The effects of gestational opioid exposure on the maternal brain, behavior and microbiome

Opioid use disorder (OUD) is a global epidemic affecting a high proportion of child-bearing women. The drastic
4-fold increase in OUD among pregnant women from 1999-2014 has promoted opioid maintenance therapies
(OMT) such as buprenorphine (BUP) to mitigate effects associated with opioid abuse. BUP is a mixed (partial
mu-receptor agonist/kappa-receptor antagonist) semi-synthetic OMT that produces better infant outcomes after
gestational treatment as compared to other OMTs (i.e. methadone). However, effects of BUP on pregnant
women transitioning to motherhood is not well understood. Endogenous opioids play a significant role in
orchestrating neuronal adaptations within the maternal brain network (MBN) for the successful ‘switch’ from a
nulliparous brain to a maternal brain to incentivize nurturing maternal behaviors from the dam. It is well known
that exogenous opioid exposure to morphine (full mu-agonist) during gestation can alter the endogenous opioid
system and disrupt maternal care. However, there is a knowledge gap about the effects of BUP on the
endogenous opioid system during the transition to motherhood and thus on maternal care behavior in the context
of OUD during pregnancy. The proposed studies aim to address this knowledge gap by implementing a
translational rodent model to evaluate the effects of BUP compared to morphine on the maternal brain, behavior
and the microbiome well as on the long-term outcome of the offspring. Female rats will be exposed to BUP
and/or morphine in clinically relevant paradigms starting before conception and continued throughout early
postpartum. Effects of gestational BUP and morphine exposure on neurochemical and activation pattern
changes in the maternal brain will be evaluated using state of the art imaging techniques. We will also evaluate
the effectiveness of oxytocin as a potential intervention to increase maternal-offspring interaction in opioid-
exposed dams and investigate the role of the microbiome in the long-term health outcome of exposed offspring.
Our proposal will be able to add to the preliminary human findings on altered functional connectivity in
buprenorphine-exposed mothers by using ‘whole (half) brain activity mapping’ which will allow us to
simultaneously illuminate activity at cellular resolution in several brain areas of the MBN and compare patterns
between opioid-exposed and control dams and investigate associations with changes in maternal behaviors. We
expect that perinatal exposure to BUP inhibits the neuronal ‘switch’ from aversive to rewarding perception of
pups that is necessary to initiate appropriate maternal behavior thus subsequently influencing offspring survival.
The scale of the opioid epidemic requires an urgent response in order to promote treatment of OUD in pregnancy
within an already marginalized population. We hope to advance science on the consequences of opioid drug
use/therapy during gestation and to apply these outcomes toward clinical knowledge to improve public health
via effective translation, implementation, and dissemination of our scientific research findings.

Grant Number: 5R01DA052386-04
NIH Institute/Center: NIH
Principal Investigator: Susanne Brummelte