Natalie Philipello

Background:

The opioid epidemic refers to the widespread and escalating crisis of opioid misuse and addiction, particularly in women of reproductive age¹. It encompasses the overuse, abuse, and dependence on prescription opioids, heroin, and synthetic opioids, leading to devastating consequences including overdose deaths, increased healthcare costs, and prenatal exposure to opioids from opioid addicted pregnant women¹. The prevalence of opioid use disorder has been escalating in the United States especially among women of reproductive age¹. This trend raises significant concerns regarding the impact on maternal and fetal health. An alarming statistic is that approximately 22-30% of pregnant women have filled at least one prescription for an opioid analgesic during pregnancy¹. This highlights the widespread use of opioids in maternal healthcare and the importance of understanding the associated risks.

Buprenorphine and Methadone are common treatments used for opioid addicted women during pregnancy to prevent withdrawal symptoms, serving as a safer alternatives to illicit opioids for mother and baby². Patients taking these drugs have been found to take better care of themselves and are less likely to relapse². Although there are some downsides, as these drugs can cross through the umbilical cord and enter the fetus’s brain².

Objective:  In this narrative review we explore the effects of opioids and opioid maintenance treatments on neonates and their future vulnerability to opioid addiction through alterations to opioid receptors.

Search Methods:   An online search in PubMed was utilized from the years 2018-2024 using the following keywords: “opioid addiction” “opioid use during pregnancy” “effects of opioids postnatally”.

Results:  Numerous receptors within the reward pathway contribute to the response to opioids, many of which are expressed as early during gestation³. In a rat model, prenatal exposure to buprenorphine and methadone was investigated using Western blot analysis to assess the N-methyl-D-aspartate receptor (NMDAR) in the brain³. This analysis revealed downregulation of NMDAR receptor subunits in prenatally exposed offspring³. Similarly, mRNA expression of NMDAR subunits was evaluated via polymerase chain reaction (PCR), indicating significant downregulation in prenatally exposed opioid offspring⁴. The mu opioid receptor (MOR) binding was examined in the brains of offspring exposed prenatally to buprenorphine or methadone². The study identified decreased MOR binding in these offspring, suggesting altered receptor function due to prenatal exposure².

Additionally, the dopamine D1 receptor was investigated for protein expression in rats prenatally exposed to morphine⁵. Western blot analysis demonstrated increased expression of D1 receptors in morphine-exposed rats⁵.

These molecular alterations are associated with increased susceptibility to addiction, as evidenced by conditioned place preference tests in prenatally exposed morphine rats, showing a higher preference score following morphine injection compared to controls⁵.

Furthermore, locomotor sensitization, a phenomenon linked to relapse and compulsive drug seeking behavior was induced in female rats prenatally exposed to morphine⁵. This suggests prenatal opioid exposure can lead to neuronal adaptations that enhance vulnerability to addiction⁵. These findings underscore the importance of understanding prenatal opioid exposure’s impact on the developing reward pathway and subsequent addiction susceptibility⁵.

Conclusions:

When neonates are exposed to opioid or opioid maintenance treatments there are alterations to reward pathway receptors that increase preference for opioids into adulthood^1-5. Potential treatments look to inject a monoclonal antibody to induce endocytosis of reward pathway receptors in the presence of opioids. This antibody serves as a means in stopping addiction in the first place, while also providing a prevention strategy for offspring⁶.

Works Cited:

1. Jantzie LL, Maxwell JR, Newville JC, et al. Prenatal opioid exposure: The next neonatal neuroinflammatory disease. Brain Behav Immun. 2020;84:45-58. doi:10.1016/j.bbi.2019.11.007
2. Kongstorp M, Bogen IL, Steinsland S, et al. Prenatal exposure to methadone or buprenorphine alters µ-opioid receptor binding and downstream signaling in the rat brain. Int J Dev Neurosci Off J Int Soc Dev Neurosci. 2020;80(5):443-453. doi:10.1002/jdn.10043
3. Fjelldal MF, Hadera MG, Kongstorp M, et al. Opioid receptor-mediated changes in the NMDA receptor in developing rat and chicken. Int J Dev Neurosci. 2019;78(1):19-27. doi:10.1016/j.ijdevneu.2019.07.009
4. Wu PL, Yang YN, Suen JL, Yang YCSH, Yang CH, Yang SN. Long-Lasting Alterations in Gene Expression of Postsynaptic Density 95 and Inotropic Glutamatergic Receptor Subunit in the Mesocorticolimbic System of Rat Offspring Born to Morphine-Addicted Mothers. BioMed Res Int. 2018;2018:5437092. doi:10.1155/2018/5437092
5. Chen Y, Du M, Kang N, et al. Prenatal Morphine Exposure Differentially Alters Addictive and Emotional Behavior in Adolescent and Adult Rats in a Sex-Specific Manner. Neurochem Res. 2022;47(8):2317-2332. doi:10.1007/s11064-022-03619-8
6. Zhang JJ, Song CG, Wang M, et al. Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis. J Pharm Anal. 2023;13(10):1135-1152. doi:10.1016/j.jpha.2023.06.008