Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy

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.

Pituitary hormones are specifically expressed in trigeminal sensory neurons and contribute to pain responses in the trigeminal system

“…Exogenous GH plays an anti-nociceptive role in the spinal system 39 . POMC, which undergoes post-translational processing into multiple peptides including alpha, beta and gamma melanocyte-stimulating hormones (MSH), and adrenocorticotropin (ACTH), is also involved in anti-nociception in the spinal system due to opioids processed from POMC 40 . Further analysis of RNA-seq data showed that several DEGs are in DRG or NG/JG, but not TG sensory neurons.…”

“…POMC-derived peptide could be involved in cell–cell communication via autocrine and paracrine mechanisms. Moreover, reduction of already low levels of POMC expression in DRG neurons of female and male mice with diabetic neuropathy contributes to hypersensitivity 40 . This effect was attributed to endorphins that could be processed from POMC 40 .…”

“…Moreover, reduction of already low levels of POMC expression in DRG neurons of female and male mice with diabetic neuropathy contributes to hypersensitivity 40 . This effect was attributed to endorphins that could be processed from POMC 40 . Overexpression of POMC-derived endo-opioids in L3–L4 DRG does not change baseline nociception in female mice but suppresses diabetic neuropathy-induced hypersensitivity 40 .…”

“…This effect was attributed to endorphins that could be processed from POMC 40 . Overexpression of POMC-derived endo-opioids in L3–L4 DRG does not change baseline nociception in female mice but suppresses diabetic neuropathy-induced hypersensitivity 40 . Interestingly, diabetic female mice develop heat hypersensitivity, as opposed to hyposensitivity in males, while POMC-MOR expression is downregulated in both female and male mice, and POMC effects in diabetic mice was not sex-dependent 40 .…”

An Integrated View on Neuronal Subsets in the Peripheral Nervous System and Their Role in Immunoregulation

“…The afferent neurons of DRGs integrate sensory information from distinct body regions and transmit the signal to the CNS ( 58 ). Sensory afferent signals from the thoracolumbar region predominantly originate from the small intestine and lumbosacral DRGs mainly project the lower extremities, but also to the large intestine ( 59 – 61 ). Different types of sensory neurons within DRGs allow sensing of distinct stimuli.…”