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

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.