Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain

• Published in: Neuropharmacology Vol. 185; p. 108439
• Main Authors: Pantouli, Fani, Grim, Travis W., Schmid, Cullen L., Acevedo-Canabal, Agnes, Kennedy, Nicole M., Cameron, Michael D., Bannister, Thomas D., Bohn, Laura M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2021
• Subjects: Analgesics, Opioid - administration & dosage; Animals; Benzimidazoles - administration & dosage; Biased agonism; Chemotherapeutic-induced pain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Efficacy; Female; Formalin; Functional selectivity; Infusion Pumps, Implantable; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Morphine; Morphine - administration & dosage; Neuralgia - drug therapy; Neuralgia - pathology; Neuropathic pain; Opioid; Oxycodone; Oxycodone - administration & dosage; Paclitaxel; Pain Measurement - drug effects; Pain Measurement - methods; Piperidines - administration & dosage; Receptors, Opioid, mu - agonists; Tolerance; Treatment Outcome; Oxycodone; Functional selectivity; Biased agonism; Paclitaxel; Tolerance; Opioid; Formalin; Morphine; Efficacy; Chemotherapeutic-induced pain; Neuropathic pain
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108439

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.
•SR-17018 retains efficacy after repeated dosing in a mouse formalin assay.•SR-17018 retains efficacy after repeated dosing in a chemotherapeutic neuropathy model.•SR-17018 produces tolerance in a mouse tail flick model upon chronic treatment.•Oxycodone and morphine produce tolerance in these models.