Endogenous and exogenous opioid effects on oligodendrocyte biology and developmental brain myelination

Highlights

• High levels of opioid receptors and ligands in the developing brain suggest maturational functions still poorly understood.

• Opioid use rates underscore the need for identifying those functions and their roles in normal and pathological conditions.

• Findings support significant opioid effects on developmental oligodendrocyte differentiation and brain myelination.

• Exogenous opioids may alter the timing of developmental brain myelination disrupting its coordination with axonal outgrowth.

Abstract

The elevated presence of opioid receptors and their ligands throughout the developing brain points to the existence of maturational functions of the endogenous opioid system that still remain poorly understood. The alarmingly increasing rates of opioid use and abuse underscore the urgent need for clear identification of those functions and the cellular bases and molecular mechanisms underlying their physiological roles under normal and pathological conditions. This review is focused on current knowledge on the direct and indirect regulatory roles that opioids may have on oligodendrocyte development and their generation of myelin, a complex insulating membrane that not only facilitates rapid impulse conduction but also participates in mechanisms of brain plasticity and adaptation. Information is examined in relation to the importance of endogenous opioid function, as well as direct and indirect effects of opioid analogues, which like methadone and buprenorphine are used in medication-assisted therapies for opioid addiction during pregnancy and pharmacotherapy in neonatal abstinence syndrome. Potential opioid effects are also discussed regarding late myelination of the brain prefrontal cortex in adolescents and young adults. Such knowledge is fundamental for the design of safer pharmacological interventions for opioid abuse, minimizing deleterious effects in the developing nervous system.

Introduction

Opioid abuse and misuse continues to represent a problem of major epidemic proportions. This is particularly alarming when considering the large number of babies exposed to opioids during pregnancy, and in addition, the significant percentage of these infants that require opioids after birth for the pharmacological treatment of neonatal abstinence syndrome (NAS) (Honein et al., 2019). Newborns affected by NAS exhibit different symptoms of variable magnitude that may include central nervous system dysfunction reflected in tremors and seizures, inconsolable crying, excessive irritability, poor sleep, and elevated muscle tone; as well as autonomic nervous system effects resulting in various digestive and respiratory problems and altered temperature regulation (Finnegan et al., 1975; Desai et al., 2015; Hoegerman et al., 1990; Jones et al., 2016; Gomez-Pomar and Finnegan, 2018). Opioids and their metabolites have the capacity of crossing the placenta (Nekhayeva et al., 2005; Krishna et al., 1997; Malek and Mattison, 2011) and blood-brain barrier (Bostrom et al., 2008; Bourasset et al., 2003). Thus, NAS symptoms are logically considered to be the result of abrupt discontinuation of maternal opioid supply after birth. Current successful and necessary medication-assisted therapies for opioid addiction during pregnancy involve the administration of the synthetic long-lasting opioid analogue and full mu-opioid receptor agonist methadone; and more recently, buprenorphine, a partial mu-opioid receptor agonist and kappa-opioid receptor antagonist that not only successfully prevents the maternal abuse of opioids but also exhibits higher efficacy than methadone in reducing the incidence and severity of NAS (Fischer et al., 2006; Lejeune et al., 2006; Welle-Strand et al., 2013; Minozzi et al., 2013; Jones et al., 2010). However, an increasing number of reports suggest that some of these opioid-based therapeutic approaches may also exert neurodevelopmental effects. While much is known about opioids and their role in pain regulation, the high expression levels of different opioid receptors and their endogenous opioid ligands throughout the developing brain point to the existence of maturational functions that still remain poorly understood. This raises the question of whether interference with the endogenous opioid system by exogenous opioids, including those used in pharmacotherapy treatments, could also alter important developmental brain processes. A recent large prospective study in which potential effects of other drug co-exposures and compounding factors were carefully controlled and periodically monitored, concluded that gestational opioid exposure sufficient to result in NAS also increased the proportion of neonates with reduced head circumference (Towers et al., 2019). Notably, the great majority of those infants were born from mothers that were maintained under methadone or buprenorphine treatment. The mechanisms behind these effects remain poorly understood but different findings suggest the possibility of opioid actions on different neural cell types. For example, animal models showed that perinatal methadone exposure alters the function of dopaminergic, noradrenergic and serotonergic neurons in the neonatal and early postnatal period (Rech et al., 1980). Furthermore, while human effects are difficult to evaluate, studies using cultured human cortical organoids indicated methadone suppressive actions on neuronal function and maturation (Wu et al., 2020a). Different lines of evidence also point to potential opioid roles on various glial cell populations (Hauser and Knapp, 2017). This review is focused on the neurodevelopmental effects that opioids may have on brain oligodendrocytes and their synthesis of myelin, the remarkably complex multilamellar structure that not only facilitates the rapid “saltatory conduction” of nerve impulses (Castelfranco and Hartline, 2015) but is also now recognized as a crucial player in brain plasticity and in active bidirectional neuron-glial communications (Fields, 2008; Hasan et al., 2019; Xiao et al., 2016). As such, oligodendrocyte generation and myelin formation are among the most critical and vulnerable processes that take place during brain development.