POST-SPINAL CORD INJURY BELOW-LESION NEUROPATHIC PAIN: MECHANISMS AND NOVEL THERAPEUTIC APPROACHES

Abstract

Neuropathic pain is a significant and frequent outcome of spinal cord injury (SCI), and is often refractory to treatment. A better understanding of the pathological processes following injury that contribute to the development of neuropathic pain will aid the search for novel therapeutics. In the second chapter of this thesis a murine model of post-SCI below-lesion neuropathic pain was utilized to investigate changes in GABAergic tone. The gad1:GFP transgenic mouse line allowed the study of a subpopulation of GFPlabeled GABAergic neurons under control of the GABA synthesizing glutamate decarboxylase enzyme. SCI was observed to result in a loss of GABAergic neurons, and secondary markers of GABAergic tone supported this observation. This finding suggests that GABAergic interneuron cell death accounts for the decreased GABAergic tone previously reported post-SCI. In the third chapter of this thesis it was attempted to prevent the death of GABAergic neurons post-SCI using a transgenic mouse line expressing increased levels of the X-linked inhibitor of apoptosis (XIAP) under the ubiquitin C promoter. No differences were observed between ubXIAP and wildtype mice, indicating that increased expression of XIAP is not sufficient to prevent the development of neuropathic pain post- SCI. The fourth chapter of this thesis attempted to prevent the development of neuropathic pain through a novel treatment schedule of the drug pregabalin. Pregabalin administered shortly after SCI prevented the development of neuropathic pain. Pregabalin initiated 1 week post-SCI had no effect. Early pregabalin treatment did not appear to dramatically alter glial activation, or expression of the pregabalin receptor, but we observed changes in markers associated with synaptic plasticity. My findings build upon our knowledge of the mechanisms underlying post-SCI below-lesion neuropathic pain, and suggest new avenues of research, such as the uses of preemptive treatment with pregabalin, that offer promise for translation to clinical use.