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CARTp/GPR160 mediates behavioral hypersensitivities in mice through NOD2
Rachel M Schafer1,2, Luigino A Giancotti1,2, John C Chrivia1,2
1Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States.
Pain
|October 2, 2024
Summary
Cocaine- and amphetamine-regulated transcript peptide (CARTp) causes neuropathic pain hypersensitivity via G-protein coupled receptor 160 (GPR160) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the spinal cord.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuropathic pain is a chronic condition with limited treatment options.
- G-protein coupled receptor 160 (GPR160) and its ligand, cocaine- and amphetamine-regulated transcript peptide (CARTp), are potential therapeutic targets.
- The mechanisms of CARTp-induced hypersensitivity in the spinal cord are not well understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying CARTp-induced behavioral hypersensitivity in the dorsal horn spinal cord (DH-SC).
- To identify novel molecular players involved in GPR160/CARTp signaling in neuropathic pain.
Main Methods:
- RNA transcriptomics screen of DH-SC tissues.
- Genetic and pharmacological manipulation of NOD2.
- Co-immunoprecipitation assays to study protein interactions.
- Immunofluorescence to determine cell co-expression.
Main Results:
- Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) was significantly upregulated following CARTp administration.
- CARTp-induced hypersensitivity was dependent on NOD2 but independent of RIPK2.
- GPR160 and NOD2 interact, and NOD2 is expressed in endothelial cells in the DH-SC.
Conclusions:
- CARTp induces behavioral hypersensitivity in the DH-SC through a novel GPR160/NOD2 signaling pathway.
- This study highlights the role of NOD2 in nonpathogenic settings, specifically in neuropathic pain.
- Targeting the CARTp/GPR160/NOD2 pathway may offer new therapeutic strategies for neuropathic pain.
