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Deuterated Buprenorphine Mitigates Fentanyl Effects in Pregnant Rats

2024; American Society for Pharmacology and Experimental Therapeutics; Linguagem: Inglês

10.1124/jpet.078.903770

1521-0103

Julia Tobacyk, Saki Fukuda, Brian J. Parks, Michael D. Berquist, Lisa K. Brents,

Diet and metabolism studies

Abstract ID 90377 Poster Board 078 During the 12-month period ending in April 2021, opioid-related deaths, primarily from fentanyl, reached an all-time high in the US, affecting up to 100,000 people annually. People undergoing medication-assisted treatment for opioid use disorder (OUD ), including pregnant women, often relapse to fentanyl use. The gold standard treatment for OUD during pregnancy is buprenorphine (BUP) , which improves maternal-fetal outcomes but causes neonatal opioid withdrawal syndrome (NOWS) in approximately 50% of newborns during their first weeks of life. We used a rat model to examine the effect of a novel drug, deuterated buprenorphine (BUP-D2) , on fentanyl-induced adverse effects in mothers and their neonates. We hypothesized that BUP-D2 would reduce fentanyl-related adverse effects in dams and neonates. Our preclinical model simulated the clinical scenario of fentanyl relapse while undergoing medication-assisted treatment with BUP or BUP-D2. Osmotic minipumps that continuously delivered vehicle ( veh ; 2% DMSO; 0.120 uL/day), 0.1 mg/kg/day BUP, or 0.1 mg/kg/day BUP-D2 for up to two weeks were subcutaneously implanted in pregnant Sprague-Dawley rats (dams) on gestational day (GD) 9. On GD 13-22, dams received daily s.c. fentanyl (100 μg/kg) or saline injections (1 mL/kg). We assessed post-injection oxygen saturation (O 2 sat.), catalepsy, and rectal temperature (temp.). Neonatal opioid withdrawal was precipitated by an i.p injection of naltrexone ( NTX ; 1 mg/kg) or saline 3-12 hours after delivery. Movement duration, a validated metric of NOWS, was determined using Noldus EthoVision XT. On GD 14, veh+fentanyl maximally induced catalepsy (i.e., to 30 sec cutoff) in all dams 15 min post-injection (p < .0001, vs veh+saline). Fentanyl-induced catalepsy was only partially blocked by BUP (21.25 ± 12.47, p = .0322), but fully blocked by BUP-D2 (10.95 ± 10.96, p = .2046). Veh+fentanyl decreased O 2 sat. by 28 ± 25.82% 15 min post-injection relative to pre-injection (p = .0035 vs veh+saline). BUP and BUP-D2 fully blocked the fentanyl-induced decrease in O 2 sat (102.0 ± 6.152 % and 100.7 ± 0.6140 % of pre-injection, respectively). Veh+fentanyl decreased temp. relative to veh+saline (35.84 ± 0.56 vs 36.58 ± 0.31 p = .0172) at 15 min post-fentanyl injection. Temp was not affected by BUP+ fentanyl (35.98 ± 1.15) or BUP-D2+fentanyl (36.20 ± 0.59). Lastly, NTX precipitated withdrawals in neonates that were prenatally exposed to BUP+fentanyl (females: 219.61 ± 71.54, p = 0.0229; males: 172.72 ± 89.32, p = 0.0046), but not neonates that were exposed to BUP-D2 + fentanyl (females: 91.46 ±59.7, p=0.8740; males: 102.67 ± 58.16, p = 0.9428). This study is the first to assess effects of fentanyl combined with BUP or BUP-D2 in pregnancy. Although BUP and BUP-D2 equally blocked fentanyl-induced respiratory depression in dams, our data suggest that BUP-D2 more effectively mitigated fentanyl-induced catalepsy and NOWS. This underscores the potential application of BUP-D2 as an improved OUD treatment during pregnancy. Funded by the UAMS Provost Innovator Award and by the NIH (NCATS: TL1 TR003109 and UL1 TR003107; NIDA: T32 DA022981). Fentanyl, BUP, and norbuprenorphine (used to synthesize BUP-D2) were provided by the NIDA Drug Supply Program.