Defense Date

2012

Document Type

Thesis

Degree Name

Master of Science

Department

Pharmacology & Toxicology

First Advisor

Steven Negus

Abstract

ANTINOCICEPTIVE EFFECTS OF MONOAMINE REUPTAKE INHIBITORS IN ASSAYS OF PAIN-STIMULATED AND PAIN-DEPRESSED BEHAVIOR By Marisa B. Rosenberg A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. Virginia Commonwealth University, 2012 Advisor: Sidney Stevens Negus, Ph.D. Professor, Department of Pharmacology/Toxicology Noxious stimuli can produce pain-related stimulation of some behaviors (e.g. withdrawal responses) and depression of other behaviors (e.g. feeding, locomotion, responding maintained by many types of positive reinforcement). Monoamine reuptake inhibitors are used clinically to treat depression and to manage some types of pain. This study examined the antinociceptive properties of a variety of monoamine reuptake inhibitors selective for SERT, NET and DAT in complementary assays of acute pain-stimulated and pain-depressed behaviors. Intraperitoneal injection of dilute lactic acid (1.8% in a volume of 1ml/kg) was used as a noxious stimulus to stimulate a stretching response and to depress intracranial self-stimulation (ICSS) of the median forebrain bundle. All eight monoamine reuptake inhibitors produced an antinociception-like blockade of acid-stimulated stretching, but only compounds with prominent DA reuptake inhibition (SDRIs RTI-113 and bupropion and the TRI RTI-112) were able to block acid-depressed ICSS, although these effects were produced only at doses that also produced an abuse-related facilitation of control ICSS. Selective or mixed-action inhibitors of 5-HT and NE failed to block acid-induced depression of ICSS. In a separate group of rats, citalopram was also tested using a repeated dosing regimen (10 mg/kg x 3 doses) shown previously to produce antidepressant effects in a forced-swim test in rats. As with acute administration, repeated citalopram decreased acid-stimulated stretching but failed to block acid-induced depression of ICSS. Taken together, these results suggest that SSRIs, SNRIs and S+NRIs produce relatively non-selective depression of all behavior rather than a selective blockade of sensory sensitivity to noxious stimuli. Conversely, dopamine reuptake may be able to block sensory detection of noxious stimuli. Additionally, these results suggest that assays of pain-depressed behavior can provide new insights on analgesia-related effects of monoamine reuptake inhibitors.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2012

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