Date of Award

8-9-2014

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Sarah Sweitzer

Abstract

Chronic neuropathic pain often decreases quality of life, incurs high medical costs and is difficult to treat. Neuropathic pain can develop as a result of nerve damage induced by trauma or diseases such as diabetes and cancer. This type of pain is often resistant to standard treatments for chronic pain. Effective and safe treatments for persistent neuropathic pain remain an unmet therapeutic need. The primary objective of this work was to test the hypotheses that peripheral opioid analgesia can be enhanced using a herpes simplex virus vector gene therapy approach and peripheral opioid tolerance can be prevented by blocking opioid receptor heterodimerization using a small peptide inhibitor in neuropathic pain conditions in rodents. L5 spinal nerve transection was used to model chronic neuropathic pain.

Utilization of an injury specific promoter to overexpress mu opioid receptors demonstrated a greater degree and an earlier onset of antinociception in animals infected with the GAL-MOR virus compared to those with the CMV-MOR virus. In addition, immunohistochemistry analysis showed a decrease in MOR expression in the dorsal horn of spinal cords in injured animals and this decrease was reversed with CMV and Gal promoter viruses. Overall, these results suggest that an injury and population specific promoter can drive gene expression in a specific population of neurons in the dorsal horn of the spinal cord.

By using a small peptide inhibitor of mu- and delta-opioid receptor heterodimerization, it was shown that an increase in heterodimer formation in HEK293 cells after chronictreatment with a MOR agonist can be prevented using a peptide inhibitor of MOR-DOR. In vivo results showed that by using a peptide inhibitor of MOR-DOR, peripheral tolerance can be prevented. Additionally, it was found that chronic opioid treatment in a rat model of neuropathic pain appears to cause changes in downstream mediators that can be augmented by the use of a peptide inhibitor of MOR-DOR heterodimer formation. These results suggest that MOR-mediated peripheral tolerance can be prevented by inhibiting MOR-DOR heterodimerization and that inhibiting MOR-DOR heterodimerization potentially has effects on downstream signaling mediators and pathways. Taken together these studies have developed both viral vector approaches to attenuate neuropathic pain and enhance opioid analgesia and a small peptide approach to prevent the development of opioid tolerance.

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