TY - JOUR T1 - <em>In utero</em> exposure to norbuprenorphine, a major metabolite of buprenorphine, induces fetal opioid dependence and leads to neonatal opioid withdrawal syndrome JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.254219 SP - jpet.118.254219 AU - Bryce A Griffin AU - Caitlin O Caperton AU - Lauren N Russell AU - Christian V Cabalong AU - Catheryn D Wilson AU - Kyle R Urquhart AU - Bradford S Martins AU - Marcelle Dina Zita AU - Amy L Patton AU - Alexander W Alund AU - S Michael Owens AU - William E Fantegrossi AU - Jeffery H Moran AU - Lisa K Brents Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/04/25/jpet.118.254219.abstract N2 - Buprenorphine is the preferred treatment for opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that inter-individual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexone-precipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg/day) on gestation day (GD) 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg/day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/mL, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as evaluated by ten withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.SIGNIFICANCE STATEMENT N/A ER -