PROJECT SUMMARY Chronic pain and depressive disorders differentially impact older adults and both conditions are often intractable, underscoring the need to investigate modifiable risk factors and better elucidate the pathophysiology of these disorders. Insomnia, a cardinal symptom of both disorders, is modifiable, yet it is not known how insomnia influences biological and central nervous system factors that increase risk for chronic pain. This knowledge is critical for refining insomnia and chronic pain management therapies to target alterations in central pain processing that contribute to chronic pain risk and morbidity. Given that insomnia and sleep disturbance activate inflammatory signaling, the proposed study hypothesizes that inflammation is a common biological substrate that dynamically links insomnia and affective disturbance with alterations in two dimensions of central pain processing associated with chronic pain risk, i.e. central sensitization (CS) and affective pain modulation (APM). Animal models demonstrate that inflammation heightens pain sensitivity and induces neuroplastic alterations that increase the responsivity of CNS nociceptive neurons to normal or subthreshold afferent input, i.e., CS. Inflammation also induces affective disturbances that may modulate and amplify pain perception (APM). Low dose endotoxin administration safely and transiently induces affective disturbance and emerging studies suggest this inflammatory challenge may alter CS. Hence, we will investigate whether insomnia, alone or combined with an experimental inflammatory challenge (endotoxin) alters CS and APM in older adults. This proposal synergizes with a newly funded study [(R01 AG051944 (Irwin)] of differences in depressive symptoms and negative and positive affect responding as a function of insomnia and inflammatory challenge. We will study a subset (N=148) of participants in this parent study of older adults with (N=74) and without (N=74) insomnia who will complete a comprehensive assessment of pain processing (CS and APM) following exposure to endotoxin vs. placebo. To further establish the translational promise of this experimental model of chronic pain risk, we will add electronic diary assessments of daily pain and depressive symptoms at 3, 6, 9, and 12 months. We will address four aims: 1) Evaluate differences in indices of central sensitization (CS) as a function of insomnia and experimental endotoxin exposure; 2) Evaluate differences in affective pain modulation (APM) as a function of insomnia and experimental endotoxin exposure and determine the extent to which endotoxin-induced affective disturbance accounts for alterations in CS and APM; 3) Determine whether individual differences in the endotoxin-induced inflammatory response are associated with alterations in CS and APM, as a function of insomnia and 4) Determine the extent to which the endotoxin-induced inflammatory response and/or alterations in CS, APM, and affective disturbance pre...