Endogenous opioid peptides and brain development: Endomorphin‐1 and Nociceptin play a sex‐specific role in the control of oligodendrocyte maturation and brain myelination

Abstract

The generation of fully functional oligodendrocytes, the myelinating cells of the central nervous system, is preceded by a complex maturational process. We previously showed that the timing of oligodendrocyte differentiation and rat brain myelination were altered by perinatal exposure to buprenorphine and methadone, opioid analogs used for the management of pregnant addicts. Those observations suggested the involvement of the μ-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOR). However, it remained to be determined if these receptors and their endogenous ligands could indeed control the timing of myelination under normal physiological conditions of brain development. We now found that the endogenous MOR ligand endomorphin-1 (EM-1) exerts a striking stimulatory action on cellular and morphological maturation of rat pre-oligodendrocytes, but unexpectedly, these effects appear to be restricted to the cells from the female pups. Critically, this stimulation is abolished by coincubation with the endogenous NOR ligand nociceptin. Furthermore, NOR antagonist treatment of 9-day-old female pups results in accelerated brain myelination.Interestingly, the lack of sex-dependent differences in developmental brain levels of EM-1 and nociceptin, or oligodendroglial expression of MOR and NOR, suggests that the observed sex-specific responses may be highly dependent on important intrinsic differences between the male and female oligodendrocytes. The discovery of a significant effect of EM-1 and nociceptin in the developing female oligodendrocytes and brain myelination, underscores the need for further studies investigating brain sexrelated differences and their implications in opioid use and abuse, pain control, and susceptibility and remyelinating capacity in demyelinating disease as multiple sclerosis. K E Y W O R D S endomorphin-1, myelination, nociceptin, nociceptin receptor, oligodendrocytes, sexual dimorphism, μ-opioid receptor

Machine Learning Classification Reveals Robust Morphometric Biomarker of Glial and Neuronal Arbors

“…( A ) Illustration of width, depth, and maximum Euclidean distance (left) in a monkey neocortical pyramidal cell (NMO_00002) from the Wearne_Hof archive (Duan et al, 2002); and of height and fragmentation (right) in a hippocampal granule cell (NMO_73103) from the Diaz archive (Sebastián-Serrano et al, 2016). ( B ) Diameter and local or remote bifurcation amplitude (left) in a rat neocortical microglia (NMO_95641) from the Roysam archive (Megjhani et al, 2015); and maximum path distance, length, and number of branches, bifurcations, and stems in a rat cortical oligodendrocyte (NMO_131081) from the Sato_Bigbee archive (Mohamed et al, 2020).…”

“…This increment in data availability in a public repository opens new doors for scientific discovery, especially when applying different analysis and modeling techniques for glia that have been productively applied to neurons since the early days of computational neuroscience. (Megjhani et al, 2015); and maximum path distance, length, and number of branches, bifurcations, and stems in a rat cortical oligodendrocyte (NMO_131081) from the Sato_Bigbee archive (Mohamed et al, 2020).…”

SPHERIOUSLY? The challenges of estimating sphere radius non-invasively in the human brain from diffusion MRI

“…With currently-available pipelines, this prevents reliable estimates of sphere radii in white matter when there is sensitivity to intra-axonal radial diffusivity, and indeed may plague grey matter modelling if there is sensitivity to water in the astrocytic processes. We should note that most of the cellular projections are smaller than 3 microns in radius, while the majority of soma are above 3 microns ( Di Benedetto, Malik, Begum, Jablonowski, Gómez-González, Neumann, Rupprecht, 2016 , Fannon, Tarmier, Fulton, 2015 , Mohamed, Paisley, Meyer, Bigbee, Sato-Bigbee, 2020 , Papageorgiou, Gabriel, Fetani, Kann, Heinemann, 2011 , Savtchenko, Bard, Jensen, Reynolds, Kraev, Medvedev, Stewart, Henneberger, Rusakov, 2018 , Zhang, Bassam, Thomas, Williams, Liu, Nance, Rojas, Slusher, Kannan, 2016 ). Therefore, the ambiguity here is more relevant to WM voxels given a low soma density there.…”

Maternal Oxycodone Treatment Results in Neurobehavioral Disruptions in Mice Offspring

“…Those infants born to mothers with OUD may not show health effects early on, but may be vulnerable to later diseases because of developmental origin of health and disease (DOHaD) effects ( Grandjean et al, 2015 ; Rosenfeld, 2015 ). Endogenous opioids are subject to homeostatic mechanisms and regulate key events during fetal brain development ( Mohamed et al, 2020 ). As such, developmental exposure to opioid drugs can also affect offspring brain development and risk for later neurobehavioral disorders ( Vathy, 1995 ; Sanchez et al, 2008 ; McPherson et al, 2015 ; Ross et al, 2015 ; Akbarabadi et al, 2018 ; Goldfarb et al, 2020 ; Jantzie et al, 2020 ; Mohamed et al, 2020 ).…”

“…Endogenous opioids are subject to homeostatic mechanisms and regulate key events during fetal brain development ( Mohamed et al, 2020 ). As such, developmental exposure to opioid drugs can also affect offspring brain development and risk for later neurobehavioral disorders ( Vathy, 1995 ; Sanchez et al, 2008 ; McPherson et al, 2015 ; Ross et al, 2015 ; Akbarabadi et al, 2018 ; Goldfarb et al, 2020 ; Jantzie et al, 2020 ; Mohamed et al, 2020 ).…”