Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model

Alireza Safa; Allison R Lau; Sydney Aten; Karl Schilling; Karen L Bales; Victoria A Miller; Julie Fitzgerald; Min Chen; Kasey Hill; Kyle Dzwigalski; Karl Obrietan; Mitch A Phelps; Wolfgang Sadee; John Oberdick

doi:10.3389/fphar.2020.613328

Pharmacological Prevention of Neonatal Opioid Withdrawal in a Pregnant Guinea Pig Model

Front Pharmacol. 2021 Feb 25:11:613328. doi: 10.3389/fphar.2020.613328. eCollection 2020.

Authors

Affiliations

¹ Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
² Department of Psychology, California National Primate Research Center, Animal Behavior Graduate Group, University of California, Davis, CA, United States.
³ Anatomisches Institute, Anatomie und Zellbiologie, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
⁴ Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, United States.
⁵ Department of Cancer Biology and Genetics, Ohio State University Wexner Medical Center, Columbus, OH, United States.
⁶ Aether Therapeutics Inc., Austin, TX, United States.

Abstract

Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS, and a therapeutic mechanism was proposed based on preferential delivery of 6BN to fetal brain with relative exclusion from maternal brain. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ∼0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies in rodents and non-human primates. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This high potency appears to run counter to our pharmacokinetic studies showing slow 6BN transit of both the placenta and maternal blood brain barrier in guinea pigs, and calls into question the preferential delivery mechanism. Rather, it suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence at all developmental stages, even in adults, as compared to its well-established low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

Keywords: cortisol; guinea pig; hypothalamic-pituitary-adrenal axis; neonatal; opioid; preventive; therapeutic; withdrawal.

Abstract

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