Opioid-based pharmacotherapy remains the most commonly prescribed treatment for patients suffering from neuropathic pain conditions. Although opioids are effective for treating neuropathic pain, when used chronically the development of adverse side effects, such as opioid analgesic tolerance, can develop. Previous studies have shown that exogenously delivered agmatine, (decarboxylated L-arginine) can prevent the development of opioid analgesic tolerance, dependence, and self-administration. This study investigated the impact of intrathecal adeno-associated virus serotype 5-human arginine decarboxylase (AAV5-hADC) in models of opioid analgesic tolerance. Pharmacological dose-response curves were collected from two cohorts using two different models of opioid analgesic tolerance. Tissues from the central nervous system of the subjects were further analyzed for hADC gene expression and for spinal agmatine levels. Investigations of the choroid plexus as a target for intrathecal gene therapeutics were also conducted. Region-directed genetic modulation of the agmatine metabolic pathway within the central nervous system could be a highly innovative approach for the control of opioid tolerance and other neuroplasticity disorders.
University of Minnesota Ph.D. dissertation. December 2014. Major: Experimental & Clinical Pharmacology. Advisor: Carolyn A. Fairbanks, Ph.D. 1 computer file (PDF); vii, 139 pages.
Churchill, Caroline Catharine.
The impact of gene transfer of arginine decarboxylase to the central nervous system on opioid analgesic tolerance.
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