of linalool concerning SG neurons of the Vc has not been completely clarified yet. To fill this knowledge gap, whole-cell patch-clamp technique was used in this study to examine how linalool acted on SG neurons of the Vc in mice. Under a high chloride pipette solution, non-desensitizing and repeatable linalool-induced inward currents were preserved in the presence of tetrodotoxin (a voltage-gated Na[Formula: see text]channel blocker), CNQX (a non-NMDA glutamate receptor antagonist), and DL-AP5 (an NMDA receptor antagonist). However, linalool-induced inward currents were partially suppressed by picrotoxin (a GABA[Formula: see text] receptor antagonist) or strychnine (a glycine receptor antagonist). These responses were almost blocked in the presence of picrotoxin and strychnine. It was also found that linalool exhibited potentiation with GABA- and glycine-induced responses. Taken together, these data show that linalool has GABA- and glycine-mimetic effects, suggesting that it can be a promising target molecule for orofacial pain management by activating inhibitory neurotransmission in the SG area of the Vc.

Linalool: Therapeutic Indication And Their Multifaceted Biomedical Applications

“…Moreover, linalool increased reactions to glycine and GABA. These results imply that linalool functions similarly to glycine and GABA, suggesting that it could be a viable target for the treatment of orofacial pain by boosting inhibitory neuronal transmission in the substantia gelatinosa of the trigeminal subnucleus caudalis [33].…”

Naringenin modulates GABA mediated response in a sexdependent manner in substantia gelatinosa neurons of trigeminal subnucleus caudalis in immature mice

“…In addition, radioligand binding assay reveals that substances like (S) naringenin, glabrol, and 8-lavandulyl- flavanones act on the GABA receptors’ benzodiazepine site [ 50 ]. Besides flavonoid naringenin, essential oil linalool [ 51 ], terpene borneol [ 52 ], and biphenyl honokiol [ 53 ] possess the potential to influence the GABA receptor-mediated action on SG neurons of Vc. Notably, 6-hydroxyflavone, a flavone, shows diverse responses towards GABA, acting as a subtype-selective partial positive allosteric modulator at the flumazenil-sensitive benzodiazepine site and flumazenil-sensitive partial inverse agonist or negative modulator at α1β3γ2, α2β3γ2, and α5β3γ2 but not at α3β3γ2 receptor subunits [ 8 ].…”

Improvement in Skin Penetration Capacity of Linalool by Using Microemulsion as a Delivery Carrier: Formulation Optimization and In Vitro Evaluation

“…Previous studies have reported that linalool has a wide range of physiological effects on humans including an anti-psoriatic effect, protects against the oxidative damage of UVB radiation of human skin cells by modulated NF-κB signaling and MAPK in HDFa cells, induces apoptosis in human leukemia cells, possesses sedative, anxiolytic and anticonvulsant proprieties by modulating the glutamate and GABA neurotransmitter systems, controls pain by potentiation with GABA- and glycine-induced responses and alleviates the side effects as well as tolerance to opioids (morphine) [ 2 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Unfortunately, its application is limited due to its lipophilicity (1590 mg/L in water at 25 °C), poor oral bioavailability and short half-life (about 44.72 min) [ 13 ].…”