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Punishment and reinforcement by opioid receptor agonists in a choice procedure in rats

Minervini, Vanessaa,c; Osteicoechea, Daniela C.a,c; Casalez, Angeloa,c; France, Charles P.a,b,c

doi: 10.1097/FBP.0000000000000436

Intravenous (i.v.) drug self-administration remains the ‘gold standard’ for assessing abuse potential of drugs. Failure of a drug to maintain self-administration might indicate merely the absence of positive-reinforcing effects but might also indicate presence of aversive effects. Sensitivity to aversive effects is thought to affect the initiation and maintenance of drug use as well as relapse. Choice procedures are used to study positive-reinforcing effects of drugs and to a much lesser extent to study punishing effects of drugs. Experiment 1 compared the μ-opioid receptor agonist remifentanil (0.001–0.01 mg/kg/infusion), the κ-opioid receptor agonist spiradoline (0.0056–0.056 mg/kg/infusion), and histamine (1.0 mg/kg/infusion) in rats choosing between a food pellet only and an i.v. infusion+a food pellet. To test whether a history with one punishing drug affects the punishing effects of a second drug, experiment 2 compared sensitivity with spiradoline in rats with and without a history of histamine punishment. All rats predominantly chose a pellet alone when histamine+a pellet was the alternative, and they predominantly chose remifentanil+a pellet over a pellet alone. In experiment 2, spiradoline was punishing in rats with a history of histamine punishment but not drug-naive rats. This food choice procedure is sensitive to reinforcing and punishing effects of different drugs in the same subjects, suggesting that the procedure is well-suited for studying drug mixtures (e.g. μ and κ agonists) and the impact of different physiological conditions (e.g. pain) on reinforcement and punishment.

Departments of aPharmacology


cThe Addiction Research, Treatment, and Training Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Correspondence to Charles P. France, PhD, Department of Pharmacology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7764, San Antonio, TX 78229, USA E-mail:

Received March 29, 2018

Accepted July 28, 2018

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