Pretreatment with AM1241 Enhances the Analgesic Effect of Intrathecally Administrated Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) possess cannabinoid (CB) receptors, specifically type 1 (CB1) and type 2 (CB2) receptors, and have been shown to have therapeutic potential in alleviating various forms of neuropathic pain, including pain resulting from chronic constriction injury (CCI). One of the key CB2 receptor agonists used in this context is AM1241. The objective of this study was to examine the effects of intrathecal (i.t.) injection of AM1241-treated MSCs on pain relief in a mouse model of CCI.
The results demonstrated that mice subjected to CCI and treated with AM1241-pretreated MSCs showed significantly prolonged durations of mechanical and thermal analgesia compared to mice injected with either untreated MSCs or AM1241 alone. Additionally, the study investigated the role of molecular signaling pathways in this analgesic effect. One such pathway involved the phosphorylated extracellular signal-regulated kinase (p-ERK1/2), a crucial molecule in pain signaling. The study found that the CCI-induced upregulation of p-ERK1/2 was inhibited following the i.t. administration of AM1241-treated MSCs, and this inhibition was significantly greater than the inhibition observed in mice injected with untreated MSCs.
Furthermore, the expression of transforming growth factor-beta 1 (TGF-β1), a cytokine involved in tissue repair and inflammation, was analyzed in the dorsal root ganglia (DRGs) and spinal cord of the CCI mice. In untreated CCI mice, the expression of TGF-β1 was elevated, indicating its potential involvement in the pain response. However, pretreatment with AM1241-treated MSCs regulated TGF-β1 expression at both 10 and 19 days post-surgery, suggesting that these stem cells modulate this inflammatory marker in a time-dependent manner.
Additionally, the role of TGF-β1 in the observed analgesic effects was further explored. When exogenous TGF-β1 was administered via i.t. injection, it modestly alleviated neuropathic pain in the CCI model. However, neutralizing TGF-β1 completely blocked the pain-relieving effects of AM1241-treated MSCs, particularly concerning thermal hyperalgesia and mechanical allodynia—two key aspects of neuropathic pain.
In an in vitro experiment, MSCs derived from bone marrow (BMSCs) were stimulated with lipopolysaccharide (LPS), and it was found that AM1241 enhanced the release of TGF-β1 into the culture supernatant. This further supports the hypothesis that AM1241-treated MSCs actively modulate TGF-β1 release as part of their therapeutic effect.
Taken together, the findings from this study suggest that the administration of AM1241-treated mesenchymal stem cells via intrathecal injection provides significant analgesic benefits. This effect is likely mediated through the modulation of TGF-β1 expression and the inhibition of p-ERK1/2 signaling pathways. The results highlight the potential of CB2 receptor activation in MSCs as a promising therapeutic approach for managing neuropathic pain, particularly through its ability to regulate inflammatory mediators like TGF-β1.