EFFECTS OF MU OPIOID RECEPTOR AGONISTS ON INTRACRANIAL SELF-STIMULATION IN THE ABSENCE AND PRESENCE OF “PAIN” IN RATS

Pain is a significant health problem. Mu opioid receptor agonists are used clinically as analgesics, but their use is constrained by high abuse liability. Intracranial self-stimulation (ICSS) is a preclinical behavioral procedure that has been used to assess abuse potential of opioids, and drug-induced facilitation of ICSS is interpreted as an abuse-related effect. ICSS can also be used as a behavioral baseline to detect affective dimensions of pain. Specifically, pain-related depression of ICSS can model pain-related depression of behavior and mood, and drug-induced blockade of pain-related ICSS depression can serve as a measure of affective analgesia. This dissertation used mu agonists that vary in efficacy at the mu receptor (methadone> fentanyl> morphine> hydrocodone> buprenorphine> nalbuphine) and compared their effects on ICSS in the absence (phase one) or presence (phase 2) of pain. Adult male Sprague-Dawley rats were equipped with intracranial electrodes targeting the medial forebrain bundle and trained to lever press for brain stimulation. Different frequencies of stimulation maintained a frequency-dependent increase in ICSS rates, and permitted detection of both rate-increasing and rate-decreasing treatment effects. During phase 1, medium- and high-efficacy mu agonists produced initial rate-decreasing effects, followed by abuse-related rate-increasing effects at later time points. Repeated morphine administration produced tolerance to its own rate-decreasing effects, cross-tolerance to rate-decreasing effects of other mu agonists, and enhanced expression of rate-increasing effects. Low efficacy mu agonists only produced rate-increasing effects, which were enhanced after repeated morphine. These results suggest that previous opioid exposure increases expression of abuse-related facilitation of ICSS by mu agonists regardless of efficacy. During phase 2, intraperitoneal administration of lactic acid (1.8%) served as a noxious stimulus to depress ICSS. All mu agonists blocked acid-induced depression of ICSS at doses similar to those that facilitated ICSS in the absence of pain. A higher intensity noxious stimulus (5.6 % acid) produced further depression of ICSS and reduced the antinociceptive potency of both methadone and nalbuphine. Morphine antinociception was resistant to tolerance in the assay of acid-depressed ICSS. Overall, these results provide a basis for comparing determinants of abuse-related opioid effects in the absence of pain with their affective analgesic effects in the presence of pain.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmacology & Toxicology

Year dc:date.available

2013

Author dc:creator

• Altarifi, Ahmad

Contributors dc:contributor

• S. Stevens Negus

• opioids
• intracranial self-stimulation
• pain
• opioid efficacy
• opioid abuse
• opioid dependence
• mu receptor
• chronic morphine
• rats
• Medical Pharmacology
• Medical Sciences
• Medicine and Health Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/518

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1517