105-OR: ADA Presidents' Select Abstract: Enhanced Dopamine and Opioid Receptor Target Engagement Predicts Neuropathic Pain Treatment Response—A Resting-State fMRI Study in Painful Diabetic Neuropathy

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Introduction and Objective: Painful diabetic neuropathy (DN) is a common and challenging complication of diabetes with limited treatments. Our research reveals that treatment responders show enhanced connectivity between the insula and corticolimbic systems, modulated by dopamine and opioid receptors. These findings highlight potential mechanisms of treatment efficacy and pathways for novel therapeutic development. Methods: 43 participants with painful-DN were classified as responders (VAS<4; n=29) or non-responders (VAS>4; n=14) and underwent comprehensive clinical, neurophysiological assessments, and resting-state functional MRI. Data analysis utilized the NITRC Functional Connectivity Toolbox and SPM8 within MatLab. MRI data were masked and binarized using an opioid+dopamine receptor atlases to focus analysis on voxels with high receptor density. Spatial maps for responders and non-responders were compared to identify differences in receptor engagement. Results: Within the dopamine receptor network, responders had significantly greater dopamine transporter enriched functional connectivity (FC) in the anterior prefrontal cortex (p-FDR=0.04), orbital frontal cortex (p-FDR=0.04), anterior cingulate cortex (p-FDR=0.04), primary somatosensory cortex (p-FDR=0.02) and midbrain (p-FDR=0.009). Responders demonstrated significantly increased opioid receptor enriched FC in two clusters including the amygdala (p-FDR=0.006) and the anterior prefrontal cortex (p-FDR=0.01) compared to non-responders. Conclusion: Treatment responders demonstrate greater engagement of both dopamine and opioid receptor systems compared to non-responders. This finding highlights the importance of an intact and functional descending pain inhibition network in achieving effective pain relief. Targeting this network through tailored interventions could enhance pain management outcomes for non-responders to neuropathic pain treatments. Disclosure K. Teh: None. A. Wade: None. G.P. Sloan: Speaker's Bureau; Eli Lilly and Company, Procter & Gamble. M. Goonoo: None. S. Tesfaye: Advisory Panel; AstraZeneca, Bayer Pharmaceuticals, Inc. Speaker's Bureau; Berlin-Chemie AG. Advisory Panel; Grünenthal. Speaker's Bureau; Metronics, Novo Nordisk. Advisory Panel; Procter & Gamble. Speaker's Bureau; Viatris Inc. Advisory Panel; Nevro Corp. D. Selvarajah: None. Funding European Foundation for the Study of DiabetesUKRI Engineering and Physical Sciences Research Council

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