Dexmedetomidine Rapidly Relieves Stress-Induced Hyperalgesia via Presynaptic α2-Adrenergic Inhibition at Orbitofrontal–Insular Glutamatergic Synapses

Abstract

Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, is widely used for its antihyperalgesic effects in perioperative pain management, yet its underlying mechanisms remain largely undefined. Here, we identify a rapid, circuit-specific mechanism by which Dex reverses stress-induced hyperalgesia (SIH) in mice. Stress exposure strengthens excitatory drive from the orbitofrontal cortex (OFC) to the anterior insula cortex (AIC), shifting the excitatory/inhibitory balance toward excitation and increasing the intrinsic excitability of AIC glutamatergic neurons. Viral tracing and optogenetics reveal a direct OFC–AIC glutamatergic projection. Optogenetic or chemogenetic activation of this pathway in otherwise naïve mice potentiates glutamatergic synaptic transmission and is sufficient to induce hyperalgesia, phenotyping SIH. Dex rapidly suppresses these effects by engaging presynaptic α2-ARs on OFC terminals, thereby reducing transmitter release at OFC–AIC synapses. Consistently, chemogenetic silencing of AIC neurons or of the OFC–AIC projection alleviates hyperalgesia in SIH mice. These findings define the OFC–AIC glutamatergic circuit as a key substrate for stress-related pain amplification and uncover a rapid presynaptic α2-AR “brake” as the mechanism underlying Dex's antihyperalgesic action, highlighting a tractable therapeutic entry point for stress-exacerbated pain states.

Keywords

anterior insula cortex / dexmedetomidine / hyperalgesia / orbitofrontal cortex / plasticity / stress

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