Abstract
Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.
Highlights
Maintenance treatment with methadone is the current recommended standard of care for opioid-dependent pregnant women, even though the m-opioid receptor agonist has been shown to predispose the infants to develop symptoms of neonatal abstinence syndrome which is characterized by autonomic and central nervous system hyperactivity, often with associated gastrointestinal tract and respiratory system dysfunction [1,2]
In the present study, a reduction of TrkB phosphorylation in the groups that received a supratherapeutic dose of buprenorphine was found (Fig. 7C, p,0.01). These results suggest that pups of a dam exposed to a supratherapeutic dose of buprenorphine showed a reduction in brain-derived neurotrophic factor (BDNF) signaling and cAMP response element-binding protein (CREB) activation
Prenatal exposure to supratherapeutic dose of buprenorphine had a negligible effect on maternal and fetal or neonatal mortality, we found that it decreased brain mass and body mass and caused a significant impact on depression-like neurobehavior in weanlings
Summary
Maintenance treatment with methadone is the current recommended standard of care for opioid-dependent pregnant women, even though the m-opioid receptor agonist has been shown to predispose the infants to develop symptoms of neonatal abstinence syndrome which is characterized by autonomic and central nervous system hyperactivity, often with associated gastrointestinal tract and respiratory system dysfunction [1,2]. Buprenorphine, a semisynthetic opioid derivative, which acts as a partial agonist at the m-opioid receptor and as an antagonist at k- and d-opioid receptors [3], was approved by the U.S Food and Drug Administration in 2002 for the management of opioid dependence in non-pregnant patients, it has been available for many years to treat pain. This drug is undergoing clinical trials for the management of pregnant opioid addicts. In spite of the well-known neurobehavioral effects of buprenorphine, the molecular and cellular basis underlying its mechanisms of action are incompletely understood
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