Opioids and the oxytocin system: Mechanistic interactions altering maternal neuroplasticity

Due to the ongoing opioid epidemic, there has been a rise in the use of medications for opioid use disorder (MOUD) during pregnancy. This paper examines how buprenorphine (BUP), the new golden standard for MOUD, may disrupt maternal care through dysregulation of the oxytocin (OXT) system. OXT is central to parturition, lactation, caregiving, and coordinating activity across the maternal brain network (MBN), including the paraventricular (PVN) and supraoptic nucleus, medial preoptic area, and nucleus accumbens. The endogenous opioid system normally regulates OXT release, with μ-opioid receptor (μOR) and κ-opioid receptor (κOR) signaling influencing OXT neurons. BUP has a unique mechanism of action as it is a partial μOR agonist and a κOR antagonist, which may lead to complex interactions with endogenous opioids and subsequently the OXT system during pregnancy. In line with this, recent preclinical research suggests that BUP exposure during gestation results in reduced maternal motivation and inconsistent pup-directed care in rodent models. Therefore, this paper will explore the possible underlying mechanisms of how BUP exposure may dysregulate the OXT system and thus play a role in the observed maternal care deficits. In particular, we propose that chronic BUP exposure dampens PVN OXT output, disrupts synchrony across the MBN, and constrains OXT-driven neuroplasticity. Further, we will discuss the potential of postpartum OXT administration to restore maternal behaviors by re-engaging OXT signaling and network activity in both clinical and preclinical models. By integrating receptor, network, and behavioral evidence, this review provides a framework for understanding BUP's impact on maternal care through oxytocinergic disruptions and for potential translational interventions.