Advances in animal models of prenatal opioid exposure

Abstract

Neonatal opioid withdrawal syndrome (NOWS) is a growing public health concern. The complexity of in utero opioid exposure in clinical studies makes it difficult to investigate underlying mechanisms that could ultimately inform early diagnosis and treatments. Clinical studies are unable to dissociate the influence of maternal polypharmacy or the environment from direct effects of in utero opioid exposure, highlighting the need for effective animal models. Early animal models of prenatal opioid exposure primarily used the prototypical opioid, morphine, and opioid exposure that was often limited to a narrow period during gestation. In recent years, the number of preclinical studies has grown rapidly. Newer models utilize both prescription and nonprescription opioids and vary the onset and duration of opioid exposure. In this review, we summarize novel prenatal opioid exposure models developed in recent years and attempt to reconcile results between studies while critically identifying gaps within the current literature.

Keywords: development; gestational; morphine; mouse; substance use disorder; withdrawal.

Figure 1:. Comparison of human and rodent neurodevelopment and opioid exposure windows.

(A) The gestational period of a rodent is approximately equivalent to the first two trimesters of a human pregnancy. Critical neurodevelopmental milestones peak within the second and third trimesters of human pregnancy, while comparable developmental processes in rodents occur throughout the first two postnatal weeks (B) In preclinical animal models opioids can be administered throughout different gestational and postnatal timepoints. Figure created by biorender.com with approved license SQ25JBE6LU.

Figure 2:. Opioid Pharmacology.

Schematic representation of common opioids, half-lives (T_1/2) in rodents [–38], and binding affinity at delta opioid receptor (DOR), mu opioid receptor (MOR), and kappa opioid receptor (KOR). Turquoise arrow indicates drug is acting as an agonist at the receptor, black dashed arrow indicates drug is acting as a partial agonist at the receptor, and orange inhibitor arrow indicates drug is acting as an antagonist at the receptor. The inhibitory constant (K_i) for each drug is listed in nanomolar (nM) [–43]. Created by biorender.com with approved license SQ25JBE6LU.