Elevated plasma CXCL12 leads to pain chronicity via positive feedback upregulation of CXCL12/CXCR4 axis in pain synapses.

Autor:	Leng, Shi-Ze, Fang, Mei-Jia, Wang, Yi-Min, Lin, Zhen-Jia, Li, Qian-Yi, Xu, Ya-Nan, Mai, Chun-Lin, Wan, Jun-Ya, Yu, Yangyinhui, Wei, Ming, Li, Ying, Zheng, Yu-Fan, Zhang, Kai-Lang, Wang, Ya-Juan, Zhou, Li-jun, Tan, Zhi, Zhang, Hui
Předmět:	CHEMOKINES NEURALGIA PAIN measurement NOCICEPTORS HETEROCYCLIC compounds FLUOROIMMUNOASSAY BIOLOGICAL models CHRONIC pain RESEARCH funding PHENOMENOLOGICAL biology NEUROPLASTICITY ENZYME-linked immunosorbent assay IMMUNOGLOBULINS BIOFEEDBACK training CELLULAR signal transduction REVERSE transcriptase polymerase chain reaction BIOCHEMISTRY MICE GENE expression HYPERALGESIA INTRAVENOUS therapy ANIMAL experimentation WESTERN immunoblotting SENSORY ganglia NERVOUS system CYTOKINES CELL receptors NERVE block CHEMICAL inhibitors
Zdroj:	Journal of Headache & Pain; 12/3/2024, Vol. 25 Issue 1, p1-18, 18p
Abstrakt:	Background: Chronic pain poses a clinical challenge due to its associated costly disability and treatment needs. Determining how pain transitions from acute to chronic is crucial for effective management. Upregulation of the chemokine C-X-C motif ligand 12 (CXCL12) in nociceptive pathway is associated with chronic pain. Our previous study has reported that elevated plasma CXCL12 mediates intracerebral neuroinflammation and the comorbidity of cognitive impairment in neuropathic pain, but whether it is also involved in the pathogenesis of pathologic pain has not been investigated. Methods: Intravenous or intrathecal injection (i.v. or i.t.) of recombinant mouse CXCL12, neutralizing antibody (anti-CXCL12) or AMD3100 [an antagonist of its receptor C-X-C chemokine receptor type 4 (CXCR4)] was used to investigate the role of CXCL12 signaling pathway in pain chronicity. Two behavioral tests were used to examine pain changes. ELISA, immunofluorescence staining, Western blot, quantitative Real Time-PCR and Cytokine array were applied to detect the expressions of different molecules. Results: We found that increased plasma CXCL12 was positively correlated with pain severity in both chronic pain patients and neuropathic pain model in mice with spared nerve injury (SNI). Neutralizing plasma CXCL12 mitigated SNI-induced hyperalgesia. A single i.v. injection of CXCL12 induced prolonged mechanical hyperalgesia and activation of the nociceptive pathway. Multiple intravenous CXCL12 caused persistent hypersensitivity, enhanced structural plasticity of nociceptors and up-regulation of the CXCL12/CXCR4 axis in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH). However, intrathecal blocking of CXCL12/CXCR4 pathway by CXCL12 antibody or CXCR4 antagonist AMD3100 significantly alleviated CXCL12-induced pain hypersensitivity and pathological changes. Conclusions: Our study provides strong evidence that a sustained increase in plasma CXCL12 contributes to neuropathic pain through a positive feedback loop that enhances nociceptor plasticity, and suggests that targeting CXCL12/CXCR4 axis in plasma or nociceptive pathways has potential value in regulating pain chronicity. Highlights: 1) Plasma CXCL12 in neuropathic pain states were positively correlated with pain severity. 2) A sustained increase in plasma CXCL12 contributes to pain chronicity. 3) Elevated plasma CXCL12 enhances spinal synaptic structural plasticity of pain through positive feedback. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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