Modulation of pain sensitivity by the locus coeruleus-paraventricular thalamic nucleus-anterior cingulate cortex pathway in mice.

Summary

Using Fos-TRAP labeling, viral tracing, and opto/chemogenetics, the study delineates a hierarchical LC–PVA–ACC thalamocortical relay that preferentially drives nociceptive sensitization over direct LC–ACC projections. Activation of LC–PVA–ACC increased ACC firing and tactile responses and more robustly modulated mechanical/thermal sensitivity.

Key Findings

• Identified monosynaptic LC–ACC and polysynaptic LC–PVA–ACC circuits; nociception-related LC neurons preferentially projected to PVA.
• Under inflammatory pain, LC–PVA–ACC activation evoked higher ACC firing and tactile-evoked responses versus direct LC–ACC activation (P < 0.001).
• Opto/chemogenetic manipulation of LC–PVA–ACC more strongly modulated mechanical and thermal pain sensitivity than LC–ACC.

Clinical Implications

While preclinical, the LC–PVA–ACC circuit suggests translational opportunities for selective neuromodulation or pharmacologic targeting of thalamocortical noradrenergic signaling to treat hyperalgesia and chronic pain.

Limitations

• Animal model; human translatability remains to be demonstrated
• Focus on inflammatory pain; generalization to neuropathic or other pain states requires study

Future Directions

Map molecular determinants within the LC–PVA–ACC relay and test targeted neuromodulation/pharmacology in translational models; validate biomarkers of thalamocortical noradrenergic activity in humans.