Preferential inhibition of the neonatal μ receptor and CREB-regulated nuclear transcription as a mechanism of treatment of opioid-dependence during pregnancy

Keirsyn Criss

Introduction. Exogenous opioids target the μ receptor which is a G-protein coupled receptor, stimulating the production of cAMP. Overuse and opioid addiction has been on the rise in recent years, with the advent of the “opioid crisis”.5-8 Maternal use of opioids during pregnancy has become a recent concern, and current guidelines fail to examine the postnatal effects of opioid use on offsprings. Neonatal opioid withdrawal syndrome (NOWS)5-8 encompasses the observable symptoms seen in affected children and is a result of decreased BDNF and subsequent decrease in neurogenesis associated with maternal opioid use; such symptoms of NOWS include psychological and neurological deficits. Current guidelines for maternal opioid treatment during pregnancy postulate using an opioid agonist to avoid spontaneous abortion; however, the guidelines dismiss the observable effects in offspring as a result of using opioid agonists.1-3 Peripheral opioid antagonists should be considered for treatment of maternal opioid use, as such drugs reduce prevalence of NOWS via promotion of normal BDNF levels, while inhibiting incidence of maternal withdrawal via lack of penetration of the maternal blood brain barrier.4 Methods. One study administered methadone, morphine, and buprenorphine to mice during pregnancy and observed the postnatal effects via behavioral analysis including social interaction, swim, and light testing.1 Another study administered buprenorphine and saline to maternal mice, and brain slices of postnatal offspring were analyzed via PCR and immunofluorescence for levels of BDNF and p-nestin.3 Finally, the last study administered a peripheral opioid antagonist (6-beta-naltrexol) concomitantly with an opioid agonist to maternal mice, and the postnatal effects of the cocktail were observed via jump count and social interaction testing.4 Results. The first study found that all three of the drugs administered had postnatal effects associated with NOWS in humans, including anxiety-like and depression like behaviors, decreased social interaction, decreased memory, and decreased processing.1 The second study found that buprenorphine use was associated with decreased BDNF and neural cell migration, with brain slice analysis demonstrating a lack of p-nestin, a marker of neurogenesis.3 The third study found that 6-beta-naltrexol decreased jumping (anxiety-like behavior) in juvenile mice and blood plasma analysis demonstrated a lack of penetrance across the maternal blood brain barrier.4 Conclusions. The current guidelines for maternal opioid addiction include treatment with opioid agonists; however, the efficacy of peripheral opioid antagonists4 in humans should be evaluated in order to decrease the prevalence of NOWS, maternal withdrawal during pregnancy, and spontaneous abortion.1-3, 5

  1. Chen H-H, Chiang Y-C, et al. Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats. Neuropsychiatric Disease and Treatment . 2015:609. doi:10.2147/ndt.s70585
  2. Lemon LS, Caritis SN, Venkataramanan R, Platt RW, Bodnar LM. Methadone versus buprenorphine for opioid use dependence and risk of neonatal abstinence syndrome. Epidemiology. 2017:1. doi:10.1097/ede.0000000000000780
  3. Wu C-C, Hung C-J, Shen C-H, et al. Prenatal buprenorphine exposure decreases neurogenesis in rats. Toxicology Letters . 2014;225(1):92-101. doi:10.1016/j.toxlet.2013.12.001
  4. Oberdick J, Ling Y, Phelps MA, Yudovich MS, Schilling K, Sadee W. Preferential Delivery of an Opioid Antagonist to the Fetal Brain in Pregnant Mice. Journal of Pharmacology and Experimental Therapeutics. 2016;358(1):22-30. doi:10.1124/jpet.115.231902
  5. Martins F, Oppolzer D, Santos C, Barroso M, Gallardo E. Opioid Use in Pregnant Women and Neonatal Abstinence Syndrome—A Review of the Literature. Toxics. 2019;7(1):9. doi:10.3390/toxics7010009
  6. Davis JM, Shenberger J, Terrin N, et al. Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome. JAMA Pediatrics. 2018;172(8):741. doi:10.1001/jamapediatrics.2018.1307
  7. Raffaeli, G. , Cavallaro, G. , Allegaert, K. , Wildschut, E. D., Fumagalli, M. , Agosti, M. , Tibboel, D. and Mosca, F. (2017), Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies. Pharmacotherapy, 37: 814-823. doi:10.1002/phar.1954
  8. Rodriguez CE, Klie KA. Pharmacological treatment of opioid use disorder in pregnancy. Seminars in Perinatology. January 2019. doi:10.1053/j.semperi.2019.01.003