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Bone-Marrow-Derived Mononuclear Cells Relieve Neuropathic Pain after Spinal Nerve Injury in Mice.

ABSTRACT: Treating neuropathic pain is a critical clinical issue. Although numerous therapies have been proposed, effective treatments have not been established. Therefore, safe and feasible treatment methods are urgently needed. In this study, we investigated the therapeutic effects of autologous intrathecal administration of bone-marrow-derived mononuclear cells (MNCs) on neuropathic pain. We generated a mouse model of neuropathic pain by transecting the spinal nerve and evaluated neuropathic pain by measuring the mechanical threshold in the following 14 days. Mice in the MNC injection group had a higher mechanical threshold than those in the buffer group. We assessed the effect of MNC treatment on the dorsal root ganglia and spinal cord by immunohistochemistry, mRNA expression, and cytokine assay. The migration and accumulation of microglia were significantly suppressed in the MNC group, and the mRNA expression of inflammatory cytokines such as interleukin (IL)-6, IL-1?, and tumor necrosis factor alpha (TNF-?) was markedly downregulated. Furthermore, MNC administration tended to suppress various cytokines in the cerebrospinal fluid of the model mice. In conclusion, our results suggest that intrathecal injection of MNCs relieves neuropathic pain and might be a promising cell therapy for the treatment of this condition.

SUBMITTER: Takamura H

PROVIDER: S-EPMC7160523 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Bone-Marrow-Derived Mononuclear Cells Relieve Neuropathic Pain after Spinal Nerve Injury in Mice.

Takamura Hiroshi H Terashima Tomoya T Mori Kanji K Katagi Miwako M Okano Junko J Suzuki Yoshihisa Y Imai Shinji S Kojima Hideto H

Molecular therapy. Methods & clinical development 20200330

Treating neuropathic pain is a critical clinical issue. Although numerous therapies have been proposed, effective treatments have not been established. Therefore, safe and feasible treatment methods are urgently needed. In this study, we investigated the therapeutic effects of autologous intrathecal administration of bone-marrow-derived mononuclear cells (MNCs) on neuropathic pain. We generated a mouse model of neuropathic pain by transecting the spinal nerve and evaluated neuropathic pain by me ...[more]

PMID: 32322604

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Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).

Project description:In the present study, the ability of baicalin to relieve neuropathic pain due to spinal nerve ligation in rats was explored, and the relationship between baicalin and ?2-adrenoceptors (?2-AR) was determined. The neuropathic pain model was established by ligating the L5-L6 spinal nerves in Sprague-Dawley rats. Several ?2-AR antagonists were injected into the intramedullary sheath to evaluate the role of baicalin in neuropathic pain. The antagonists included nonselective ?2-AR antagonist idazoxan, ?2a-AR antagonist BRL 44408, ?2b-AR antagonist ARC 239 and ?2c-AR antagonist JP 1302. The rats were divided into an untreated control group, saline group, baicalin group and baicalin + ?2-AR antagonist groups. Paw withdrawal threshold (PWT) was tested to assess the level of pain felt by the rats. The levels of ?2-AR mRNA were tested by reverse transcription-quantitative PCR. Inflammatory factors, including tumor necrosis factor (TNF)-?, interleukin (IL)-6, IL-17 and IL-1?, were analyzed by ELISA. The histopathological changes were assessed by hematoxylin and eosin staining. Flow cytometry was used to examine the percentage of CD4+ peripheral blood mononuclear cells (PBMCs). Compared with the saline group, the PWT value increased after treating with baicalin. However, intrathecal injection of ?2-AR antagonist reversed the antinociceptive effects of baicalin. Compared with the saline group, the expression of ?2a-AR and ?2c-AR mRNA was upregulated significantly in the baicalin group (P<0.05). Levels of ?2-AR mRNA were also decreased in the baicalin + idazoxan group compared with the baicalin group (P<0.05). The levels of TNF-?, IL-6, IL-17 and IL-1? were raised after treatment with baicalin. In addition, baicalin treatment ameliorated the histological damage in the spinal cord. The percentage of CD4+ PBMCs was increased in the saline group compared with the control group (P<0.05). Compared with the baicalin group, the percentage of CD4+ PBMCs was raised after treatment with the ?2-AR antagonists. In conclusion, intrathecal injection of baicalin produced an antiallodynic effect in a spinal nerve ligation-induced neuropathic pain model. The mechanism may be related to the regulation of a2-AR expression.

Dataset Information

Bone-Marrow-Derived Mononuclear Cells Relieve Neuropathic Pain after Spinal Nerve Injury in Mice.

Publications

Bone-Marrow-Derived Mononuclear Cells Relieve Neuropathic Pain after Spinal Nerve Injury in Mice.

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