Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy

Divija Deshpande, Nitin Agarwal, Thomas Fleming, Claire Gaveriaux-Ruff, Christoph S. N. Klose, Anke Tappe-Theodor, Rohini Kuner and Peter Nawroth ()
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Divija Deshpande: University Hospital of Heidelberg
Nitin Agarwal: Heidelberg University, INF 366
Thomas Fleming: University Hospital of Heidelberg
Claire Gaveriaux-Ruff: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Translational Medicine and Neurogenetics
Christoph S. N. Klose: Charité -Universitätsmedizin Berlin
Anke Tappe-Theodor: Heidelberg University, INF 366
Rohini Kuner: Heidelberg University, INF 366
Peter Nawroth: University Hospital of Heidelberg

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.

Date: 2021
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DOI: 10.1038/s41467-020-20677-0

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