Authors: Kuai S et al.
Anesthesiology. December 2025. DOI: 10.1097/ALN.0000000000005897
Summary
This preclinical study investigated how noradrenergic signaling from the locus coeruleus (LC) modulates pain sensitivity through interactions with the paraventricular thalamic nucleus (PVA) and the anterior cingulate cortex (ACC). While LC projections to both the thalamus and cortex have been implicated in pain processing, the hierarchical organization and functional relevance of these pathways had not been fully defined.
Using a mouse model of inflammatory pain induced by complete Freund’s adjuvant, the authors combined activity-dependent neuronal labeling (Fos-TRAP), in vivo electrophysiology, viral tracing, and optogenetic and chemogenetic manipulations to map and interrogate LC-centered pain circuits. Inflammatory pain was associated with marked increases in neuronal activation across the LC, PVA, and ACC, reflected by elevated c-Fos expression, enhanced gamma-band oscillations, and increased single-unit firing rates.
Circuit mapping revealed both a direct monosynaptic LC–ACC projection and an indirect polysynaptic LC–PVA–ACC pathway. Critically, LC neurons activated by nociceptive stimuli preferentially projected to the PVA, which in turn targeted hyperactive ACC neurons. Under inflammatory pain conditions, activation of the LC–PVA–ACC pathway produced significantly greater ACC firing and tactile-evoked responses than direct LC–ACC stimulation. Behavioral experiments were concordant with these electrophysiologic findings: selective manipulation of the LC–PVA–ACC circuit resulted in stronger modulation of both mechanical and thermal pain sensitivity compared with manipulation of the direct LC–ACC pathway.
These results support a hierarchical model in which LC-derived norepinephrine regulates nociceptive sensitization primarily through a thalamocortical relay involving the PVA, rather than through direct cortical innervation alone. The findings provide mechanistic insight into how central noradrenergic systems shape pain perception and may inform future neuromodulatory or pharmacologic strategies targeting chronic pain.
Key Points
Inflammatory pain activates LC, PVA, and ACC neurons and increases cortical excitability.
LC neurons involved in nociception preferentially project to the PVA rather than directly to the ACC.
The LC–PVA–ACC pathway exerts stronger effects on ACC activity and pain sensitivity than the direct LC–ACC pathway.
Thalamocortical relays play a critical role in noradrenergic modulation of nociceptive sensitization.
These findings clarify the circuit-level organization of LC-mediated pain control.
Thank you for allowing us to review and summarize this important mechanistic study from Anesthesiology.