(279) Management of SCI-Induced Chronic Pain in Rats: Intensive Locomotor Training and Recombinant GABAergic Cell Tranplants

Management of chronic pain induced by spinal cord injury (SCI) requires a multifactorial approach. Reduced inhibitory GABAergic signaling in the spinal pain processing sites and enhanced excitatory NMDA signaling are among the key events that lead to development of chronic pain. Inflammation related to the SCI also negatively influences the overall behavioral outcome. The goal of this study was to evaluate the analgesic effect of multitargeted approach using intraspinal graft of GABAergic progenitors expressing NMDA antagonist Serine-histogranin in combination with intensive physical exercise. Male Sprague Dawley rats underwent spinal clip compression injury and developed hypersensitivity in the hind paws. Treadmill training was initiated at 5 days or 5 weeks post SCI, with GABAergic cells grafted at 4 weeks post SCI. Tactile allodynia, heat and cold hyperalgesia were monitored bi-weekly up to 15 weeks. Our results show that combined treatment significantly reduced established hypersensitivity (with early training) or in some animals even prevented its development (with late training). The behavioral outcome in animals with recombinant grafts producing SHG was more robust and stable compared to animals with nonrecombinant cells, although both groups show significant recovery from pain related behavior compared with non-transplanted and sedentary controls. The level of inflammatory cytokines in the spinal tissue was reduced in treadmill trained animals and further reduced in animals with combined treatment. Immunohistochemical analysis showed reduced expression of KCC2 transporter, involved in GABAergic inhibition, in the sedentary rats with SCI, compared to treadmill trained animals. Such changes may underlie the persistence of chronic pain in sedentary animals and the beneficial effects of training in restoring of inhibitory signaling in the spinal cord. These findings support the proposed approach of targeting multiple pain-related events in order to manage chronic pain after SCI.