Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro

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Abstract
To determine whether one or more opioid receptor types might be preferentially involved in gliogenesis, primary mixed glial cultures derived from mouse ce‐rebra were continuously treated with varying concentrations of opioid agonists selective for mu (μ), delta DAGO ([D‐Ala2, MePhe4, Gly(ol) 5] enkephalin), (δ), i.e., DPDPE ([D‐PEN2, D‐PEN5]enkephalin), kappa (κ), i.e., U69,593, opioid receptor types. In addition, a group of cultures was treated with [Met5]‐enkephalin, an agonist for δ opioid receptors as well as putative zeta (ζ) opioid receptors. Opioid‐depen‐dent changes in growth were assessed by examining alterations in (1) the number of cells in mixed glial cultures at 3, .6, and 8 days in. vitro (DIV), (2) [3H]thymidine incorporation by glial fibrillary acidic protein (GFAP) immunoreactive, flat (type 1) as‐trocytes at 6 DIV, and (3) the area and form factor of GFAP‐immunoreactive, flat (type 1) astrocytes‐ DPDPE at 10−8 or 10−10 as M significant M enkephalin at 10−6, 10−8, 10−10 reduced the total number of glial cells in culture; but this effect was not observed with DAGO or U69, 593 (both at 10−6, 10−8 10−10) Equimolar or trations (i.e.), 10−6 M of [Met5]enkephalin U69,593, but not DPDPE or DAGO, suppressed the rate of [3H]thymidine incorporation by GFAP‐immunoreactive, flat (type 1) astrocytes. DAGO had no effect on growth, although in previous studies morphine was found to inhibit glial numbers and astro cyte DNA synthesis. [Met5]enkephalin (10−6 the only agonist to significantly influence astrocyte area. Collectively, these results indicate that δ (and perhaps μ) opioid receptor agonists reduce the total number of cells in mixed glial cultures; while [Met15]enkephalin‐responsive and perhaps κ‐respon‐sive) opioid receptors mediate DNA synthesis in astrocytes. This implies that δ opioid receptors, as well as [Met5]enkephalm, sensitive, non‐δ pioid receptors, mediate opioid‐dependent regulation of astrocyte and astrocyte progenitor growth. These data support the concept that opioid‐dependent changes in central nervous system growth are the result of endogenous opioid peptides acting through multiple opioid receptor types.