Neuropathic pain, which occurs from damage to or dysfunction of the peripheral or central nervous system, is a major source of chronic pain and is often resistant to analgesics. Although neuropathic pain can have numerous etiologies, from diseases (eg, cancer, viral infections) to injuries/trauma (eg, stroke, surgery, spinal cord injuries), neuroinflammation is an underlying driving factor. Studies have suggested that stem cells might offer a way to inhibit chronic pain by modulating neuroinflammation, potentially providing a more complete and definitive strategy for treating neuropathic pain.
During the American Pain Society 35th Annual Scientific Meeting, Ru-Rong Ji, PhD, professor of anesthesiology and neurobiology in the Duke School of Medicine, presented the results of an animal study that indicated that injections of bone marrow stromal cells (BMSCs) might provide an effective strategy for relieving neuropathic pain.1,2 The study also answered several key questions surrounding the use of this treatment, paving the way for its use in humans.
In Dr Ji and colleagues’ study, mice with chronic pain from nerve damage were administered intrathecal BMSCs via lumbar puncture. BMSCs were chosen because of their many advantages, including high expansion potential, genetic stability, stable phenotype, strong immunosuppressive properties, availability in human adult bone marrow, and the ability to be transplanted without the need for immunosuppressants.2 Although Dr Ji noted that previous studies have already shown BMSCs to alleviate inflammatory and neuropathic pain, numerous key issues have limited their clinical applicability, including a lack of understanding of the molecular mechanisms by which BMSCs attenuate chronic pain, knowing how and where to best inject or implant the BMSCs, and the analgesic capabilities of BMSCs.
“We found that a single intrathecal injection of BMSCs could reduce nerve injury-induced neuropathic pain in mice for more than 6 weeks,” Dr Ji told Clinical Pain Advisor. “Intrathecal injection of BMSCs caused a long-term survival of stem cells in the targeted tissue (dorsal root ganglia [DRG]) for up to 3 months, whereas direct injection into a targeted tissue (eg, joint) only showed short-term survival (<1 week) of BMSCs,” he said.
In the study, early- and late-phase neuropathic pain symptoms were relieved in mice with chronic constriction injuries (CCIs) as well as those with spared nerve injuries. Additionally, intrathecal injection of BMSCs reduced CCI-induced spontaneous pain and axonal injury of DRG neurons and inhibited CCI-evoked neuroinflammation in DRGs and spinal cord tissues.
To determine the mechanisms behind the stem cells’ pain-relieving effects, Ji and colleagues measured levels of anti-inflammatory molecules that have been associated with pain relief. They found that BMSC-treated mice had higher levels of TGF-β1 in their spinal fluid than untreated mice.
“TGF- β1 is a potent cytokine that controls inflammation and can also directly inhibit neuronal excitability of nociceptive neurons,” Ji explained. In the study, TGF- β1 was shown to suppress CCI-evoked spinal synaptic plasticity and DRG neuronal hyperexcitability within minutes.
“We regard BMSCs as ‘portable mini-drug stores’ that can move to the right tissue, due to a chemotaxic signal CXCL12, for tissue repair. This may fit the idea of ‘precision medicine,’” Dr Ji said.
Dr Ji noted that he and his colleagues are testing the use of intrathecal injection of BMSCs in other chronic pain models, including for trigeminal pain. They have also found it to be effective in blocking chemotherapy-induced neuropathic pain.
1. Ji RR. Intrathecal bone marrow stem cells produce long-lasting pain relief in mice via TGF-b secretion. Presented at: 35th Annual Scientific Meeting of the American Pain Society; May 11-14, 2016; Austin, Texas.
2. Chen G, Park CK, Xie RG, Ji RR. Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion. J Clin Invest. 2015;125:3226-3240.