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.
This application proposes to investigate the neurochemical and behavioral toxic effects of the chemotherapeutic paclitaxel and its ability to change mu-opioid receptor functioning in terms of analgesia and abuse potential. The following studies will be conducted following a dosing regimen of the chemotherapeutic: (a) behavioral assays of intracranial self-stimulation and mechanical allodynia focusing on the neuropathic side-effect often seen with paclitaxel, (b) behavioral assay of intracranial self-stimulation with a chronic morphine dosing regimen to study changes in opioid abuse or analgesic potential in animals suffering from a chronic neuropathy, and (c) agonist-stimulated [35S]GTP?S binding studies to probe the effects on mu-opioid receptor signaling in the brain and spinal cord. These experiments aim to elucidate information about the impact of this chemotherapy-induced neuropathy on the abuse and analgesic potentials of mu-opioid receptor agonists as these drugs are frequently administered concurrently to patients receiving chemotherapy.
|Legakis, Luke P; Bigbee, John W; Negus, S Stevens (2018) Lack of paclitaxel effects on intracranial self-stimulation in male and female rats: comparison to mechanical sensitivity. Behav Pharmacol 29:290-298|
|Legakis, L P; Negus, S S (2018) Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy. J Pharmacol Exp Ther 365:9-19|