An Olfactory Piriform Cortex-Lateral Hypothalamus Neural Circuit Contributes to Linalool-Induced Analgesia

Aromatherapy-mediated analgesia is widely applied, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the neurobiological basis underlying linalool-induced attenuation of inflammatory pain.

A complete Freund's adjuvant (CFA)-induced hind-paw inflammatory pain model was used to evaluate the antinociceptive effects of linalool odor exposure through mechanical and thermal nociceptive threshold tests, together with conditioned place preference. Viral tracing, in vivo fiber photometry, electrophysiological recordings, and chemogenetic or optogenetic manipulations were employed to identify and functionally characterize the neural circuits underlying linalool-induced analgesia.

Linalool odor exposure increased mechanical and thermal nociceptive thresholds and induced pain relief-associated place preference in CFA mice. Linalool exposure activated orexin A-expressing neurons in the lateral hypothalamus (LH^{orexin A}) and LH-projecting glutamatergic neurons in the piriform cortex (Piri^Glu-LH). Electrophysiological recordings demonstrated functional excitatory monosynaptic connectivity from the Piri to the LH. Activation of LH-projecting Piri^Glu neurons produced analgesic effects in CFA mice, whereas inhibition of this pathway attenuated linalool-induced analgesia.

Our study identified an olfactory cortex-hypothalamic circuit contributing to linalool-induced antinociceptive effects, providing mechanistic insight into olfactory modulation of inflammatory pain.