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Biodegradable Nanoparticles Modulate Central and Peripheral Mechanisms of Neuropathic Pain Following Thoracic Spinal Cord Injury
Michael N Saunders, BSE1; Irina Kalashnikova, PhD2; Daniel Kolpek, BS2; Kate Griffin, BS1; Eiji Saito, PhD1; Lonnie Shea, PhD1; Jonghyuck Park, PhD2
1University of Michigan, Ann Arbor, MI; 2University of Kentucky, Lexington, KY

Introduction Thoracic spinal cord injury (SCI) is a devastating condition worsened by the development of chronic and spontaneous neuropathic pain. Treatment is currently limited to symptomatic management, with few disease-modifying therapies available. We previously developed a drug-free, biodegradable nanoparticle (NP) therapy that reprograms innate immune cells both in circulation and at the site of SCI, ultimately conferring a proregenerative environment within the spinal cord and improved locomotor outcomes. In this work, we assess whether these NPs alter post-SCI neuropathic pain outcomes and provide mechanistic insights into their function.
Materials & Methods A water/oil/water double emulsion method was used to generate poly(lactide-co-glycolide) NPs with a diameter of 500 nm and a zeta potential of between -40 and -60 mV. Balb/c mice were given a T9/10 hemisection SCI followed by placement of a thoracic spinal cord biomaterial bridge at day 0. NPs or control phosphate buffered saline (PBS) were intravenously administered starting 2 hours after surgery, and mice continued to receive daily doses of NPs or control through day 6. Mechanical hypersensitivity was evaluated using von Frey filament testing, while thermal hypersensitivity was assessed using the acetone test. At the indicated time points, spinal cord bridges and L2-L6 dorsal root ganglia (DRG) were harvested and processed for single cell RNA sequencing, qRT-PCR, or immunocytochemistry.
Results NP-mediated reductions in mechanical and thermal hypersensitivity were observed starting at 2 weeks post-injury and were maintained through 12 weeks. Upon evaluation of central and peripheral mechanisms of neuropathic pain, we found that NPs minimally altered the expression of neuropathic pain-associated genes in the spinal cord in the subacute period. However, peripherally, subacute evaluation of the DRG revealed NP-mediated reductions in genes linked to mechanical signaling, neuronal hyperexcitability, and pro-inflammatory immune cell infiltration. Additionally, fewer neurons expressing the pain-associated nociceptor TPRA1 were present. In the chronic period post-injury, both proinflammatory immune cell and neuropathic pain-associated genes were decreased in the spinal cord and DRG. Conclusions Intravenously-delivered drug-free NPs modulate both central and peripheral mechanisms of neuropathic pain. NPs attenuate the expression of neuropathic pain-associated genes and nociceptors in the spinal cord and DRGs, thereby alleviating neuronal hypersensitivity after SCI. This report provides evidence for a novel therapy that could have long-term efficacy in the reduction of neuropathic pain following thoracic SCI and other traumatic neurological injuries.


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