The increasing trend in the addiction to opioids is a problem of critical importance during pregnancy. New options for substitution therapies in pregnant opioid addicts include buprenorphine, a mu-opioid receptor partial agonist and kappa- opioid receptor antagonist. However, there is a lack of information on the potential effects of this drug on child brain development. In this regard, recent results from our laboratory showed that perinatal exposure to buprenorphine affects myelination in the developing rat brain. Therapeutic levels of buprenorphine caused an accelerated brain expression of the four major splicing isoforms of myelin basic protein (MBP), oligodendroglial and myelin components that are considered to be markers of mature oligodendrocytes (OLGs). In contrast, supra-therapeutic levels of the drug resulted in a developmental delay in MBP expression and a decrease in the number of axons that were myelinated. Surprisingly, analysis of the corpus callosum indicated that, regardless of the dose, pups exposed to buprenorphine exhibited a significant increase in the caliber of myelinated axons. Moreover, these axons were characterized by having a disproportionately thinner myelin sheath. Based on these observations, this proposal is based on the central hypothesis that perinatal exposure to buprenorphine and interference with the endogenous opioid system cause (1) abnormal OLG development and (2) significant alterations at the level of glial-neuronal interactions crucial to the coordination of myelin formation with radial axonal growth. With these possibilities in mind, Specific Aim 1 will use an animal model of perinatal buprenorphine exposure and oligodendroglial cultures to investigate buprenorphine effects on OLG development.
Specific Aim 2 will study the effect of buprenorphine on the axonal cytoskeleton of myelinated axons, investigating potential alterations of axonal features thought to be regulated by the myelinating glial cells, including neurofilament accumulation, spacing and phosphorylation, and the local distribution of Cdk5 and ERK1/2, two major kinases involved in neurofilament phosphorylation . Further characterization of the buprenorphine animal model will provide a novel and important tool to investigate the role of the opioid system as a regulator of oligodendroglial-neuronal interactions, an opioid function never studied before. Moreover, identification of buprenorphine actions at this still exploratory stage of the project will provide solid bases for future studies on the effects of the drug in complex models of addiction that will consider, as it occurs in pregnant addicts, prior exposure to other opioids and drugs of abuse. Clear understanding of these effects is crucial to the design of management strategies for pregnant opioid addicts minimizing harmful effects in the maturing brain.
The opioid analogue buprenorphine is currently on trials for the management of pregnant opioid addicts. However, our studies indicated that this drug may affect the formation of myelin, a membrane that facilitates the conduction of nerve impulses. The proposed studies will further characterize the animal model of perinatal exposure to buprenorphine, providing solid bases for future studies on the effects of the drug in complex models of addiction that will consider, as it occurs in pregnant addicts, prior exposure to other opioids and drugs of abuse. Clear understanding of these effects is crucial to the design and management strategies for pregnant opioid addicts minimizing harmful effects in the maturing CNS.
|Vestal-Laborde, Allison A; Eschenroeder, Andrew C; Bigbee, John W et al. (2014) The opioid system and brain development: effects of methadone on the oligodendrocyte lineage and the early stages of myelination. Dev Neurosci 36:409-21|
|Eschenroeder, Andrew C; Vestal-Laborde, Allison A; Sanchez, Emilse S et al. (2012) Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of ?-opioid- and nociceptin/orphanin FQ receptors in cell development: implications for drug addiction treatment during pregnancy. Glia 60:125-36|
|Coelho, Rochelle P; Yuelling, Larra M; Fuss, Babette et al. (2009) Neurotrophin-3 targets the translational initiation machinery in oligodendrocytes. Glia 57:1754-64|