Comparison of the reinforcing, antinociceptive, and respiratory depressant effects of prototypical and G-protein biased mu-opioid receptor agonists in male and female Sprague–Dawley rats

• Published in: Psychopharmacology Vol. 241; no. 12; pp. 2453 - 2469
• Main Authors: Zamarripa, C. Austin, Pareek, Tanya, Pham, Loc M., Blough, Bruce E., Schrock, Hayley M., Vallender, Eric J., Sufka, Kenneth J., Freeman, Kevin B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2024; Springer Nature B.V
• Subjects: Agonists; Analgesics; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; Biomedical and Life Sciences; Biomedicine; Dose-Response Relationship, Drug; Drug abuse; Female; Fentanyl; Fentanyl - administration & dosage; Fentanyl - pharmacology; Male; Narcotics; Neurosciences; Opioid receptors (type mu); Original Investigation; Oxycodone; Oxycodone - administration & dosage; Oxycodone - pharmacology; Pain perception; Pharmacology/Toxicology; Proteins; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - agonists; Reinforcement Schedule; Reinforcement, Psychology; Respiratory Insufficiency - chemically induced; Respiratory Insufficiency - drug therapy; Self Administration; Spiro Compounds; Thiophenes; Self-administration; SR14968; Oxycodone; Fentanyl; Antinociception; Respiratory depression; SR17018
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-024-06690-x

Rationale G-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints. Objectives The aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats. Methods In the self-administration study, four separate groups of Sprague–Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography. Results All MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner. Conclusion The present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics.