Individual differences in orexin‐I receptor modulation of motivation for the opioid remifentanil

• Published in: Addiction biology Vol. 22; no. 2; pp. 303 - 317
• Main Authors: Porter‐Stransky, Kirsten A., Bentzley, Brandon S., Aston‐Jones, Gary
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.03.2017
• Subjects: Addiction; Analgesics, Opioid - pharmacology; Animals; Bacterial Outer Membrane Proteins; Behavior, Animal - drug effects; behavioral economics; Benzoxazoles - pharmacology; Conditioning, Operant; Drug abuse; Economics; Economics, Behavioral; Elasticity of demand; Escherichia coli Proteins; Footshock; Individuality; Lipoproteins; Male; Motivation; Motivation - drug effects; Naphthyridines; Narcotics; Opioid receptors; orexin; Orexin Receptor Antagonists - pharmacology; Orexin Receptors - drug effects; Orexin Receptors - metabolism; Orexins; Piperidines - pharmacology; Rats; Rats, Sprague-Dawley; Reinstatement; Remifentanil; Self Administration; Urea - analogs & derivatives; Urea - pharmacology; behavioral economics; drug abuse; orexin; remifentanil; Addiction; self-administration
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12323

Orexin‐1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within‐session behavioral‐economics threshold procedure to screen for individual differences in economic demand for the ultra‐short‐acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral‐economics procedure revealed robust individual differences in free consumption of remifentanil (Q0 parameter; hedonic set point). Rats with low baseline Q0 (low takers) displayed high demand elasticity (α parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q0 (high takers) exhibit low demand elasticity (low α) by continuing to self‐administer remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self‐administering remifentanil. Interestingly, Ox1R antagonism with SB‐334867 reduced Q0 and increased α in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue‐induced, but not drug‐induced, reinstatement of remifentanil seeking in low takers but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictive‐like behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders. Using a within‐session behavioral economic procedure, we observed in rats robust individual differences in motivation for the short‐acting opioid remifentanil. High takers exhibited greater drug consumption at low cost, continued to work for drug despite increases in price (low demand elasticity), and withstood greater electrical shock to continue self‐administering remifentanil. Antagonism of orexin 1 receptors reduced free consumption, demand elasticity, and cue‐induced reinstatement of drug seeking in low takers but not in high takers, which exhibit an addition‐like phenotype.