CELF4 Modulates Neuropathic Pain Development by Regulating Pain-related Molecular Targets

Despite significant advancements, the mechanisms underlying neuropathic pain remain poorly understood, making it challenging for effective pain management. This study investigated the role of CUGBP Elav-Like Family Member 4 (CELF4), an RNA-binding protein, in modulating pain pathways in neuropathic pain conditions. The results showed a reduction in both mRNA and protein levels of CELF4 in the spinal cord of a chronic constriction injury (CCI) mouse model, suggesting its potential role in response to nerve injury. To further explore the role of CELF4 in modulating pain pathways in vivo , an adeno-associated virus (AAV) was injected into mice to overexpress CELF4. The mice overexpressing CELF4 showed reduced hypersensitivity to mechanical and thermal stimuli as compared to controls, indicating effective mitigation of neuropathic pain symptoms. Mechanistically, the overexpression of CELF4 significantly downregulated the expressions of Transient Receptor Potential Vanilloid-1 (TRPV1), Voltage-Gated Sodium Channel Nav1.8 (Nav1.8), and Cyclooxygenase-2 (COX2), which are crucial mediators of pain signaling. In contrast, the knockdown of CELF4 rescued the TRPV1, Nav1.8, and COX2 expressions, indicating that CELF4 might act as a suppressive regulator in neuropathic pain pathways. These results suggested that CELF4 played a critical role in regulating neuropathic pain by modulating specific ion channels and inflammatory markers, thus offering potential targets for therapeutic intervention in pain management.