Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy

Divija Deshpande,Claire Gaveriaux-Ruff,Christoph S. N. Klose,Anke Tappe-Theodor,Nitin Agarwal,Thomas Fleming,Rohini Kuner,Peter Nawroth

doi:10.1038/s41467-020-20677-0

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.

Highlights

Painful neuropathy is a frequent complication in diabetes
Confocal dual-immunofluorescence analysis revealed that the POMC-specific immunoreactivity was primarily localized in ß-tubulin III+ neuronal somata in the lumbar dorsal root ganglia (DRG) and axons in sciatic nerves (Fig. 1b), supporting the concept that POMC is expressed in the peripheral sensory neuronal somata and undergoes axonal transport
Our study demonstrates the presence of the endogenous opioid precursor, POMC, in the sensory ganglia of mice and humans and its importance in antinociception, especially during painful diabetic peripheral neuropathy (DPN)

Summary

Introduction

Painful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Endogenous opioid precursors (classically, proopiomelanocortin (POMC), pro-dynorphin (PDYN), and pro-enkephalin (PENK)) are proteolytically cleaved to produce opioid peptides These bind to their cognate opioid receptors and trigger downstream signaling events (activation of K+ channels and inhibition of Ca++ channels), resulting in the inhibition of neuronal excitability. Persistent neuropathic pain in DPN patients suggests a dysfunction in endogenous opioid-mediated antinociceptive mechanisms. We report that the sensory neurons of the PNS express POMC in mice and humans and further demonstrate that the endogenous opioid pathway mediated by POMC is impaired during experimental and clinical diabetes. This study, identifies a pivotal antinociceptive mechanism in the PNS and provides a therapeutic target for the treatment of painful DPN and possibly other painful peripheral neuropathies

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Results

Conclusion