The rat model of cervical dorsal root injury mimics the avulsion of dorsal roots in humans following brachial plexus injury, a condition that leads to debilitating sensory disturbances and intractable neuropathic pain that is not amenable to repair. This injury disrupts sensory inputs from the dorsal roots to the spinal cord and the damaged axons do not regenerate across the PNS-CNS interface, the dorsal root entry zone. This thesis investigated the role of OECs for repairing DRI-associated neuropathic pain, which has never been previously explored. Chapter 2 of this thesis characterised two DRI models, a partial (2-root) or complete (4-root) deafferentation of the rat forepaw. The 2-root animals developed persistent allodynia and hyperalgesia, whereas in the 4-root DRI, in contrast, reduced sensation (desensitisation) was found within the affected forepaw. The degree of deficits on performing complex, skilled forepaw movements was proportional to the severity of DRI. Sensory control of forepaw movements was permanently abolishes in animals with 4-root DRI. With the goal of repairing DRI-associated neuropathic pain, the efficacy of genetically modified OECs that carry a novel GDNF construct was examined. These modified GDNF-OECs were able to produce GDNF in vitro, however, died rapidly and failed to yield long term GDNF expression after both acute and delayed transplantation into the DRI spinal cord. Unmodified plain OECs were then used. The results show that delayed transplantation of OECs attenuated the development of DRI-associated allodynia and hyperalgesia. Central reorganisations occurred within the dorsal horn following DRI, including reduction in the area of deep dorsal horn, permanent depletion of IB4-labeled axons and restoration of CGRP-labelled afferents in the denervated superficial laminae. The development of neuropathic pain is suggested to be mediated by the aberrant expansion of large myelinated VGLUT1-positive afferents into the superficial laminae, which normally receive nociceptive inputs. The effect of OECs on modulating nociception seems to be mediated by factors other than inhibition of afferent sprouting. In conclusion, the results in this thesis demonstrated the potential effect of OECs for modulating DRI-associated neuropathic pain. This finding could have clinical applicability for resistant pain sequelae resulting from neurotrauma.
| Identifer | oai:union.ndltd.org:ADTP/275901 |
| Date | January 2009 |
| Creators | Wu, Ann Shang, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Wu Ann Shang., http://unsworks.unsw.edu.au/copyright |
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