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Abstract
Intraspinal quisqualic acid (QUIS) injury induce (i) mechanical and thermal hyperalgesia, (ii) progressive self-injurious overgrooming of the affected dermatome. The latter is thought to resemble painful dysesthesia observed in spinal cord injury (SCI) patients. We have reported previously loss of endogenous GABA immunoreactive (IR) cells in the superficial dorsal horn of QUIS rats 2 weeks post injury. Further histological evaluation showed that GABA-, glycine-, and synaptic vesicular transporter VIAAT-IR persisted but were substantially decreased in the injured spinal cord. In this study, partially differentiated GABA-IR embryonic neural precursor cells (NPCs) were transplanted into the spinal cord of QUIS rats to reverse overgrooming by replenishing lost inhibitory circuitry. Rat E14 NPCs were predifferentiated in 0.1 ng/ml FGF-2 for 4 h prior to transplantation. In vitro immunocytochemistry of transplant cohort showed large population of GABA-IR NPCs that double labeled with nestin but few colocalized with NeuN, indicating partial maturation. Two weeks following QUIS lesion at T12-L1, and following the onset of overgrooming, NPCs were transplanted into the QUIS lesion sites; bovine adrenal fibroblast cells were used as control. Overgrooming was reduced in >55.5% of NPC grafted animals, with inverse relationship between the number of surviving GABA-IR cells and the size of overgrooming. Fibroblast-control animals showed a progressive worsening of overgrooming. At 3 weeks post-transplantation, numerous GABA-, nestin-, and GFAP-IR cells were present in the lesion site. Surviving grafted GABA-IR NPCs were NeuN+ and GFAP−. These results indicate that partially differentiated NPCs survive and differentiate in vivo into neuronal cells following transplantation into an injured spinal cord. GABA-IR NPC transplants can restore lost dorsal horn inhibitory signaling and are useful in alleviating central pain following SCI.
Highlights
Pain is a major complication in patients with spinal cord injury (SCI) where conventional pharmacological, electrical, or psychological treatments provide only minor and temporary relief (Finnerup et al, 2002; Finnerup and Jensen, 2004; WiderstromNoga et al, 2008; Siddall, 2009; Kwon et al, 2010; Mann et al, 2010)
Results from the present study show that intraspinal transplantation of predifferentiated embryonic GABAergic neural precursor cells (NPCs), but not bovine fibroblast cells, significantly decreases self-injurious overgrooming lesions observed in quisqualic acid (QUIS) injured rats
The decrease in overgrooming may be mediated by the GABA released from the transplanted precursor cells since the reduction in grooming was observed primarily GABA-transplated QUIS animals
Summary
Pain is a major complication in patients with spinal cord injury (SCI) where conventional pharmacological, electrical, or psychological treatments provide only minor and temporary relief (Finnerup et al, 2002; Finnerup and Jensen, 2004; WiderstromNoga et al, 2008; Siddall, 2009; Kwon et al, 2010; Mann et al, 2010). Biochemical events leading to abnormal firing of spinal neurons (Mills et al, 2001; Yezierski et al, 2004), up-regulation of voltage-gated ion channels (Nashmi and Fehlings, 2001; Edwards et al, 2002; Hains et al, 2003a), recruitment of reactive glia (Carlton et al, 2009), and excessive release of excitatory amino acids (excitotoxicity) in the spinal gray and white matters add to the complexity of neuropathic pain in SCI patients (Mills et al, 2001; Zeilig et al, 2012). QUIS injured rats exhibit nociceptive behaviors for mechanical and cold allodynia and selfinjurious overgrooming behaviors (Brewer and Yezierski, 1998; Gorman et al, 2001). Overgrooming behavior is thought to be mediated by dysesthetic sensations originating from the affected www.frontiersin.org
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