title: Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil.
abstract: 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 (Q0parameter; 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 Q0and 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.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Porter-Stransky
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Brandon S
authors.identifier: http://orcid.org/0000-0001-6014-4514
authors.initials: BS
authors.lastname: Bentzley
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Aston-Jones
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001425:Bacterial Outer Membrane Proteins; D001522:Behavior, Animal / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology; D003216:Conditioning, Operant; D060909:Economics, Behavioral; D029968:Escherichia coli Proteins; D007206:Individuality; D008074:Lipoproteins; D008297:Male; D009042:Motivation / Q000187:drug effects*; D009287:Naphthyridines; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D064446:Orexin Receptors / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077208:Remifentanil; D012646:Self Administration; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000701:Analgesics, Opioid; D001425:Bacterial Outer Membrane Proteins; D001583:Benzoxazoles; D029968:Escherichia coli Proteins; C578627:Hcrtr1 protein, rat; D008074:Lipoproteins; D009287:Naphthyridines; C095021:NlpE protein, E coli; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D010880:Piperidines; D014508:Urea; D000077208:Remifentanil
keywords: Addiction; behavioral economics; drug abuse; orexin; remifentanil; self-administration