Social Exclusion Amplifies Behavioral Responses to Physical Pain via Insular Neuromodulation

The "Pain Overlap Theory"¹ proposes that the experience of social pain overlaps with and amplifies the experience of physical pain by sharing parts of the same underlying processing systems ^2-6. In humans, the insular cortex has been implicated in this overlap of physical and social pain, but a mechanistic link has not been made^2,4,5,7-9. To determine whether social pain can subsequently impact responses to nociceptive stimuli via convergent electrical signals (spikes) or convergent chemical signals (neuromodulators), we designed a novel Social Exclusion paradigm termed the Fear of Missing Out (FOMO) Task which facilitates a mechanistic investigation in mice. We found that socially-excluded mice display more severe responses to physical pain, disrupted valence encoding, and impaired neural representations of nociceptive stimuli. We performed a systematic biosensor panel and found that endocannabinoid and oxytocin signaling in the insular cortex have opposing responses during trials where mice were attending or not attending to the Social Exclusion events respectively, demonstrating distinct neuromodulatory substrates underpin different states of Social Exclusion. We also found that intra-insular blockade of oxytocin signaling increased the impact of Social Exclusion on physical pain. Together these findings suggest Social Exclusion effectively alters physical pain perception using neuromodulatory signaling in the insular cortex.