Lack of effect of the nociceptin opioid peptide agonist Ro 64-6198 on pain-depressed behavior and heroin choice in rats. (1st February 2022)

• Record Type: Journal Article
• Authors: Moerke, Megan Jo; Negus, S. Stevens; Banks, Matthew L.
• Is Part Of: Drug and alcohol dependence. Volume 231(2022)
• Publication Date: 2022-02-01
• Subjects: OUD opioid use disorder -- NOP nociceptin opioid peptide -- N/OFQ nociceptin/orphanin FQ -- ICSS intracranial self-stimulation -- HEAL Help End Addiction over the Long-term -- FR fixed-ratio -- MCR maximum control rate; Nociceptin opioid peptide -- Intracranial self-stimulation -- Opioid self-administration -- Drug choice -- Medication development -- Pain-depressed behavior; Drug abuse -- Periodicals; Alcoholism -- Periodicals; 616.86
• DOI: 10.1016/j.drugalcdep.2021.109255
• Languages: English
• ISSNs: 0376-8716

Abstract

Abstract: Rationale and objective: One objective of the National Institutes of Health Helping to End Addiction Long-term (HEAL) initiative is to accelerate research on safer and more effective medications for both pain and opioid use disorder. Ligands that activate the nociceptin opioid peptide receptor (NOP) constitute one class of candidate drugs for both applications. The present preclinical study determined the effectiveness of the NOP agonist Ro 64-6198 to produce antinociception in a pain-depressed behavior procedure and attenuate opioid self-administration in a heroin-vs-food choice procedure. Methods: In Experiment 1, Adult Sprague-Dawley rats were equipped with microelectrodes and trained to respond for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. The potency, time course, and receptor mechanism of effects produced by R0 64-6198 alone (0.32–3.2 mg/kg) on ICSS were examined, followed by evaluation of 0.32–1.0 mg/kg Ro 64-6198 effectiveness to block lactic acid-induced depression of ICSS. In Experiment 2, rats self-administered heroin under a heroin-vs-food choice procedure during a regimen of repeated, daily intraperitoneal administration of vehicle or Ro 64-6198 (1–3.2 mg/kg/day). Results: Ro 64-6198 produced dose- and time-dependent ICSS depression that was blocked by the selective NOP antagonist SB612111 but not by naltrexone. Ro 64-6198 failed to block acid-induced depression of ICSS. Repeated Ro 64-6198 pretreatment also failed to attenuate heroin-vs-food choice up to doses that significantly decreased operant behavior. Conclusions: These results do not support the utility of Ro 64-6198 as a stand-alone medication for either acute pain or opioid use disorder. Highlights: Ro 64-6198 depressed intracranial self-stimulation. Ro 64-6198 effects on ICSS were mediated by NOP receptors. Ro 64-6198 failed to block acid-depressed ICSS. Ro 64-6198 failed to attenuate heroin choice in rats.