Author ORCID Identifier

https://orcid.org/0000-0001-9279-1142

Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

S. Stevens Negus

Abstract

Paclitaxel, vincristine, oxaliplatin, and bortezomib are cancer chemotherapy drugs with adverse effects that include chemotherapy-induced neuropathic pain (CINP) as well as depression of behavior and mood. In the clinical setting, opioids are often used concurrently with or following chemotherapy to treat pain related to the cancer or CINP, but repeated opioid exposure can also increase the risk of opioid abuse. This dissertation evaluated the effect of chemotherapy treatment on motivated behaviors and opioid reward in rats. The main findings of this evaluation are as follows: (1) Chemotherapy, at doses that produce robust and sustained mechanical hypersensitivity produce only weak or nonexistent depression of positively reinforced operant responding maintained either by electrical brain stimulation in an assay of intracranial self-stimulation or by food pellets in an assay of food-maintained responding. (2) There was no correlation between the expression of mechanical hypersensitivity and depression of motivated behaviors across individual animals, suggesting that these two effects of chemotherapy do not share common mechanisms of action. (3) Mechanical hypersensitivity, but not behavioral depression could be reversed with morphine. (4) The class of chemotherapeutic used in preclinical models is a determinant of the severity of effects on neuropathy-related endpoints and on the time course of these effects. (5) Chemotherapy does not protect against the rewarding effects of repeated morphine administration and does not alter the time course of the enhancement of reward with repeated morphine exposure. These findings suggest that administration of chemotherapy to rats induces mechanical hypersensitivity while failing to decrease behaviors dependent on mesolimbic dopamine signaling or protecting against morphine abuse-related effects. While apparent that chemotherapy can produce peripheral neuropathy, the data in this dissertation does not support the hypothesis that chemotherapy can produce behavioral depressant manifestations of chemotherapy-induced neuropathic pain (CINP) in rats.

Rights

© Luke P Legakis

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

4-20-2018

Available for download on Wednesday, April 19, 2023

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