IUPHAR review: The neurobiological outcomes of prenatal opioid exposure: evidence from preclinical models

Prenatal opioid exposure is a major public health concern as opioid use during pregnancy has increased drastically over recent decades. This exposure is linked to a spectrum of adverse developmental outcomes in exposed children. However, interpretations of clinical data are confounded by the prevalent co-use of other drugs and socioeconomic factors. Preclinical animal models present an avenue to overcome these confounds by affording precise control over opioid type, dosing regimen, and developmental timing. In this review, we highlight recent discoveries from animal models that illuminate how prenatal opioid exposure disrupts neurobiological development. We first discuss important considerations in the design of various models of prenatal opioid exposure. We then focus on synthesizing evidence from preclinical animal models that delineate how prenatal opioid exposure alters neurobiological development at multiple scales, from cellular and synaptic architecture to neural circuits and behavior. Prenatal opioid exposure disrupts neural progenitor proliferation, synaptogenesis, and neurotransmitter system development and signaling, with brain region-specific alterations. Behaviorally, prenatal opioid exposure produces a range of persistent deficits in learning, memory, executive function, sensory processing, motor outcomes, and affective regulation in offspring. Preclinical evidence also points to heightened vulnerability to drug reward and substance-seeking behavior, likely mediated by lasting adaptations in mesocorticolimbic circuitry. Importantly, sex differences emerge across neurobiological and behavioral endpoints, underscoring the need for sex-inclusive experimental designs. Through this preclinical lens, we aim to summarize the neurobiological and behavioral phenotypes associated with prenatal opioid exposure and outline directions for future research that can enhance translational relevance and therapeutic innovation.