The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder
Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson
Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson
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Research Article Neuroscience

The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder

Abstract

Opioid use disorder (OUD) has become a leading cause of death in the United States, yet current therapeutic strategies remain highly inadequate. To identify potential treatments for OUD, we screened a targeted selection of over 100 drugs using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride reduced the physical signs associated with opioid withdrawal. In rat models of neuropathic pain, finasteride did not alter the antinociceptive effect of opioids and reduced withdrawal-induced hyperalgesia. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish in a fashion akin to the effects of finasteride. These results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new treatment option for this disorder.

Authors

Gabriel D. Bosse, Roberto Cadeddu, Gabriele Floris, Ryan D. Farero, Eva Vigato, Suhjung J. Lee, Tejia Zhang, Nilesh W. Gaikwad, Kristen A. Keefe, Paul E.M. Phillips, Marco Bortolato, Randall T. Peterson

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Figure 6

Finasteride does not affect the antinociceptive effect of opioids in a neuropathic pain model.

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Finasteride does not affect the antinociceptive effect of opioids in a n...
(A) Paw-withdrawal thresholds (PWTs) in the Randall-Selitto test. Pain tolerance was measured over 180 minutes after treatment. Both doses of morphine significantly increased PWT compared with animals tested immediately before injection. Two-way ANOVA significant effect of time [F(6, 72) = 31.09, P < 0.0001]. Morphine 1 mg/kg: n = 6; morphine 3 mg/kg: n = 8 per condition. (B) Cotreatment with finasteride (50 mg/kg) did not block the antinociceptive effect of morphine (3 mg/kg). Two-way ANOVA significant effect of time [F(6, 48) = 45.31, P < 0.0001] but no significant effect of treatment [F(1, 8) = 0.19, P = 0.68] and no effect of interaction [F(6, 48) = 0.37, P = 0.89]. n = 5 rats per condition. (C) Finasteride did not affect the thermal antinociceptive effect of morphine as measured by the time before paw lick in response to different temperatures 30 minutes after treatment with morphine. Two-way ANOVA: at 48.5°C, significant effect of treatment [F(2, 9) = 770, P < 0.0001]; at 51.5°C, significant effect of treatment [F(2, 9) = 33.12), P < 0.0001]. The results for vehicle plus morphine and finasteride plus morphine were significantly different from those seen in the untreated animals. No difference was observed between vehicle plus morphine and finasteride plus morphine treatments. n = 4 rats per condition. (D) Finasteride reduced hyperalgesia associated with opioid withdrawal. Rats subjected to SNL and a 6-day escalating morphine treatment were injected with finasteride (50 mg/kg, i.p.) or vehicle. Mechanical nociception was measured immediately on the injured paw after naloxone treatment and repeated 30 and 60 minutes later. Two-way ANOVA significant effect of interaction [F(2, 20) = 4.53, P = 0.024], time [F(2, 20) = 19.4, P < 0.0001], treatment [F(1, 10) = 13.1, P = 0.0046]. *P < 0.05, **P < 0.01. Data are shown as the mean ± SEM. Adult male Sprague-Dawley rats were used to test the effect of finasteride treatment on morphine antinociceptive effects, and adult male Long-Evans rats were used for the naloxone-precipitated withdrawal experiment. These experiments were performed using a between-subject design.