Interaction between buprenorphine and norbuprenorphine in neonatal opioid withdrawal syndrome.
Buprenorphine (BUP) is the preferred treatment for opioid use disorder during pregnancy but can cause neonatal opioid withdrawal syndrome (NOWS). Norbuprenorphine (NorBUP), an active metabolite of BUP, is implicated in BUP-associated NOWS. We hypothesized that BUP, a low-efficacy agonist of mu opioid receptors, will not antagonize NorBUP, a high-efficacy agonist of mu opioid receptors, in producing NOWS. To test this hypothesis, we treated pregnant Long-Evans rats with BUP (0, 0.01, 0.1 or 1 mg/kg/day) {+/-} NorBUP (1 mg/kg/day) from gestation day 9 until pup delivery, and tested pups for opioid dependence using our established NOWS model. We used LC-MS-MS to quantify brain concentrations of BUP, NorBUP, and their glucuronide conjugates. BUP had little effect on NorBUP-induced NOWS, with the exception of 1 mg/kg/day BUP significantly increasing NorBUP-induced NOWS by 58% in females. BUP and NorBUP brain concentrations predicted NOWS in multiple linear regression models. Interestingly, NorBUP contributed more to NOWS in females ({beta}NorBUP = 51.34, p = 0.0001) than in males ({beta}NorBUP = 19.21, P = 0.093), while BUP was similar for females ({beta}BUP = 10.62, P = 0.0017) and males ({beta}BUP = 11.38, P = 0.009). We are the first to report that NorBUP induces NOWS in the presence of BUP and that there is sexual divergence in the contribution of NorBUP to BUP-associated NOWS. These findings suggest that females are more susceptible to NorBUP-induced NOWS, and that treatment strategies that reduce prenatal NorBUP exposure may be more effective for females than males. O_LIBuprenorphine does not antagonize fetal norbuprenorphine dependence. C_LIO_LIIn females, buprenorphine and norbuprenorphine have an additive effect. C_LIO_LINorbuprenorphine contributes to NOWS in females more than in males. C_LIO_LIThe glucuronide of norbuprenorphine accumulates in fetal brain. C_LIO_LIThe glucuronide of buprenorphine does not accumulate in fetal brain. C_LI