Lack of effect of different pain-related manipulations on opioid self-administration, reinstatement of opioid seeking, and opioid choice in rats

• Published in: Psychopharmacology Vol. 238; no. 7; pp. 1885 - 1897
• Main Authors: Reiner, David J., Townsend, E. Andrew, Orihuel, Javier, Applebey, Sarah V., Claypool, Sarah M., Banks, Matthew L., Shaham, Yavin, Negus, S. Stevens
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2021; Springer; Springer Nature B.V
• Subjects: Acids; Addictions; Analgesics, Opioid - administration & dosage; Animal experimentation; Animals; Biomedical and Life Sciences; Biomedicine; Capsaicin; Care and treatment; Choice Behavior - drug effects; Choice Behavior - physiology; Chronic pain; Conditioning, Operant - drug effects; Conditioning, Operant - physiology; Drug self-administration; Drug-Seeking Behavior - drug effects; Drug-Seeking Behavior - physiology; Experiments; Extinction behavior; Extinction, Psychological - drug effects; Extinction, Psychological - physiology; Female; Fentanyl; Fentanyl - pharmacology; Heroin; Inflammation; Lactic acid; Male; Methods; Narcotics; Neurosciences; Opioid-Related Disorders - psychology; Opioids; Original Investigation; Pain; Pain - drug therapy; Pain - psychology; Pain Measurement - methods; Pain Measurement - psychology; Pain perception; Pharmacology/Toxicology; Physiological aspects; Psychiatry; Rats; Reinforcement; Reinforcement, Psychology; Reinstatement; Self Administration - methods; United States; Relapse; Pain; Opioid self-administration; Extinction; Reinstatement; Opioid choice
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-021-05816-9

Rationale and objective Pain-related factors increase the risk for opioid addiction, and pain may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here, we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food. Methods In Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund’s Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food. Results In Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice. Conclusions Results extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.