DOI
https://doi.org/10.25772/B6X1-YA05
Defense Date
2015
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
S. Stevens Negus
Abstract
Pain is often associated with depression of behavior and mood, and relief of pain-related depression is a common goal of treatment. This goal of this dissertation was to conduct preclinical research experiments designed to address a set of three inter-related aims that examine the expression, mechanisms and treatment of pain-related depression of Intracranial Self-Stimulation (ICSS) in rats. First, studies evaluated the hypothesis that acute acid-induced depression of ICSS was mediated by a kappa opioid receptor mediated decrease in mesolimbic dopamine release in the nucleus accumbens. Results support a role for depressed mesolimbic dopamine release in pain-related depression of ICSS; however, a role for kappa opioid receptors is not supported. Second, studies evaluated the effectiveness of a more sustained inflammatory noxious stimulus (intraplantar CFA) and a sustained neuropathic stimulus (intraplantar formalin) to produce a long-term pain-related depression of ICSS, and the role of kappa opioid receptors in mediating this sustained pain-related depression of ICSS. Results indicated that only the neuropathic stimulus (formalin) was sufficient to produce sustained depression of ICSS, and as in the initial studies, our data did not support a role for kappa receptors in mediating this effect. Given the poor effectiveness of a kappa receptor antagonist to block acute or chronic pain-related depression of ICSS, the final set of studies evaluated the pharmacology of representative drugs from five different classes of established or candidate analgesics (mu opioid agonists, non-steroidal anti-inflammatory drugs, monoamine uptake inhibitors, anticonvulsants, and cannabinoid agonists) to reverse the sustained depression of ICSS produced by formalin as a neuropathic stimulus. Results demonstrate the mu agonist morphine, the monoamine uptake inhibitor bupropion, the anticonvulsant gabapentin, and the cannabinoid agonist THC were able to reverse formalin-induced mechanical allodynia as a pain-stimulated behavior, but only the mu agonist morphine and the monoamine uptake inhibitor bupropion were effective to reverse formalin-induced depression of ICSS. These results provided additional evidence for dissociable drug effects in preclinical assays of pain-stimulated and pain-depressed behavior and also support further studies with monoamine uptake inhibitors with a dopaminergic component (like bupropion) for treatment of neuropathic pain.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-11-2015