Kappa opioid receptor availability correlates with depressive symptom burden in chronic migraine: a preliminary...

Chronic pain is frequently accompanied by affective disturbances, yet the neurobiological mechanisms linking pain perception and affective vulnerability remain poorly understood. The kappa opioid receptor (KOR)/dynorphin system has emerged as a key modulator of nociceptive and affective processes, in part through regulation of dopamine signaling within mesocorticolimbic circuits. However, the role of KOR signaling to pain-related affect and functional integration in migraine has not been characterized.

We measured KOR availability using positron emission tomography (PET) with [¹¹C]LY2795050, a selective KOR antagonist radioligand in 12 individuals with chronic migraine (CM; 11 F/1 M; 42.0 ± 15.1 years) and 11 healthy controls (HC; 9 F/2 M; 40.9 ± 17.0 years). PET scans included an early resting and late sustained thermal pain stimulus stress (STPTS) phase, with KOR availability quantified as non-displaceable binding potential (BP_ND). Group differences in KOR BP_ND were assessed using region-of-interest (ROI) and voxel-wise analyses focusing on corticolimbic regions. Resting-state functional MRI (rs-fMRI) was additionally acquired to explore ROI-to-ROI functional connectivity (rsFC) within predefined regions. Exploratory interaction analyses examined whether group moderated the relationship between KOR BP_ND and rsFC strength. Associations between KOR BP_ND and clinical measures of pain intensity and affective symptoms were assessed using Spearman's rho correlation.

Compared with HC, individuals with CM showed significantly elevated KOR BP_ND in the left anterior insula and lateral orbitofrontal cortex, particularly during STPTS phase. Exploratory interaction analyses revealed a differential relationship between fronto-insular KOR BP_ND and rsFC between the anterior and posterior insula. In addition, higher fronto-insular KOR BP_ND was positively correlated with greater subclinical depressive symptom scores, which were predominantly in the minimal-to-mild range, in the CM group.

These findings indicate altered fronto-insular KOR availability in individuals with CM and suggest that KOR signaling may contribute to affective symptom burden, even at subclinical levels. The observed associations between KOR availability and rs-fMRI measures warrant cautious interpretation and further investigation in larger samples.