Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy.

BACKGROUND: Neuropathic pain caused by peripheral nerve injury is a chronic disorder that represents a significant clinical challenge because the pathological mechanisms have not been fully elucidated. Several studies have suggested the involvement of various sodium channels, including tetrodotoxin-resistant NaV1.8, in affected dorsal root ganglion (DRG) neurons. We have hypothesized that altered local expression of NaV1.8 in the peripheral axons of DRG neurons could facilitate nociceptive signal generation and propagation after neuropathic injury. RESULTS: After unilateral sciatic nerve entrapment injury in rats, compound action potential amplitudes were increased in both myelinated and unmyelinated fibers of the ipsilateral sciatic nerve. Tetrodotoxin resistance of both fiber populations and sciatic nerve NaV1.8 immunoreactivity were also increased. Further analysis of NaV1.8 distribution revealed that immunoreactivity and mRNA levels were decreased and unaffected, respectively, in the ipsilateral L4 and L5 DRG; however sciatic nerve NaV1.8 mRNA showed nearly an 11-fold ipsilateral increase. Nav1.8 mRNA observed in the sciatic nerve was likely of axonal origin since it was not detected in non-neuronal cells cultured from nerve tissue. Absence of changes in NaV1.8 mRNA polyadenylation suggests that increased mRNA stability was not responsible for the selective peripheral mRNA increase. Furthermore, mRNA levels of NaV1.3, NaV1.5, NaV1.6, NaV1.7, and NaV1.9 were not significantly different between ipsilateral and contralateral nerves. We therefore propose that selective NaV1.8 mRNA axonal transport and local up-regulation could contribute to the hyperexcitability of peripheral nerves in some neuropathic pain states. CONCLUSION: Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves. The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain.

Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study.

BACKGROUND: Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. METHODS: We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. RESULTS: No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. CONCLUSIONS: Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02338271 . Registered 7 January 2015.