Elsevier

Toxicology Letters

Volume 225, Issue 1, 10 February 2014, Pages 92-101
Toxicology Letters

Prenatal buprenorphine exposure decreases neurogenesis in rats

https://doi.org/10.1016/j.toxlet.2013.12.001Get rights and content

Highlights

  • Prenatal buprenorphine exposure induces depression-like neurobehavior in weanlings.

  • Prenatal buprenorphine exposure impairs BDNF action and neurogenesis.

  • Buprenorphine decreases cell proliferation, differentiation, and BDNF expression in cultured neurospheres.

Abstract

Perinatal opioid exposure has a negative effect on neurogenesis and produces neurological consequences. However, its mechanisms of action are incompletely understood. Buprenorphine, a mixed opioid agonist/antagonist, is an alternative medication for managing pregnant opioid addicts. This study provides evidence of decreased neurogenesis and depression-like consequences following prenatal exposure to buprenorphine and sheds light on mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant rats starting from gestation day 7 and lasting for 14 days and a cultured neurosphere model. Results of forced swimming test and tail suspension test showed that pups at postnatal day 21 had worse parameters of depression-like neurobehaviors, independent of gender. Neurobehavioral changes were accompanied by reduction of neuronal composition, biochemical parameters of neural stem/progenitor cells, brain-derived neurotrophic factor (BDNF) expression, tropomyosin-related kinase receptor type B phosphorylation, protein kinase A (PKA) activity, and cAMP response element-binding protein phosphorylation. Results of parallel cell studies further demonstrated a negative impact of buprenorphine on cultured neurospheres, including proliferation, differentiation, BDNF expression and signaling, and PKA activity. Taken together, our results suggest that prenatal exposure to buprenorphine might result in depression-like phenotypes associated with impaired BDNF action and decreased neurogenesis in the developing brain of weanlings.

Introduction

Opioid dependency during pregnancy is a global health dilemma. In addition to fatal overdose, infectious disease transmission, and undesirable social consequences, the substantial impacts on child brain development are issues of concern (Compton and Volkow, 2006). Maintenance treatment with methadone is the current recommended standard of care for opioid-dependent pregnant women (Jarvis and Schnoll, 1994, Velez et al., 2009). Buprenorphine, a semisynthetic opioid derivative, which acts as a partial agonist at the μ-opioid receptor and as an antagonist at κ- and δ-opioid receptors (Walsh and Eissenberg, 2003), is approved by the Food and Drug Administration (FDA) for the management of opioid dependence in non-pregnant patients, although it has been available for many years to treat pain. There is growing evidence that buprenorphine may serve as a reasonable alternative medication for the management of pregnant opioid addicts (Alto and O’Connor, 2011, Farid et al., 2008, Kakko et al., 2008, Lund et al., 2013).

Infants exposed in utero to opioids have a chance of developing neonatal withdrawal and exhibit an increased risk of sudden infant death syndrome. Of particular note, perinatal opioid exposure has been demonstrated to produce a variety of short- and long-term neurobehavioral consequences in offspring, including neonatal abstinence syndrome which is characterized by autonomic and central nervous system hyperactivity, often with associated gastrointestinal tract and respiratory system dysfunction (Blandthorn et al., 2011, Coyle et al., 2012, Fischer et al., 2006, Jansson et al., 2011, Lejeune et al., 2006, Lund et al., 2013). These studies have raised concerns regarding the potential adverse effects of opioid treatments, particularly perinatal exposure.

Buprenorphine can simultaneously act as an agonist and/or antagonist at different classes of opioid receptors and has a high affinity for and slow association and dissociation from receptors, which results in a long duration of action (Engelberger et al., 2006). These pharmacological characteristics of buprenorphine highlight its potential involvement in the development of fetal brain and neurobehavioral consequences, although these mechanisms are not fully understood (Malanga and Kosofsky, 1999). A deficit of circulating stem/progenitor cells has been reported in subjects of opiate addiction (Reece and Davidson, 2007). Chronic administration of opioids has been shown to inhibit proliferation of neural stem/progenitor cell populations in adult animals and prenatal methadone exposure predicates a disruption of neural maturation in exposed fetuses (Arguello et al., 2009, Eisch et al., 2000, Seidler et al., 1982). Results of an animal study suggest that routine administration of buprenorphine has the potential to decrease proliferation of adult hippocampal neuroblasts (Pettit et al., 2012). Experimental studies have further shown that perinatal exposure to buprenorphine affects neurotrophic factor and neurotransmitter biosynthesis and myelination (Robinson, 2002, Sanchez et al., 2008, Wu et al., 2001). Depression is common among opioid-dependent patients and is associated with a poor prognosis (Rounsaville et al., 1982). A growing body of evidence suggests a strong association between depression and impaired neurogenesis (Dranovsky and Hen, 2006, Hanson et al., 2011). These relevant studies highlight the potentially crucial role of neurogenesis in perinatal buprenorphine exposure-provoked neurological problems and exposure of the developing brain of the fetus to unfavorable effects. At present, the effects of prenatal buprenorphine exposure on neurogenesis in the developing brain are unknown.

In spite of the well-known neurological consequences of buprenorphine, the molecular and cellular bases underlying its mechanisms of action are incompletely understood. To extend the scope of relevant studies, we therefore undertook the present investigation to examine the potential effects of prenatal buprenorphine exposure on neurogenesis in the developing brain of weanlings and identify the causative mediators involved.

Section snippets

Animals and buprenorphine treatment

The Animal Experimental Committee of Taichung Veterans General Hospital approved the protocol of the animal study. Female Sprague-Dawley rats (200–250 g) were placed individually with male conspecifics during breeding. The detection of a vaginal sperm plug was used to indicate successful mating and was defined as gestation day 0. After confirmation of mating, female rats (20 animals) were randomly allocated into two experimental groups (n = 10 per group). On day 7 of gestation, these pregnant rats

Prenatal buprenorphine exposure caused neurobehavioral change

Perinatal buprenorphine (0–3 mg/kg/day) exposure has been widely used to investigate its impact on rat pups from postnatal days 0 to 21. Within the tested doses (0.3, 0.5, 1, 3, and 5 mg/kg/day), our preliminary study showed that more than 1 mg/kg/day of buprenorphine had apparent neurological impacts (data not shown). Relevant studies have suggested that a dose of 1 mg/kg/day of buprenorphine is equivalent to overexposure level (Robinson, 2002, Sanchez et al., 2008, Wu et al., 2001). To extend and

Discussion

Opioids have been shown to predispose infants to neurobehavioral consequences and the development of neonatal withdrawal syndrome. Of particular note, neonatal abstinence syndrome and depression are common among opioid-dependent patients (Blandthorn et al., 2011, Coyle et al., 2012, Fischer et al., 2006, Jansson et al., 2011, Lejeune et al., 2006, Lund et al., 2013, Rounsaville et al., 1982). It has been shown that acute buprenorphine exposure in adults induces locomotor stimulation and

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This study was supported by grants from Taichung Veterans General Hospital (TCVGH-1007306C) and the Yen Tjing Ling Medical Foundation (CI-98-10), Taiwan, Republic of China.

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