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Papers of the Week

Papers: 14 May 2022 - 20 May 2022

Animal Studies

2022 May


36 Suppl 1

A Role of NOD2 in CARTp-mediated Mechano-hypersensitivity.


Schafer R, Giancotti L, Chen Z, Doyle T, Harada C, Zhang J, Salvemini D
FASEB J. 2022 May; 36 Suppl 1.
PMID: 35554568.


Neuropathic pain is a debilitating chronic condition that remains difficult to treat. There is a high priority to identify novel non-opioid-based therapeutic targets as long-term use of opioids is problematic due to its severe side effects and strong abuse potential. Our lab recently discovered G-protein coupled receptor 160 (GPR160) has a role in neuropathic pain. Gpr160 was upregulated in the dorsal horn of the spinal cord (DH-SC) on the side of nerve injury relative to the uninjured side in mice. Blocking GPR160 using siRNA or a neutralizing antibody (Ab) reversed and prevented pain hypersensitivity. In addition, our lab deorphanized GPR160 as the receptor for cocaine- and amphetamine-regulated transcript peptide (CARTp). We showed that an intrathecal (i.th.) injection of CARTp in naive mice caused mechano-hypersensitivity that was dependent on GPR160. CARTp-induced gene expression is relatively unexplored and the mechanism by which CARTp/GPR160 signaling promotes chronic pain is not well known. Therefore, our objective was to perform an unbiased RNA transcriptomics analysis to identify which genes were altered at the time of CARTp-mediated peak pain in the DH-SC. We found that Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) expression was increased upon i.th. injection of CARTp and its expression decreased after CARTp was co-administered with GPR160 Ab, pointing to a potential interaction between CARTp/GPR160 and NOD2. NOD2 is a cytosolic pattern recognition receptor that is involved in activating the immune system in response to pathogens. Moreover, a recent study linked NOD2 to the development of neuropathic pain. This led to our hypothesis that CARTp/GPR160 causes mechano-hypersensitivity through NOD2 and NOD2 has a functional role in neuropathic pain. C57BL/6 (WT) and NOD2 mice received an i.th. injection of CARTp and mechano-allodynia was assessed. The WT mice developed mechano-allodynia by 30min and persisted for 5hrs. In contrast, mechano-allodynia was attenuated for 4hrs in NOD2 mice, suggesting CARTp/GPR160 induces mechano-hypersensitivity through NOD2. Furthermore, we found that NOD2 has a functional role in a chronic constriction injury (CCI) model of neuropathic pain. WT mice started developing mechano-allodynia on day 3 (D3) after CCI, reached a maximum by D7, and persisted until D14. However, NOD2 mice did not develop mechano-allodynia until D10, indicating that NOD2 is involved in the development of CCI neuropathic pain. Overall, our results provide a potential mechanistic insight on how CARTp causes mechano-sensitivity and NOD2 has a functional role in CCI-mediated neuropathic pain.