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, 9 (8), e104860
eCollection

Central Administration of C-X-C Chemokine Receptor Type 4 Antagonist Alleviates the Development and Maintenance of Peripheral Neuropathic Pain in Mice

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Central Administration of C-X-C Chemokine Receptor Type 4 Antagonist Alleviates the Development and Maintenance of Peripheral Neuropathic Pain in Mice

Xin Luo et al. PLoS One.

Abstract

Aim: To explore the roles of C-X-C chemokine receptor type 4 (CXCR4) in spinal processing of neuropathic pain at the central nervous system (CNS).

Methods: Peripheral neuropathic pain (PNP) induced by partial sciatic nerve ligation (pSNL) model was assessed in mice. Effects of a single intrathecal (central) administration of AMD3100 (intrathecal AMD3100), a CXCR4 antagonist, on pain behavior and pain-related spinal pathways and molecules in the L3-L5 spinal cord segment was studied compare to saline treatment.

Results: Rotarod test showed that intrathecal AMD3100 did not impair mice motor function. In pSNL-induced mice, intrathecal AMD3100 delayed the development of mechanical allodynia and reversed the established mechanical allodynia in a dose-dependent way. Moreover, intrathecal AMD3100 downregulated the activation of JNK1 and p38 pathways and the protein expression of p65 as assessed by western blotting. Real-time PCR test also demonstrated that substance P mRNA was decreased, while adrenomedullin and intercellular adhesion molecule mRNA was increased following AMD3100 treatment.

Conclusion: Our results suggest that central (spinal) CXCR4 is involved in the development and maintenance of PNP and the regulation of multiple spinal molecular events under pain condition, implicating that CXCR4 would potentially be a therapeutic target for chronic neuropathic pain.

Conflict of interest statement

Competing Interests: Co-author Professor Sookja K. Chung is a PLOS ONE Editorial Board member but this does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

Figures

Figure 1
Figure 1. The effects of intrathecal AMD3100 on the motor function of normal mice.
There was no significant change in falling latency among the three groups with intrathecal AMD3100, compared to the saline group from hour 1 to day 3 after the injection. Results are mean ± SEM (n = 5). Sec.  =  second, D  =  day, Hr  =  hour, 0  =  time of intrathecal injection.
Figure 2
Figure 2. The effects of intrathecal AMD3100 on the development and maintenance of PNP in pSNL-injured mice.
The preemptive intrathecal AMD3100, but not intrathecal saline, increased ipsilateral PWT of pSNL mice for 3 days after the surgery (A), but did not affect contralateral PWT (B). On POD 7, intrathecal AMD3100 at dosages of 1 µg, 5 µg and 25 µg increased the ipsilateral PWT of pSNL mice for 2, 3 and 3 days, respectively (C), but did not affect contralateral PWT (D). Results are mean ± SEM (n = 5–12). ***p<0.001 versus the pSNL group at the corresponding timepoints. ### p<0.001 versus the Saline + pSNL group at the corresponding timepoints. ααα p<0.001, α p<0.05, βββ p<0.001, ββ p<0.01, β p<0.05, ΨΨ p<0.01 and Ψ p<0.05 versus the baseline. g  =  gram, D  =  day, Hr  =  hour, 0  =  time of intrathecal injection.
Figure 3
Figure 3. The effects of intrathecal AMD3100 on the production of neuropeptides and pro-inflammatory cytokines, and cellular adhesion molecules in the ipsilateral L3-L5 spinal cord segment of pSNL-injured mice.
Real time PCR revealed that intrathecal AMD3100 decreased mRNA level of SP (B) and increased mRNA level of AM (C) and ICAM (G), but did not affect mRNA levels of CGRP (A), TNF-α (D) and IL-1β (E), IL-6 (F), VCAM (H) or EAAT-2 (I) at hour 8 after the injection. Results are means ± SEM (n = 6). *p<0.01, # p and Ψ p<0.05 versus the saline group.
Figure 4
Figure 4. The effects of intrathecal AMD3100 on pain pathways in the ipsilateral L3-L5 spinal cord segment of pSNL-injured mice.
Western blotting revealed that intrathecal AMD3100 decreased the phosphorylation level of the JNK1 (C), p38 (E) and p65 (H) pathway, but did not affect the phosphorylation levels of the ERK1 (A), ERK2 (B), JNK2 (D), AKT (F) or STAT3 (G) at hour 8 after the injection. Results are means ± SEM (n = 8). **p<0.01, # p and Ψ p<0.05 versus the saline group.

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Funding for this study was provided by the departmental fund, Department of Anaesthesiology, The University of Hong Kong; the department fund, Department of Anaesthesiology, The University of Hong Kong had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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