The Opioid System and Brain Development: Effects of Methadone on the Oligodendrocyte Lineage and the Early Stages of Myelination

Abstract

Oligodendrocytes express opioid receptors throughout development, but the role of the opioid system in myelination remains poorly understood. This is a significant problem as opioid use and abuse continue to increase in two particular populations: pregnant addicts (in whom drug effects could target early myelination in the fetus and newborn) and adolescents and young adults (in whom late myelination of ‘higher-order' regions takes place). Maintenance treatments for opioid addicts include the long-lasting opioids methadone and buprenorphine. Similar to our previous findings on the effects of buprenorphine, we have now found that early myelination in the developing rat brain is also altered by perinatal exposure to therapeutic doses of methadone. Pups exposed to this drug exhibited elevated brain levels of the 4 major splicing variants of myelin basic protein, myelin proteolipid protein, and myelin-oligodendrocyte glycoprotein. Consistent with the enrichment and function of these proteins in mature myelin, analysis of the corpus callosum in these young animals also indicated an elevated number of axons with already highly compacted myelin sheaths. Moreover, studies in cultured cells showed that methadone exerts direct effects at specific stages of the oligodendrocyte lineage, stimulating the proliferation of progenitor cells while on the other hand accelerating the maturation of the more differentiated but still immature preoligodendrocytes. While the long-term effects of these observations remain unknown, accelerated or increased oligodendrocyte maturation and myelination could both disrupt the complex sequence of synchronized events leading to normal connectivity in the developing brain. Together with our previous observations on the effects of buprenorphine, the present findings further underscore a crucial function of the endogenous opioid system in the control of oligodendrocyte development and the timing of myelination. Interference with these regulatory systems by opioid use or maintenance treatments could disrupt the normal process of brain maturation at critical stages of myelin formation.

Effects of Methadone Exposure during Development on Avian Brain and Blood Cells

“…In medium and high dose methadone-exposed tissue, clusters of undifferentiated cells were evident, which is consistent with findings reported by Vestal-Laborde et al [4], and immature neurons were reported. These effects may be directly related to the smaller than average head circumference seen in human infants prenatally exposed to methadone.…”

“…Substitution therapy frequently leads to the newborn suffering through neonatal abstinence syndrome [3]. In developing rats, myelination is altered by perinatal exposure to therapeutic doses of methadone [4].…”

Association between prenatal opioid exposure, neonatal opioid withdrawal syndrome, and neurodevelopmental and behavioral outcomes at 5–8 months of age

“…Decreased neuronal counts were obtained in studies using both subcutaneous and intraperitoneal injection during the 2 nd trimester equivalent age [9, 10]. Further studies indicated that therapeutic equivalent doses of subcutaneously-administered buprenorphine and methadone during 2 nd and 3 rd trimester equivalents led to increased myelination and alterations in myelin structure in adolescent rats [11]. While a primary limitation of rodent models is the known differences in metabolism rate relative to humans, consistency of results was obtained in preclinical studies despite differences in animal model and opioid form and dose, suggesting alterations in brain development due to POE.…”

The Unifying Effects of Maternal-Placental-Fetal Axis Dysregulation on Neurodevelopment Following Infectious and Toxic In Utero Insults

“…Additionally, opioid receptors are present on neurons, oligodendroglia and astroglia (169), and opioid receptor activation may directly affect neural cell migration and survival (164). In preclinical studies, opioid exposure results in an increase of apoptosis in human neurons and microglia in vitro (168), as well as reduced dendrite length and branching in cortical neurons concomitant with deficits in learning and memory in rodents (134,170,171). Collectively, these data emphasize the detrimental effects of opioid exposure on CNS structure and function.…”