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Effect of TRV130 and methadone on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats

Abstract

The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.–6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2–4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.

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Fig. 1: Baseline on fentanyl-vs.-food choice prior to extended access fentanyl self-administration.
Fig. 2: TRV130 and methadone decrease somatic withdrawal sign expression and weight loss following withdrawal from extended access to fentanyl self-administration.
Fig. 3: Effects of repeated vehicle, TRV130, and methadone treatment on fentanyl-vs.-food choice in male opioid-dependent rats assessed 8 h after overnight (6:00 p.m.–6:00 a.m.) extended access fentanyl self-administration sessions.
Fig. 4: Effects of repeated vehicle, TRV130, and methadone treatment on fentanyl-vs.-food choice in male post-opioid-dependent rats.

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Funding

Research was supported by the National Institute on Drug Abuse of the National Institutes of Health under R01DA026946 (PI, SSN), P30DA033934 (PI, William L. Dewey), and NIH Bench-to-Bedside Grant (PI, DHE). The research was supported [in part] by the Intramural Research Program of the NIH, NIDA. The National Institute on Drug Abuse had no role in study design, collection, analysis or interpretation of the data, in the writing or decision to submit the manuscript for publication. The manuscript content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. YS is an associate editor for Neuropsychopharmacology.

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EAT, MLB, SSN, DHE, and YS designed and conceptualized the study. EAT carried out the experiments. EAT, MLB, and SSN performed the data analyses. BEB synthesized TRV130. DHE and SSN secured funding. All authors reviewed the content and approved the final version prior to submission.

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Correspondence to E. Andrew Townsend.

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Townsend, E.A., Blough, B.E., Epstein, D.H. et al. Effect of TRV130 and methadone on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01393-3

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