DIVERGENT ROLES OF LOCUS COERULEUS IN PAIN MODULATION AND PUPILLARY DYNAMICS

The locus coeruleus (LC), a brainstem nucleus rich in noradrenergic neurons, plays a crucial role in modulating pain and arousal states. It contributes to the processing of nociceptive information and regulates pupil size via its widespread projections. However, the LC is increasingly recognized as a functionally heterogeneous structure, with distinct subpopulations of neurons capable of divergent influences on sensory and affective states.
This study investigated the contribution of the LC to nociceptive processing and pupil dynamics, aiming to assess the utility of pupillometry as a translational biomarker of pain modulation. Adult male and female TH-Cre transgenic mice underwent chemogenetic manipulation of LC neurons using excitatory or inhibitory DREADDs. Animals were subjected to chronic constriction injury (CCI) of the sciatic nerve and evaluated at early (CCI-ST) and late (CCI-LT) stages of neuropathy. Pupil diameter was recorded at rest and during mechanical hindpaw stimulation. Complementary behavioral assays (von Frey, acetone, and hot plate) assessed pain sensitivity.
Activation of LC neurons in Sham and CCI-ST animals increased baseline pupil diameter and enhanced evoked pupillary responses, coinciding with reduced nociceptive sensitivity in both sexes. Conversely, LC inhibition in CCI-LT animals reduced pupil reactivity, particularly in females, and was associated with analgesia.
These findings support a bidirectional role of LC activity in pain modulation, reflected in pupil dynamics. The results suggest that time-dependent changes in LC function following neuropathic injury may underlie stage- and sex-specific effects on nociceptive and autonomic responses, highlighting the importance of timing in targeting LC-driven pain modulation strategies.