Vascular endothelial growth factors (VEGFs) and angiopoietins (ANGs) are involved in pathophysiological responses in damaged nerve tissues. Astrocytes produce VEGFs and ANGs upon brain ischemia and traumatic injury. To clarify the extracellular signals regulating VEGF and ANG production, effects of endothelins (ETs), a family of endothelium-derived peptides, were examined in cultured rat astrocytes. ET-1 (100 nM) and Ala(1,3,11,15)-ET-1 (100 nM), an ET(B) receptor agonist, increased VEGF-A mRNA levels in cultured astrocytes, while ANG-1 mRNA was decreased by ETs. ET-1 did not affect astrocytic VEGF-B, placental growth factor (PLGF), and ANG-2 mRNA levels. The effects of ET-1 on VEGF-A and ANG-1 mRNAs were inhibited by BQ788, an ET(B) antagonist. Release of VEGF-A proteins from cultured astrocytes was increased by ET-1. In contrast, ET-1 reduced release of astrocytic ANG-1. Exogenous ET-1 (100 nM) and VEGF(165) (100 ng/mL), an isopeptide of VEGF-A, stimulated bromodeoxyuridine (BrdU) incorporation into cultured astrocytes. Treatment with ET-1 and VEGF(165) increased the numbers of cyclin D1-positive astrocytes. Exogenous ANG-1 (250 ng/mL) did not stimulate the BrdU incorporation. Increases in BrdU incorporation by ET-1 and VEGF(165) were not affected by ANG-1. In 60-70% confluent cultures, SU4312 (10 μM), a VEGF receptor tyrosine kinase inhibitor, partially reduced the effects of ET-1 on BrdU incorporation and cyclin D1 expression. ET-induced BrdU incorporation and cyclin D1 expression were reduced by a neutralizing antibody against VEGF-A. Our findings suggest that ET-1 is a factor regulating astrocytic VEGF-A and ANG-1, and that increased VEGF-A production potentiates ET-induced astrocytic proliferation by an autocrine mechanism.
This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.
Expressions of vascular endothelial growth factor (VEGF) receptors in astrocytes are increased in damaged brains. To clarify the regulatory mechanisms of VEGF receptors, the effects of endothelin-1 (ET-1) were examined in rat cultured astrocytes. Expressions of VEGF-R1 and -R2 receptor mRNA were at similar levels, whereas the mRNA expressions of VEGF-R3 and Tie-2, a receptor for angiopoietins, were lower. Placenta growth factor, a selective agonist of the VEGF-R1 receptor, induced phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase 1/2 (ERK1/2). Phosphorylations of FAK and ERK 1/2 were also stimulated by VEGF-E, a selective VEGF-R2 agonist. Increased phosphorylations of FAK and ERK1/2 by VEGF 165 were reduced by selective antagonists for VEGF-R1 and -R2. Treatment with ET-1 increased VEGF-R1 mRNA and protein levels. The effects of ET-1 on VEGF-R1 mRNA were mimicked by Ala 1,3,11,15 -ET-1, a selective agonist for ET B receptors, and inhibited by BQ788, an ET B antagonist. ET-1 did not affect the mRNA levels of VEGF-R2, -R3, and Tie-2. Pre-treatment with ET-1 potentiated the effects of placenta growth factor on phosphorylations of FAK and ERK1/2. These findings suggest that ET-1 induces up-regulation of VEGF-R1 receptors in astrocytes, and potentiates VEGF signals in damaged nerve tissues.
These results indicate that KOR plays an important role in the inhibition of repeated morphine-induced cPKC up-regulation under chronic pain condition. Furthermore, this may result in the increase of MOR activity and in the inhibition of morphine tolerance under chronic pain condition.
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