PROJECT SUMMARY: This new F30 application proposes preclinical research to examine interactions between opioid pharmacology and chemotherapy-induced neuropathy (CIPN) produced in male and female rats by the commonly administered antineoplastic drug paclitaxel (PTX). PTX is known to cause a CIPN frequently associated with behavioral depression that cannot be fully reversed by treatment with mu-opioid receptor (MOR) agonists. Recently, clinical studies have demonstrated an increased vulnerability to opioid abuse in patients treated with MOR agonists for chronic cancer pain, finding a high rate of abuse in this cohort. This application will test the hypothesis that PTX is able to alter MOR functioning in different regions of the central nervous system (CNS) resulting in depression of behavior, reduced efficacy of MOR agonists to produce analgesia, and increased sensitivity to abuse-related effects of MOR agonists. To evaluate this hypothesis, this proposal includes novel studies to investigate a sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) and of increase in mechanical allodynia in male and female rats. Behavioral studies will investigate the impact of PTX on the effectiveness of acute and repeated morphine to produce analgesic and abuse-related effects. Finally, complementary neurochemical studies will examine the effect of PTX on MOR signaling using the functional assay of agonist-stimulated [35S]GTP?S binding in regions of the CNS associated with pain, analgesia, and abuse. Completion of this project will provide an improved understanding of the mechanisms of CIPN-associated depression of behavior and the behavioral and neurochemical implications of PTX-treatment for MOR functioning and opioid abuse.