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Pro-resolving Mediator Maresin 1 Ameliorates Pain Hypersensitivity in a Rat Spinal Nerve Ligation Model of Neuropathic Pain

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Pro-resolving Mediator Maresin 1 Ameliorates Pain Hypersensitivity in a Rat Spinal Nerve Ligation Model of Neuropathic Pain

Jie Gao et al. J Pain Res.

Abstract

Background: Pro-resolving mediators (PRMs) are considered as emerging analgesics for chronic pain. Maresin 1 (MaR1) is a newly identified member of PRMs, and recent studies implicate its potential role in some pain conditions. As the function of MaR1 in neuropathic pain remains unclear, we investigated the effects of MaR1 on pain hypersensitivity and the underlying mechanism using a rat spinal nerve ligation (SNL) model of neuropathic pain.

Materials and methods: MaR1 (100 ng/10 μL) or commensurable artificial cerebrospinal fluid was delivered via intrathecal catheter from days 3 to 5 post-SNL followed by assessment of mechanical allodynia and thermal hyperalgesia. Ipsilateral L4-L5 spinal cord tissue was collected on day 7 post-SNL and assessed by Western blotting, enzyme-linked immunosorbent assay or immunohistochemistry.

Results: Intrathecal MaR1 significantly attenuated mechanical allodynia and thermal hyperalgesia from day 5 to day 7 post-SNL, which was associated with decreased spinal levels of glial markers, GFAP and IBA1. It was also found that intrathecal MaR1 downregulated phosphorylation levels of NF-κB p65 and its nuclear translocation, as well as decreased protein levels of pro-inflammatory cytokines, TNF-α, IL-1β and IL-6. Further, MaR1 treatment restored PSD95 and synapsin II levels, suggesting that MarR1 also protected synaptic integrity.

Conclusion: Our results indicate that MaR1 ameliorates the SNL-induced neuropathic pain by regulating glial activities and pro-inflammatory cytokines release. The present study offers insight into the potential of MaR1 as a novel intervention to ameliorate neuropathic pain.

Keywords: NF-κB p65; inflammation; maresin 1; neuropathic pain; spinal nerve ligation.

Conflict of interest statement

Disclosure The authors report no conflict of interest in this work.

Figures

Figure 1
Figure 1
Intrathecal injection of MaR1 attenuated the mechanical allodynia and thermal hyperalgesia induced by SNL in ipsilateral spinal cord. MWT (A) and PWL (B) showed a sharp decrease after SNL in rats, whereas intrathecal injection of MaR1 alleviated the mechanical allodynia and thermal hyperalgesia induced by SNL. *P < 0.05 and **P < 0.01 vs SNL. Data are expressed as mean ± SD (n = 10). Abbreviations: MaR1, maresin 1; SNL, spinal nerve ligation; MWT, mechanical withdrawal threshold; PWL, paw withdrawal latency; ACSF, artificial cerebrospinal fluid; POD, postoperative day.
Figure 2
Figure 2
MaR1 suppressed the activation of microglia and astrocytes. Representative immunofluorescent staining of GFAP (A, marker for astrocytes) and IBA1 (B, marker for microglia) to detect activated microglia and astrocytes in the ipsilateral L4–L5 spinal dorsal horn. Western blotting indicated that administration of MaR1 significantly inhibited the expression of GFAP and IBA1 (C and D). ***P < 0.001 vs sham and ##P < 0.01 vs SNL. Data are expressed as mean ± SD (n = 10). Abbreviations: GFAP, glial fibrillary acidic protein; MaR1, maresin 1; SNL, spinal nerve ligation; ACSF, artificial cerebrospinal fluid.
Figure 3
Figure 3
MaR1 inhibited SNL-induced NF-κB activation and nuclear translocation. (A) Representative immunofluorescent staining of p65 nuclear translocation (arrows) in ipsilateral L4–L5 spinal cord dorsal horn. (B) Western blotting was used to analyze nuclear and cytoplasmic p65 and p65 phosphorylation. Treatment with MaR1 significantly decreased p65 nuclear translocation and phosphorylation. ***P < 0.001 vs sham and ##P < 0.01 vs SNL. Data are expressed as mean ± SD (n = 10). Abbreviations: MaR1, maresin 1; SNL, spinal nerve ligation; ACSF, artificial cerebrospinal fluid.
Figure 4
Figure 4
MaR1 inhibited SNL-induced production of cytokines and preserved the synaptic-related proteins from destruction. After the behavioral test on day 7 after surgery, ipsilateral L4–L5 spinal cord tissue was collected for ELISA detection of TNF-α, IL-1β and IL-6 (AC). MaR1 significantly downregulated the production of TNF-α, IL-1β and IL-6 after 3 days’ continuous injection. Western blotting was used to examine the expression of PSD95 and synapsin II (D and E). MaR1 treatment protected the PSD95 and synapsin II from degradation. ***P < 0.01 vs. sham and ##P < 0.05 vs. SNL. Data are expressed as mean ± SD (n = 10). Abbreviations: MaR1, maresin 1; SNL, spinal nerve ligation; ELISA, enzyme-linked immunosorbent assay; ACSF, artificial cerebrospinal fluid.

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