A subpopulation of peripheral sensory neurons expressing the Mas-related G Protein-Coupled Receptor d (Mrgprd) generates pain hypersensitivity in painful diabetic neuropathy.

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes. PDN is characterized by neuropathic pain accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability, axonal degeneration, and loss of cutaneous innervation. However, the complete molecular profile underlying the hyper-excitable cellular phenotype of DRG nociceptors in PDN has not been elucidated. This gap in our knowledge is a critical barrier to developing effective, mechanism-based, and disease-modifying therapeutic approaches which are urgently needed to relieve the symptoms of PDN. Using single-cell RNA sequencing we demonstrated an increased expression of the Mas-related G Protein- Coupled Receptor d (Mrgprd) in a subpopulation of DRG neurons in the well-established High-Fat Diet (HFD) mouse model of PDN. In vivo calcium imaging allowed us to demonstrate that activation of Mrgprd receptors expressed by cutaneous afferents produced DRG neuron hyper-excitability and oscillatory calcium waves. Furthermore, Mrgprd-positive cutaneous afferents persist in diabetic mice skin. Importantly, limiting Mrgprd signaling or Mrgprd-positive DRG neuron excitability, reversed mechanical allodynia in the HFD mouse model of PDN. Taken together, our data highlights a key role of Mrgprd-mediated DRG neuron excitability in the generation and maintenance of neuropathic pain in a mouse model of PDN. Hence, we propose Mrgprd as a promising accessible target for developing effective therapeutics currently unavailable for treating neuropathic pain in PDN. Furthermore, understanding which DRG neurons cell type is mediating mechanical allodynia in PDN is of fundamental importance to our basic understanding of somatosensation and may provide an important way forward for identifying cell-type-specific therapeutics to optimize neuropathic pain treatment and nerve regeneration in PDN. ### Competing Interest Statement The authors have declared no competing interest.