Central administration of CXCR4 antagonist prevents the development of peripheral neuropathic pain and modulates the spinal expression of neuropeptides and pro-inflammatory cytokines in mice

Abstract

Background and Goal of Study: C-X-C chemokine receptor type 4 (CXCR4) is receptor of chemokine CXCL12 with wide distribution and multiple functions in the central nerve system. We firstly reported that central administration of AMD3100, a CXCR4 antagonist, attenuated peripheral neuropathic pain (PNP). However, the effects of central administration of AMD3100 on the development of PNP and its underlying mechanism are still unknown. Therefore, this study aimed to explore the molecular events involved in anti-nociceptive effect of intrathecal AMD3100 on PNP at the early stage following peripheral neuropathic injury. Materials and Methods: Partial sciatic nerve ligation surgery (pSNL) was performed on adult male C57BL/6 wild-type mice in order to induce PNP. A single dose of AMD3100 (10µg / 5µl) was injected intrathecally in mice 1 hour prior to pSNL surgery, on post-operative day (POD) 1, POD 2 and POD 3 consecutively, while saline was given in control group. Pain response of mice to mechanical stimuli was assessed by Von Frey test (AMD3100 group n=10 and Saline group n=6). After 4-consecutive-day treatment of AMD3100 (n=8) or saline (n=6), L3-L5 spinal cord segment of pSNL-injured mice was harvested for examining spinal mRNA expression of neuropeptides and pro-inflammatory cytokines by real time PCR analysis. Results and Discussion: pSNL surgery produced PNP in mice of control group, which was manifested as significantly reduced paw withdrawal threshold (PWT) (p< 0.001). Intrathecal AMD3100 attenuated the development of PNP and increased PWT as compared to the control group for 6 days (p< 0.05). Among mRNA levels of neuropeptides and pro-inflammatory cytokines contributing to the development of PNP, intrathecal AMD3100 upregulated adrenomedullin (AM, p< 0.001) and downregulated tumor necrosis factor-α (TNF-α, p< 0.05) and interleukin-6 (IL-6, p< 0.05). However, it has no effect on mRNA levels of calcitonin gene-related peptide (αCGRP), substance P (SP), enkephalin (ENK1) and interleukin-1β (IL-1β). Conclusion: Our study showed that intrathecal AMD3100 given before and immediate after pSNL for 3 consecutive days attenuated the development of PNP. It was associated with downregulation of TNF-α and IL-6 and upregulation of AM. CXCR4 signaling pathway appears to be important for the development of PNP. Central CXCR4 antagonist administrated at early stage following nerve injury would potentially be an effective way to prevent neuropathic pain development.