Abstract
BackgroundNeuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive.MethodsWe evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X4 (P2X4R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons.ResultsI.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X4R expression in the spinal cord microglia. BMSC-lysate also reduced P2X4R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X4R confirmed that modulation of P2X4R might be a key mechanism for the analgesic effects of i.t. BMSC.ConclusionAltogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC’s analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X4R downregulation.
Highlights
Neuropathic pain is a common and debilitating manifestation of various peripheral nerves diseases [1, 2]
To explore the mechanism of and provide critical insight into bone marrow stromal cell (BMSC) therapy for optimization and clinical translation, we investigated the analgesic effect of i.t. injection of BMSC in a chronic compression of dorsal root ganglion (CCD) model in rats, studied the microglial reaction in response to CCD and BMSC, and explored interactions between BMSCs and microglia
To validate the effect of i.t. administration of BMSC on neuropathic pain in our CCD model, we employed a quantitative behavior test by enumerating hind paw withdrawals elicited by a defined innocuous mechanical stimulus (12 g von Frey filaments) as a measure for the severity of tactile allodynia
Summary
Neuropathic pain is a common and debilitating manifestation of various peripheral nerves diseases [1, 2]. Local injection of BMSCs can result in traumatic nerve damage [13] Given these concerns with intravenous and local administration of BMSCs, the safety and efficacy of intrathecal (i.t.) delivery of BMSC have been explored and investigated. In the context of neuropathic pain, efficacy results of i.t. BMSC have been variable, ranging from a significant improvement in symptoms for several weeks [9] to negligible behavioral changes [14, 15]. BMSC have been variable, ranging from a significant improvement in symptoms for several weeks [9] to negligible behavioral changes [14, 15] These conflicting results might be due in part to the lack of a thorough understanding of how BMSCs act to alleviate neuropathic pain, thereby resulting in sub-optimal experimental designs to investigate its efficacy. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive
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