An orexinergic circuit driving migraine relief by lavender essential oil.

Pharmacological interventions can reduce immediate headache, but long-term effectiveness and suitability for chronic migraine remain limited. Although aromatherapy with lavender essential oil (LEO) reportedly alleviates headaches, the neural mechanisms remain uncertain. Here, we found that LEO inhalation exerts antinociceptive effects by activating orexinergic neurons in the lateral hypothalamus (LHOX) of mice with nitroglycerin-induced chronic migraine. Viral tracing, in vivo fiber photometry, and behavior assays revealed that LEO activates glutamatergic inputs from the anterior olfactory nucleus (AONGlu) to LHOX neurons, which subsequently inhibit the lateral parabrachial nucleus expressing calcitonin gene-related protein (LPBNCGRP) by activating local GABAergic neurons in LPBN (LPBNGABA) through orexin receptor type 2 (OX2R) signaling, ultimately alleviating chronic migraine-like behaviors. Chemogenetic activation of the AONGlu→LHOX→LPBNGABA→CGRP circuit mimics LEO-induced antinociception, while its inhibition or pharmacological OX2R blockade abolishes this effect in migraine mouse models. This study thus uncovers an orexinergic mechanism underlying the antinociceptive effects of LEO.