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

Abstract

The mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPS binding over beta-arrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPgammaS 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.

Influence of G protein-biased agonists of μ-opioid receptor on addiction-related behaviors

“…Moreover, it prevented the onset of morphine withdrawal. However, recent data show that SR-17018 did not reverse morphine tolerance in tail flick assay [86]. These results suggest that SR-17018 may efficiently attenuate some aspects of opioid addictive behavior, but not under all circumstances.…”

“…As far as their addictive properties are considered, Grim et al [85] have shown that SR-17018 does not induce hot plate antinociceptive tolerance when administered chronically. A recently published study by Pantouli et al [86] was aimed to determine the effectiveness of SR-17018 in mouse models of pain. Under repeated dosing, SR-17018 developed tolerance in the tail immersion test, suggesting that tolerance to antinociceptive effects of SR-17018 may occur when tests measuring spinal reflexes are used.…”

“…No effects on the development of antinociceptive tolerance to morphine [83] Attenuation of rewarding properties of morphine in conditioned place preference test [83] No effects on morphine-induced locomotor activity and sensitization [83] Piperidine benzimidazoles (SR-compounds) SR-17018 Reversion of antinociceptive tolerance to morphine in hot plate [85], but not in tail flick test [86] Prevention of morphine withdrawal [85] recruit β-arr2, mice displayed unchanged respiratory depression and constipation following treatment with morphine and fentanyl. Somatic signs of withdrawal were also retained in these mice, regardless of no β-arr2 binding to μ-OR.…”