Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats

Abstract

Nociceptin/orphanin FQ peptide (NOP) receptor agonists attenuate morphine-induced conditioned place preference in rodents. However, it is not known whether NOP agonists have reinforcing properties or can inhibit mu opioid receptor (MOP)-mediated reinforcement as measured by drug self-administration in rodents. Further understanding the behavioral effects of NOP agonists could suggest them as having potential in attenuating reinforcing effects of opioids. In the first part of the study, reinforcing properties of selective NOP agonist SCH221510 were determined and compared with the full MOP agonist remifentanil under fixed-ratio 5 (FR5) and progressive-ratio (PR) schedules of drug self-administration. In the second part, effects of systemic and intracisternal pretreatment of SCH221510 were determined and compared with MOP antagonist naltrexone in attenuating reinforcing effects of remifentanil and a non-drug reinforcer (sucrose pellets). Remifentanil self-administration (0.3-10 µg/kg/infusion) generated a biphasic dose-response curve, characteristic of drugs with reinforcing properties. SCH221510 (3-300 µg/kg/infusion) self-administration resulted in flat dose-response curves and early break-points under the PR, indicative of drugs lacking reinforcing value. Intracisternally, but not systemically, administered SCH221510 (0.3-3 µg) attenuated remifentanil self-administration, comparable with systemic naltrexone (0.03-0.3 mg/kg). SCH221510 (1-3 µg), unlike naltrexone (0.03-1 mg/kg), attenuated responding for sucrose pellets. Both effects of SCH221510 were reversed by the NOP antagonist J-113397 (0.3-3 µg). These results suggest that SCH221510 does not function as a reinforcer in rats, and that it can attenuate the reinforcing value of MOP agonists; therefore, the potential utility of NOP agonists for the treatment of drug addiction warrants further evaluation.

Keywords: Drug self-administration; NOP receptor; Nociceptin/orphanin FQ; Opioids; Remifentanil; SCH221510.

Fig. 1

Dose-response curves for self-administration of remifentanil and SCH221510 under a fixed ratio 5 schedule of reinforcement. Results are expressed as the mean ± S.E.M. number of active nose-poke responses (A) and number of infusions obtained (B) in a 1 h session. Each data point represents mean data from the final 3 sessions at each dose of both drugs. Asterisks (*) denote significant differences from the respective vehicle (P<0.05).

Fig. 2

Dose-response curves for self-administration of remifentanil and SCH221510 under the progressive ratio schedule of reinforcement. Results are expressed as the mean ± S.E.M. number of active nose-poke responses (A), number of infusions (B) and final ratio completed (C) per session. Each value represents mean data from the final 2 sessions at each dose of remifentanil or SCH221510. Asterisks (*) denote significant differences from the respective vehicle (P<0.05).

Fig. 3

Effects of naltrexone on remifentanil- and sucrose pellet-maintained responding under a fixed ratio 5 schedule of reinforcement. Naltrexone was administered subcutaneously as a 20 min pretreatment to determine its effects on remifentanil (left panels) or sucrose pellet-maintained responding (right panels) in a single session. Results are expressed as the mean ± S.E.M. (n=6) number of active nose-poke responses (A) and rate of responding (responses/sec) (B) for remifentanil and number of active nose-poke responses (C) and rate of responding (responses/sec) (D) for sucrose pellets at each dose of naltrexone. ‘BL’ denotes mean data across-subject at the end of remifentanil acquisition. ‘Pre-’ denotes mean data across-subjects from a session without a naltrexone pretreatment. Asterisks (*) denote significant differences from the vehicle pretreatment (P<0.05).

Fig. 4

Effect of SCH221510 on remifentanil self-administration under a fixed ratio 5 schedule of reinforcement. SCH221510 was administered subcutaneously (left panels) or intracisternally (right panels) as a 20 min pretreatment. Results are expressed as the mean ± S.E.M. (n=6) number of active nose-poke responses (A & C) and rate of responding (responses/sec) (B & C) in a single 1 h remifentanil self-administration session at each dose of SCH221510. ‘BL’ denotes mean data across-subject at the end of remifentanil acquisition ‘Pre-’ denotes data from a session without a SCH221510 pretreatment. Asterisks (*) denote significant differences from the vehicle pretreatment (P<0.05).

Fig. 5

Effect of SCH221510 on sucrose pellet-maintained responding under a fixed ratio 5 schedule of reinforcement. SCH221510 was intracisternally administered as a 20 min pretreatment. Results are expressed as the mean ± S.E.M. (n=6) number of active nose-poke responses (A) and rate of responding (responses/sec) (B) for sucrose pellets in a single session at each dose of SCH221510. ‘Pre-’ denotes data from a session without a SCH221510 pretreatment. Asterisks (*) denote significant differences from the vehicle pretreatment (P<0.05).

Fig. 6

Effect of J-113397 on SCH221510-induced attenuation of remifentanil- and sucrose pellet-maintained responding under a fixed ratio 5 schedule of reinforcement. J-113397 and SCH22150 were intracisternally co-administered as a 20 min pretreatment. Results are expressed as the mean ± S.E.M (n=6) number of active nose-poke responses (A) and rate of responding (responses/sec) (B) for remifentanil and number of active nose-poke responses (C) and rate of responding (responses/sec) (D) for sucrose pellets in a single session. Asterisks (*) denote significant differences from the J-113397 vehicle co-administered with 0.3 μg (grey bars) or 1 μg (black bars) of SCH221510 (P<0.05).