Authors: Kuai S et al.
Journal: Anesthesiology, December 11, 2025. DOI: 10.1097/ALN.0000000000005897
Summary
This preclinical neurocircuitry study investigated how noradrenergic signaling from the locus coeruleus (LC) modulates pain sensitivity through distinct downstream pathways involving the paraventricular thalamic nucleus (PVA) and the anterior cingulate cortex (ACC). Although LC projections to both the thalamus and cortex are known to influence pain-related behaviors, their hierarchical organization and relative functional importance had not been clearly defined.
Using male and female mice with inflammatory pain induced by complete Freund’s adjuvant, the investigators combined activity-dependent neuronal labeling, in vivo electrophysiology, viral tracing, and optogenetic and chemogenetic manipulations. Inflammatory pain robustly increased neuronal activation in the LC, PVA, and ACC, accompanied by heightened gamma-band activity and firing rates. Circuit mapping revealed both a direct monosynaptic LC–ACC pathway and an indirect polysynaptic LC–PVA–ACC pathway.
Functionally, nociception-related LC neurons preferentially projected to the PVA, which in turn strongly excited hyperactive ACC neurons during pain states. Activation of the LC–PVA–ACC circuit produced greater ACC firing, stronger tactile-evoked responses, and more pronounced modulation of mechanical and thermal pain sensitivity than stimulation of the direct LC–ACC projection alone. Manipulation of this indirect pathway consistently exerted a stronger influence on nociceptive behaviors.
These findings identify the LC–PVA–ACC pathway as a hierarchical noradrenergic circuit that amplifies nociceptive sensitization through a thalamocortical relay. The study provides mechanistic insight into how LC-derived norepinephrine shapes pain perception at the circuit level and highlights thalamic gating as a key modulator of cortical pain processing.
Key Points
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Inflammatory pain activates LC, PVA, and ACC neurons with increased firing and gamma activity.
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The LC projects to the ACC both directly and indirectly via the PVA.
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Nociception-related LC neurons preferentially engage the LC–PVA–ACC pathway.
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Activation of the LC–PVA–ACC circuit produces stronger ACC excitation than direct LC–ACC signaling.
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Modulation of this circuit more effectively alters mechanical and thermal pain sensitivity.
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Thalamocortical relay through the PVA is a key amplifier of noradrenergic pain signaling.
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