Abstract
Mesenchymal stem cells have cannabinoid (CB) receptors type 1 and type 2 and can alleviate a variety of neuropathic pains, including chronic constriction injury (CCI). A selective CB2 receptor agonist is AM1241. In the present study, it was found that mice with CCI displayed a longer duration of mechanical and thermal analgesia when intrathecally (i.t.) injected with AM1241-treated mesenchymal stem cells, compared to those injected with untreated mesenchymal stem cells or AM1241 alone. Moreover, CCI-induced upregulation of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (p-ERK1/2) was inhibited following i.t. injection of AM1241-treated mesenchymal stem cells and this inhibition was noticeably higher compared to injection with untreated mesenchymal stem cells. The expression of transforming growth factor-β1 (TGF-β1) was also analyzed in the dorsal root ganglion (DRGs) and spinal cord of CCI mice. In untreated CCI mice, expression of TGF-β1 was increased, whereas pretreatment with AM1241-treated mesenchymal stem cells regulated the expression of TGF-β1 on 10 days and 19 days after surgery. In addition, i.t. injection of exogenous TGF-β1 slightly alleviated neuropathic pain whilst neutralization of TGF-β1 potently blocked the effect of AM1241-treated mesenchymal stem cells on thermal hyperalgesia and mechanical allodynia of CCI mice. In an in vitro experiment, AM1241 could enhance the release of TGF-β1 in the supernatant of BMSCs after lipopolysaccharide (LPS) simulation. Taken together, the findings of the current study show that i.t. administration of AM1241-treated mesenchymal stem cells has a positive effect on analgesia and that TGF-β1 and p-ERK1/2 may be the molecular signaling pathway involved in this process.
Highlights
Neuropathic pain is chronic pain caused by nervous system damage or dysfunction, including chronic constriction injury (CCI), trauma, infection, tumor, metabolic disease, chemotherapy drugs [1,2,3], the peripheral sensory nerve, and changes in the central sensory nerves of the spinal cord or brain that lead to increased sensitivity to pain [4]
The results of this study reveal that AM1241-pretreated bone marrow mesenchymal stem cells (BMSCs) can alleviate neuropathic pain, compared to BMSCs or AM1241 alone, and that p-ERK1/2 and transforming growth factor-β1 (TGF-β1) may be involved in this process
The several investigations conducted show that the analgesic effects of BMSCs are enhanced by pretreating BMSCs with the CB2 receptor agonist AM1241, which results in slight inhibition of p-ERK1/2 compared with BMSCs or AM1241 treatment alone, and that TGF-β1 acts as a “middle bridge” in this process by affecting the expression of p-ERK1/2
Summary
Neuropathic pain is chronic pain caused by nervous system damage or dysfunction, including chronic constriction injury (CCI), trauma, infection, tumor (bone cancer), metabolic disease (diabetes), chemotherapy drugs (paclitaxel for example) [1,2,3], the peripheral sensory nerve (peripheral sensitization), and changes in the central sensory nerves (central sensitization) of the spinal cord or brain that lead to increased sensitivity to pain [4]. Stem cell transplantation has been regarded as an effective therapeutic method for the treatment of neuropathic pain [7]. Mesenchymal stem cells are the foremost source of cell therapy, derived from the umbilical cord [8], placenta, bone marrow [9], and adipose tissue [10], to name a few sources. With their extensive ability to differentiate and migrate, mesenchymal stem cells, once injected to the injured site, can promote tissue and nerve repair. Bone marrow mesenchymal stem cells (BMSCs) grow in vitro and elicit immunomodulatory features and multipotentiality with high genetic stability
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