Morphine alters astrocyte growth in primary cultures of mouse glial cells: evidence for a direct effect of opiates on neural maturation

Abstract

SUMMARYTo determine whether exogenous opiate drugs with abuse liability directly modify neural growth, the present study investigated the effects of morphine on astrocyte proliferation and differentiation in primary cultures of murine glial cells. The results indicate that morphine decreases glial cell production in a dose-dependent, naloxone reversible manner. Most notably, gliogenesis virtually ceased in the presence of 10 −6 M morphine during the first week in culture, whereas 10 −8 M or 10 −10 M morphine caused an intermediate suppression of growth compared to control or 10 −6 M morphine treated cultures. Moreover, morphine-treatment inhibited [ 3 H]thymidine incorporation by glial fibrillary acidic protein (GFAP) immunoreactive, flat (type 1) astrocytes, suggesting that the decrease in glial cell production was due in part to an inhibition of astrocyte proliferation. Morphine also caused significant increases in both cytoplasmic area and process elaboration in flat (type 1) astrocytes indicating greater morphologic differentiation. In the above experiments, morphine-dependent alterations in astrocyte growth were antagonized by naloxone, indicating that morphine action was mediated by specific opioid receptors. These observations suggest that opiate drugs can directly modify neural growth by influencing two critical developmental events in astrocytes, i.e., inhibiting proliferation and inducing morphologic differentiation.

μ-Opioid receptor-induced Ca2+ mobilization and astroglial development: morphine inhibits DNA synthesis and stimulates cellular hypertrophy through a Ca2+-dependent mechanism

“…Primary cultures, enriched in astrocytes were obtained from 1-to 2-day-old Swiss-Webster mice (ICR strain, Harlen Sprague Dawley, IN) as previously described 55,57 . Briefly, using aseptic technique, cells were isolated from the cerebral hemispheres of mouse pups killed by ether anesthesia and decapitation.…”

“…Not only do astrocytes themselves express endogenous opioid peptides during development 22,36,49,50,53 , but opioids inhibit astrocyte proliferation and promote premature morphologic differentiation in vitro 22,55,57 and in vivo 45,64 . Opioid drugs with abuse liability, such as heroin or morphine, affect glial development by disrupting the normal interactions between endogenous opioids and opioid receptors.…”

“…Opioid drugs with abuse liability, such as heroin or morphine, affect glial development by disrupting the normal interactions between endogenous opioids and opioid receptors. Depending on the parameter measured, morphine is as potent as the endogenous opioid Met-enkephalin in affecting astrocyte growth 23,55 . Morphine is particularly efficacious at inducing changes in morphologic differentiation including increases in astrocyte area and cell processes 55,57 .…”

“…Depending on the parameter measured, morphine is as potent as the endogenous opioid Met-enkephalin in affecting astrocyte growth 23,55 . Morphine is particularly efficacious at inducing changes in morphologic differentiation including increases in astrocyte area and cell processes 55,57 . Recently, diffuse, reactive astrocytosis, with regressive astrocytic changes, has been noted in the postmortem brains of chronic (non-HIV-infected) i.v.…”

Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation

“…However, the mechanisms involved in this dynamic partnership with neurons are not well characterized. The targets of opiate drugs of abuse are opioid receptors, G proteincoupled receptors that are found in astrocytes and are capable of modulating their proliferation in vitro and in vivo (43)(44)(45)(46)(47)(48)(49)(50)(51)(52). Using an astrocytoma model system, C6 glioma cells, and immortalized type 1 astrocytes, we implicated phosphatidylinositol turnover, discrete PKC isoforms, different secondary messengers, and transactivation of EGFR as well as FGF receptor in and opioid receptor (MOR and KOR) activation of ERK (53)(54)(55)(56)(57).…”