Mrgp receptor d mediates pain hypersensitivity in painful diabetic neuropathy

Aims: This new study explores the molecular mechanisms underlying painful diabetic neuropathy (PDN). This condition, characterized by severe neuropathic pain, affects until 25% of diabetic patients and lacks effective treatments. The aim was to identify potential therapeutic targets by investigating the role of the Mrgprd receptor in PDN.

Methods: Researchers employed single-cell RNA sequencing and in vivo calcium imaging in a high-fat diet (HFD) mouse model of PDN.

Results: They found increased expression of Mrgprd in a subset of dorsal root ganglion (DRG) neurons, which are associated with nociceptor hyperexcitability and neuropathic pain. Limiting Mrgprd signaling reversed mechanical allodynia, a common symptom in PDN, suggesting that Mrgprd plays a crucial role in maintaining neuropathic pain.

Conclusions: These findings highlight Mrgprd as a promising target for developing new treatments for PDN.

Comments. As novel aspects, the study identifies the Mrgprd receptor as a critical player in PDN, presenting it as a novel therapeutic target. This receptor's role in mediating pain hypersensitivity provides new insights into the molecular mechanisms of PDN. The use of single-cell RNA sequencing allows for a detailed molecular profile of DRG neurons, distinguishing this study from all previous research that never used this approach. In addition, in vivo calcium imaging in DRG further strengthens the findings by demonstrating the functional impact of Mrgprd activation on nociceptor hyperexcitability. Combining transcriptomic analysis with functional imaging offers a robust methodological framework, ensuring the reliability and validity of the results. By identifying a specific receptor involved in PDN, the study opens avenues for targeted drug development, potentially leading to more effective treatments for patients suffering from neuropathic pain.

While the HFD mouse model is well-established, there are inherent limitations in translating findings from animal models to human patients and to call this animal diabetic. Further research is needed to validate these results in human subjects. The study focuses on mechanical allodynia. Future research should explore whether targeting Mrgprd can alleviate other types of pain and symptoms associated with PDN.

Overall, this study represents a significant advancement in understanding PDN's molecular underpinnings and offers hope for new, more effective treatments.

Virgine Mansuy-Aubert

Reference. George DS, Jayaraj ND, Pacifico P, Ren D, Sriram N, Miller RE, Malfait AM, Miller RJ, Menichella DM. The Mas-related G protein-coupled receptor d (Mrgprd) mediates pain hypersensitivity in painful diabetic neuropathy. Pain. 2024 May 1;165(5):1154-1168. doi: 10.1097/j.pain.0000000000003120. Epub 2023 Dec 22. PMID: 38147415; PMCID: PMC11017747.

https://journals.lww.com/pain/fulltext/2024/05000/the_mas_related_g_protein_coupled_receptor_d.22.aspx