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

NEUROPHARMACOLOGY

卷:185

Article

Pantouli, Fani^1,2  Grim, Travis W.^1,2  Schmid, Cullen L.^1,2  Acevedo-Canabal, Agnes^1,2  Kennedy, Nicole M.^1,3  Cameron, Michael D.^1,3  Bannister, Thomas D.^1,3  Bohn, Laura M.^1,2 

[1] Scripps Res Inst, Dept Mol Med, Jupiter, FL USA

[2] Scripps Res Inst, Dept Neurosci, Jupiter, FL USA

[3] Scripps Res Inst, Dept Chem, Jupiter, FL USA

关键词: Tolerance;    Oxycodone;    Opioid;    Chemotherapeutic-induced pain;    Neuropathic pain;    Biased agonism;    Paclitaxel;    Formalin;    Functional selectivity;    Morphine;    Efficacy;   

DOI  :  10.1016/j.neuropharm.2020.108439

来源: Elsevier

【 摘 要 】

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTP gamma S binding over beta arrestin2 recruitment in cellular assays, thereby demonstrating signaling bias. In mice, SR-17018 stimulates GTPyS 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.

【 授权许可】

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