Antinociceptive effects of G-protein biased mu opioid receptor agonists in male and female rats with chemotherapy-induced neuropathy
Document Type
Basic Science Research
Date of Poster
2022
Date of Submission
June 2022
Abstract
Aim: Mu-opioid receptor (MOR) agonists are often prescribed for the treatment of chemotherapy-induced neuropathy (CIN). Recent drug development strategies have focused on opioids with signaling profiles that “bias” activation of specific intracellular pathways (e.g., G-protein signaling) over others with the aim of increasing therapeutic selectivity. However, it is unknown if the variances in these signaling profiles at the MOR differentially modulate the antinociceptive effects of MOR agonists against neuropathic pain. In the present study, we tested a series of MOR agonists of varying G-protein signaling bias in a rat model of CIN. Methods: CIN was induced in male and female rats with injections of paclitaxel (PTX; N=10, 5 per sex) and compared to PTX-vehicle treated rats (N=10, 5 per sex). Antinociception was measured using the von Frey procedure with intravenous fentanyl (0.0018-0.01 mg/kg), oxycodone (0.1-0.56 mg/kg), SR14968 (0.0056-0.32 mg/kg), or SR17018 (0.18-1.0 mg/kg) in a counterbalanced order. ED50 values and 95% confidence intervals were calculated using linear regression to compare potencies between the agonists. To confirm that the antinociceptive effects were mediated by opioid receptors, the dose that produced 80% of the maximum effect for each agonist was tested before and after pretreatment with naltrexone. Results: All drugs were equi-effective but varied in potency, yielding a potency order of: Fentanyl > SR14968 > Oxycodone = SR17018. Additionally, no sex differences in efficacy or potency occurred for any drug. The antinociceptive effects of all agonists were blocked by naltrexone. Conclusion: This study confirms that biased MOR agonists produce antinociception in a neuropathy model that is typical of the MOR agonist drug class.
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VCU School of Medicine GME Resident and Fellow Research Day Posters