Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model

Abstract

Neonatal opioid dependence is an enormous and growing medical challenge. Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS). They may also show delays in developmental milestones. Thus, a pharmacotherapy that could be delivered in conjunction with a prenatal opioid, and that could prevent fetal opioid dependence without interfering with pain or opioid use management of the mother, would be highly desirable. In a prior study in mice we demonstrated that the peripherally selective neutral opioid antagonist, 6β-naltrexol (6BN), has properties that make it a promising candidate for such an approach. In the current work we extend our studies of 6BN to pregnant guinea pigs, which are a more suitable model than mice and rats, and allows for the detection of robust spontaneous neonatal withdrawal. We find that prenatal methadone (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 exposed to maternal separation stress, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. Most importantly, our work shows that 6BN can prevent all these effects of prenatal methadone with high potency (50% inhibitory dose, ID50, of ~0.02 mg/kg), at doses unlikely to induce maternal withdrawal or to interfere with opioid analgesia based on many prior published studies. This potency is surprising in the face of both the long half-life of methadone and our pharmacokinetic (PK) studies showing slow placental transit of 6BN in guinea pigs. Furthermore, we demonstrate an unexpectedly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg), in spite of the fact that our PK data in both mice and guinea pigs show the relative exclusion of 6BN from the adult CNS, presumably by virtue of the blood brain barrier and associated extrusion pumps. Thus, novel opioid receptor mechanisms may need to be hypothesized to account for the high potency of 6BN for preventing opioid withdrawal. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS, and guinea pigs are an ideal model to further test it.

Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management

“…Recent results indicate that 6BN's peripheral selectivity is not solely due to slow penetration of the BBB. Whereas we have found higher blood than brain 6BN levels in mice (42) and guinea pigs (43), 6BN enters the brain of rhesus monkeys with less restriction, resulting in equal blood and brain levels (Fig. 3).…”

“…Lastly, Oberdick et al have tested daily 6BN co-treatment with methadone (5-7 mg/kg, s.c.) in pregnant guinea pig dams, starting at gestational day 50 until delivery (GD~60), to prevent withdrawal behavior in guinea pig pups measured one day after birth. Even though placental 6BN transfer is slower in pregnant guinea pigs compared to mice and rhesus monkeys, the IC50 of 6BN is ~0.025 mg/kg, again displaying unexpected potency (43).…”

“…Encouraged by these results, we subsequently tested co-administration to adult guinea pigs of 6BN with methadone (10 mg/kg) for 3 days, with withdrawal testing on day 4, finding an IC50 6BN dose of ~0.01 mg/kg to block naloxone-induced locomotion (43), two orders of magnitude below the dose required to block antinociception (26). Similarly, co-administration of an s.c. dose as low as 0.03 mg/kg 6BN completely suppresses naloxone-induced withdrawal jumping in adult mice made dependent on morphine (10 mg/kg for 5 days) (Z. Wang; unpublished data).…”

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

“…Opioid agonists and antagonists were provided by the NIDA Drug Supply Program. This manuscript has been released as a pre-print at bioRxiv (Safa et al, 2020).…”

“…Moreover, the high potency does not appear to require preferential delivery of 6BN to the fetal CNS. (This manuscript has been released as a pre-print (Safa et al, 2020)).…”