Ontogenesis of Proopiomelanocortin and Its Processing to β-Endorphin by the Fetal and Neonatal Rat Brain

Abstract

A number of reports suggest that β-endorphin (β-END) may play an important role in the regulation of cell proliferation and neuronal differentiation. Proopiomelanocortin (POMC), the common precursor ofadrenocorticotropic hormone and β-END, is detected very early in embryonic life in hypothalamic neurons of the developing rat. However, very little is known about the degree to which POMC is processed to β-END during fetal and early postnatal life. Thus, it was the objective of the present study to estimate the hypothalamic content of POMC mRNA, as well as the biosynthesis and posttranslational processing of POMC by hypothalamic neurons on fetal day 20 and on days 1, 8 and 22 of postnatal life. Hypothalamic POMC mRNA, as determined by Northern blot analysis, was higher on fetal day 20 than on postnatal days 1, 8 and 22. A higher rate of incorporation of [³H]phenylalanine into β-END immunoreactive peptides was observed on fetal day 20 than on postnatal day 1. However, the rate of incorporation was significantly increased by day 8 of postnatal life and was similar to that on day 22. POMC was processed to β-lipotropin (β-LPH) and β-END at all ages examined, but the relative proportions of POMC:β-LPH:β-END changed during development. Thus, β-END accounted only for 34.89 ± 6.14% of the total [³H]phenylalanine-labeled β-END immunoreactive peptides on fetal day 20, while it accounted for 57.37 ± 5.20, 62.81 ± 1.38 and 79.25 ± 6.57% on days 1, 8 and 22 of postnatal life, respectively. Thus, POMC is processed to a considerable extent into β-END-sized peptides by the fetal hypothalamus and may influence brain development. Furthermore, the rate of processing of hypothalamic POMC into β-END increases with development, probably due to the increased activity of the enzymes specific for POMC processing.

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

“…However, opioid receptors are known to be ubiquitously expressed in both neuronal and glial populations and thus, it is plausible that in vivo effects on myelination detected in this study as well as those previously observed in pups exposed to buprenorphine [31], may in addition reflect indirect actions mediated by other cells. Rat brain levels of the μ and δ -opioid receptor agonist β -endorphine are elevated at embryonic and postnatal ages that coincide with periods of proliferative activity of both neuronal and glial progenitors [62]. Prolonged administration of morphine to neonatal rats was shown to be associated to increased neuronal apoptosis in selective areas of the brain [63], and morphine exposure in adolescent rats results in increased Toll-like receptor 4 signaling and microglial activation [64].…”

Oligodendrocyte responses to buprenorphine uncover novel and opposing roles of μ‐opioid‐ and nociceptin/orphanin FQ receptors in cell development: Implications for drug addiction treatment during pregnancy

“…Early studies implicated this receptor as a stimulator of proliferation for both neonatal oligodendrocyte progenitors (Knapp and Hauser 1996) and adult neuroprogenitors (Persson et al 2003). The supposition of an in vivo role of the endogenous opioid system in controlling cell proliferation during CNS development is strengthened by the observation that synthesis of pro-opiomelanocortin and its processing into the MOR and DOR agonist β-endorphin in the rat brain are elevated at embryonic days and postnatal ages that coincide with periods of crucial proliferative activity of neuronal and glial progenitors (Angelogianni et al 2000). Moreover, several lines of evidence support the idea that opioid signaling may not only be important during development but also play a role in maintaining adequate numbers of different cell populations in the adult brain.…”

Mu‐ and delta‐opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors

“…The endogenous opioid β‐endorphin, a potent ligand for both the MOR and the DOR (Mansour et al. , 1995b), has previously been shown to be expressed in hippocampal extracts during the main proliferative periods at rat CNS development, embryonal days 15–20 and postnatal days 2–10 (Angelogianni et al. , 2000).…”