Effect of U-50488h, a selective opioid κ receptor agonist, on vascular injury after spinal cord trauma

Qu, Zhi; Xu, Jian; Hogan, Edward L.; Hsu, Chung Y.

doi:10.1016/0006-8993(93)90561-z

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…In vivo studies generally suggest that selective KOP signaling is protective against CNS damage due to ischemia or trauma [3–5, 17, 18]. Much of this effect is probably indirect, mediated by reduced production of inflammatory agents or vascular changes [18, 37]. However, direct protective effects of KOP signaling may occur.…”

Section: Resultsmentioning

confidence: 99%

Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse

Knapp

Adjan

Hauser

2009

Neuroscience Letters

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Jimpy is a murine mutation in myelin proteolipid protein, leading to premature death of oligodendrocytes and severe central nervous system hypomyelination. Jimpy is a bona fide model of human Pelizaeus-Merzbacher disease. This paper describes a severe reduction in expression of κ-opioid receptors (KOP) in oligodendrocytes of jimpy mice. A cell specific reduction of >90% is apparent by 5 days of age. Expression is not reduced in neurons, and μ-opioid receptor expression is normal. Mechanism(s) leading to deficient KOP expression in jimpy mice remain unclear. We speculate that loss of KOP may be related to increased [Ca2+]i and premature death of jimpy oligodendrocytes.

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Section: Resultsmentioning

confidence: 99%

Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse

Knapp

Adjan

Hauser

2009

Neuroscience Letters

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“…In adults, the endogenous opioid system has been shown to be active in hemodynamic and cardiovascular responses, such as haemorrhagic shock, sepsis and trauma (Molina, ). The κ opioid receptor agonist U‐50,488H has beneficial effects on vascular injury after spinal cord trauma by improving vascular permeability and oedema (Qu et al ., ). Moreover, morphine, an agonist at μ opioid receptors, suppresses tumour angiogenesis through the inhibition of hypoxia‐inducible transcription factors (HIFs), which enhances the expression of VEGF‐A and VEGF receptors (Koodie et al ., ).…”

Section: Introductionmentioning

confidence: 97%

κ Opioid receptor ligands regulate angiogenesis in development and in tumours

Yamamizu

Hamada

Narita

2014

British J Pharmacology

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Opioid systems mainly regulate physiological functions such as pain, emotional tone and reward circuitry in neural tissues (brain and spinal cord). These systems are also found in extraneural tissues (ganglia, gut, spleen, stomach, lung, pancreas, liver, heart, blood and blood vessels), and recent studies have elucidated their roles in various organs. The current review focuses on the roles of opioid systems in blood vessels, especially angiogenesis, during development and tumour malignancy. The balance between endogenous activators and inhibitors of angiogenesis delicately maintains a normally quiescent vasculature to sustain homeostasis. Disturbance of this balance causes pathogenic angiogenesis and, especially in tumours, several activators such as VEGF are highly expressed in the tumour microenvironment and strongly induce tumour angiogenesis, the so-called angiogenic switch. Recently, we demonstrated that κ opioid receptor agonists function as anti-angiogenic factors, which impede the angiogenic switch, in vascular development and tumour angiogenesis by inhibiting the expression of receptors for VEGF. In clinical medicine, angiogenesis inhibitors that target VEGF signalling such as bevacizumab are used as anti-cancer drugs. Although therapies that inhibit tumour angiogenesis have been highly successful for tumour therapy, most patients eventually develop resistance to this anti-angiogenic therapy. Thus, we must identify novel targets for anti-angiogenic agents to sustain inhibition of angiogenesis for tumour therapy. The regulation of responses to κ opioid receptor ligands could be useful for controlling vascular formation under physiological conditions and in cancers, and thus could offer therapeutic benefits beyond the relief of pain. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 AbbreviationsBBB, blood-brain barrier; E, embryonic day; ECs, endothelial cells; ES, embryonic stem; FGF, fibroblast growth factor; Gi, inhibitory G protein; HIF, hypoxia inducible factor; iPS, induced pluripotent stem; LLC, Lewis lung carcinoma; NRP, neuropilin; TKIs, tyrosine kinase inhibitors; TSP1, thrombospondin1 IntroductionOne of the earliest events in organogenesis is the development of the vascular system, which contributes to the formation of most organs in our bodies. The vascular system is first formed as a primitive vascular network by the differentiation and assembly of vascular progenitor cells derived from mesodermal cells. These progenitor cells undergo a complex remodelling process, in which growth, migration, sprouting and pruning lead to the development of a functional circulatory system. Earlier studies have suggested that many of the events in normal vascular formation during embryogenesis are recapitulated during de novo angiogenesis in adults such as tumour angiogenesis and neovascularization induced after tissue damage (Carmeliet, 2003). Furthermore,...

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Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

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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Effect of U-50488h, a selective opioid κ receptor agonist, on vascular injury after spinal cord trauma

Cited by 11 publications

References 38 publications

Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse

Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse

κ Opioid receptor ligands regulate angiogenesis in development and in tumours

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

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