PT  - JOURNAL ARTICLE
AU  - Bryce A. Griffin
AU  - Caitlin O. Caperton
AU  - Lauren N. Russell
AU  - Christian V. Cabanlong
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
TI  - In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome
AID  - 10.1124/jpet.118.254219
DP  - 2019 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 9--17
VI  - 370
IP  - 1
4099  - http://jpet.aspetjournals.org/content/370/1/9.short
4100  - http://jpet.aspetjournals.org/content/370/1/9.full
SO  - J Pharmacol Exp Ther2019 Jul 01; 370
AB  - Buprenorphine is the preferred treatment of 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 interindividual 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 per day) on gestation day 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 per 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 shown by an evaluation of 10 withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.