Painful diabetic neuropathy (DN) is a common and distressing complication. New approaches are required to identify novel targets that will serve as a catalyst for future drug discovery programmes. We have demonstrated that responders to neuropathic pain treatment have greater functional connectivity between the insula cortex and the corticolimbic system compared to non-responders. Activity within these networks is mediated by endogenous opioid receptor systems and may hold clues to possible future treatment targets. Methods: 43 painful-DN subjects [responders (VAS<4; n=29) and non-responders (VAS≥4; n=14) ] underwent detailed clinical and neurophysiological assessment, and RS-fMRI. Data analysis was performed using the NITRC Functional ConnectivityToolbox and SPM8 in MatLab. RS-fMRI data was masked and binarised using an opioid receptor atlas to restrict the analysis to the voxels with high receptor density. Subject-specific spatial maps of responders and non-responders were compared. Results: Compared to painful-DN non-responders, responders had greater functional connectivity between the corticolimbic system with the opioid receptor networks [F (2) (41) =43.53;intensity=128.7; R-amygdala beta=0.48; p-FDR<0.0001; R-putamen beta=0.3; p-FDR<0.0001; dorsal lateral prefrontal cortex beta=0.25; p-FDR=0.0002 and the posterior parietal cortex networks beta0.25; p-FDR=0.0002]. Conclusion: Painful DN treatment responders have better target engagement of opioid receptors systems compared to non-responders. This indicates that a functioning/intact descending pain inhibition network is crucial for a better pain response. Interventions targeted at this network could provide better pain relief in non-responders to neuropathic pain treatment.


K.Teh: None. G.P.Sloan: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc. D.Selvarajah: None.


National Institute of Health Research EME grant; European Foundation for the Study of Diabetes

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