Mu and kappa opioids modulate mouse embryonic stem cell‐derived neural progenitor differentiation via MAP kinases

Hahn, Jason W.; Jagwani, Shana; Kim, Eun Hae; Rendell, Victoria R.; He, Joy Wei; Ezerskiy, Lubov; Wesselschmidt, Robin L.; Coscia, Carmine J.; Belcheva, Mariana M.

doi:10.1111/j.1471-4159.2009.06479.x

Cited by 36 publications

(30 citation statements)

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“…Chronic opioid administration has been shown to decrease neural stem cell (NSC) proliferation and suppresses glial cell growth, while inhibiting the generation of new neurons [9], [10], [13]. These observed effects appear to be primarily mediated via the opioid receptors [35], [36]. Chronic prenatal exposure to morphine has been shown to produce considerable somatosensory and cognitive deficits in mice [37].…”

Section: Discussionmentioning

confidence: 99%

Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors

Willner

Cohen-Yeshurun

Avidan³

et al. 2014

PLoS ONE

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BackgroundChronic morphine treatment inhibits neural progenitor cell (NPC) progression and negatively effects hippocampal neurogenesis. However, the effect of acute opioid treatment on cell development and its influence on NPC differentiation and proliferation in vitro is unknown. We aim to investigate the effect of a single, short term exposure of morphine on the proliferation, differentiation and apoptosis of NPCs and the mechanism involved.MethodsCell cultures from 14-day mouse embryos were exposed to different concentrations of morphine and its antagonist naloxone for 24 hours and proliferation, differentiation and apoptosis were studied. Proliferating cells were labeled with bromodeoxyuridine (BrdU) and cell fate was studied with immunocytochemistry.ResultsCells treated with morphine demonstrated decreased BrdU expression with increased morphine concentrations. Analysis of double-labeled cells showed a decrease in cells co-stained for BrdU with nestin and an increase in cells co-stained with BrdU and neuron-specific class III β-tubuline (TUJ1) in a dose dependent manner. Furthermore, a significant increase in caspase-3 activity was observed in the nestin- positive cells. Addition of naloxone to morphine-treated NPCs reversed the anti-proliferative and pro-apoptotic effects of morphine.ConclusionsShort term morphine exposure induced inhibition of NPC proliferation and increased active caspase-3 expression in a dose dependent manner. Morphine induces neuronal and glial differentiation and decreases the expression of nestin- positive cells. These effects were reversed with the addition of the opioid antagonist naloxone. Our results demonstrate the effects of short term morphine administration on the proliferation and differentiation of NPCs and imply a mu-receptor mechanism in the regulation of NPC survival.

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Section: Discussionmentioning

confidence: 99%

Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors

Willner

Cohen-Yeshurun

Avidan³

et al. 2014

PLoS ONE

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“…KORs signal through both Gα and Gβγ subunits, and then activate a host of downstream signaling molecules, thereby activating g-protein gated inwardly rectifying potassium channels (GIRKs), reducing calcium currents, and decreasing cyclic AMP. KORs have been shown to activate both MEK/ERK (Belcheva et al 2005, Hahn et al 2010, Kivell et al 2014a, Li et al 2012, McLennan et al 2008, Potter et al 2011, Yoshizawa et al 2011) (although some groups do not see significant MEK/ERK activation following KOR activation, see (Asensio et al 2006)) and MAPK signaling cascades, and in particular, p38 (Bruchas et al 2006, Bruchas et al 2011, Hahn et al 2010, Yoshizawa et al 2011). This KOR interaction with p38 is thought to be mediated by arrestin signaling; co-expression with the dominant-mutant of β-arrestin prevents human KOR internalization in CHO cells (Li et al 1999).…”

Section: Pharmacologymentioning

confidence: 99%

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

Crowley

Kash

2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

103

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Kappa opioid receptors (KORs) in the central nervous system have been known to be important regulators of a variety of psychiatry illnesses, including anxiety and addiction, but their precise involvement in these behaviors is complex and has yet to be fully elucidated. Here, we briefly review the pharmacology of KORs in the brain, including KOR's involvement in anxiety, depression, and alcohol addiction. We also review the known neuronal circuitry impacted by KOR signaling, and interactions with corticotrophin-releasing factor (CRF), another key peptide in anxiety-related illnesses, as well as the role of glucocorticoids. We suggest that KORs are a promising therapeutic target for a host of neuropsychiatric conditions.

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“…4 In recent studies that used embryonic stem (ES) cells, MOR and KOR were shown to promote neural progenitor differentiation and regulate cell specification from neural progenitors. 5,6 Moreover, KOR is highly expressed in human neural precursor cells and functions during neurogenesis in the fetal brain. 7 These results indicate that the opioid systems are involved in neurogenesis from neural stem and progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development

Yamamizu

Furuta

Katayama

et al. 2011

Blood

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The opioid system (opioid peptides and receptors) regulates a variety of neurophysiologic functions, including pain control. Here we show novel roles of the opioid system in vascular development. IntroductionOpioids are defined by their ability to bind to and influence opioid receptors on cell membranes. Three opioid receptors, , ␦, and (MOR, DOR, and KOR), are inhibitory G (Gi) protein-coupled receptors through which endogenous opioids (endorphins, enkephalins, and dynorphins) regulate physiologic functions, such as pain regulation, emotional tone, and reward circuitry. 1 These opioid receptors are the principle physiologic target for most clinically important opioid analgesics, such as morphine. Opioid systems are mainly present in neural tissue and could be involved in neurogenesis during brain development. 2,3 We previously showed that DOR, but not MOR or KOR, plays a crucial role in neurogenesis and neuroprotection in neural stem cells obtained from embryonic C3H mouse forebrain. 4 In recent studies that used embryonic stem (ES) cells, MOR and KOR were shown to promote neural progenitor differentiation and regulate cell specification from neural progenitors. 5,6 Moreover, KOR is highly expressed in human neural precursor cells and functions during neurogenesis in the fetal brain. 7 These results indicate that the opioid systems are involved in neurogenesis from neural stem and progenitor cells.Although endogenous opioids were first characterized in the brain, these opioid systems are found both in neural (brain and spinal cord) and extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood, and blood vessels). Opioids and opioid receptors were reported to exist in blood vessels in the later stage rat embryo (embryonic day [E]Ϫ16) through adult. 8,9 The addition of opioid peptides inhibited angiogenesis in a chick chorioallantoic membrane model 10 and DNA synthesis in rat vascular walls. 8 In the adult, the endogenous opioid system has been shown to be active in hemodynamic and cardiovascular responses, such as hemorrhagic shock, sepsis, and trauma. 11 The selective opioid receptor agonist U-50,488H has beneficial effects on vascular injury after spinal cord trauma by improving vascular permeability and edema. 12 These findings suggest that the opioid system plays an important role in vascular functions though its physiologic roles and molecular mechanisms remain largely unknown.VEGF/VEGF receptor-2 (fetal liver kinase 1; Flk1) signaling is a key regulator of vascular development during embryogenesis. A VEGF coreceptor, Neuropilin1 (NRP1), is largely coexpressed with Flk1 in vascular progenitors and forms a specific and sensitive receptor for VEGF 164 , an isoform of VEGF. 13,14 The Flk1-VEGF 164 -NRP1 complex potently enhances Flk1 signaling in vascular development. 13 NRP1 is also expressed in particular classes of developing neurons and functions as a receptor for class 3 semaphorins by forming a heterodimer with plexins. [15][16][17] PlexinD1 and semaphorin regulate not onl...

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Mu and kappa opioids modulate mouse embryonic stem cell‐derived neural progenitor differentiation via MAP kinases

Cited by 36 publications

References 50 publications

Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors

Short Term Morphine Exposure In Vitro Alters Proliferation and Differentiation of Neural Progenitor Cells and Promotes Apoptosis via Mu Receptors

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development

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