Expression of Opioid Receptors During Heart Ontogeny in Normotensive and Hypertensive Rats

Zimlichman, Reuven; Gefel, Dov; Eliahou, H. E.; Matas, Zipora; Rosen, Boaz D.; Gass, Steffen; Ela, Catherine; Eilam, Y.; Vogel, Zvi; Barg, Jacob

doi:10.1161/01.cir.93.5.1020

Cited by 81 publications

(64 citation statements)

References 28 publications

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“…A brain site of opioid action is suspected (24,39,40). As an alternative, a direct peripheral action might be considered, although the presence of the MOR in liver and skeletal muscle remains poorly documented (41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 99%

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the -opioid receptor (MOR) gene (MOR ؊/؊ ), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR ؊/؊ mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR ؊/؊ mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets. Diabetes 54: 3510 -3516, 2005 T he endogenous opioid system encompasses cloned receptor populations (, ␦, and ) and ligands (␤-endorphin, the enkephalins, and the dynorphins). Extensive work indicates that the opioid system plays a role in the regulation of appetite. Opioid receptors and peptides are expressed in sites of the central nervous system that play a role in regulating feeding behavior, and pharmacological experiments using opioid receptor ligands show that agonists promote eating and antagonists decrease food intake, at least in the short term (1-3). Numerous pharmacological studies indicate that opioids also play a role in modulating the rewarding effects of food (3-5). In contrast, little information suggests that opioids have a role in energy metabolism (6 -8).The need to establish the specific role of the opioid receptors in energy homeostasis has led to studies using putative specific opioid receptor ligands or, more recently, antisense probes directed against specific exons of opioid receptor genes (3,9). Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).Recent studies conducted in mutant mice null for the opioid receptors have complemented pharmacological approaches and clarified the role of each receptor in nociception, anxiety, and drug abuse (14). To further define the role of the -opioid receptor (MOR) pathway in energy homeostasis, we characterized mice lacking the MOR gene ...

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Section: Discussionmentioning

confidence: 99%

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

et al. 2005

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“…Liang and Gross also reported a cytoprotective effect of morphine in isolated cardiomyocytes obtained from 14-day old chick embryos (Liang and Gross, 1999). Both the ␦-and -opioid receptor subtypes have been demonstrated to mediate the cardioprotective effects of the opioids (Schultz et al, 1998;Wu et al, 1999;Zimlichman et al, 1996). These effects were assumed to be dependent on the opening of the K ATP channels (Liang and Gross, 1999).…”

Section: Introductionmentioning

confidence: 99%

Survivin mediates the anti-apoptotic effect of δ-opioid receptor stimulation in cardiomyocytes

Yao

Wang

Cai

et al. 2007

Journal of Cell Science

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Survivin is known to be essential for cell division and to inhibit apoptosis during embryonic development and in adult cancerous tissues. However, the cardiovascular role of survivin is unknown. We observed that in cardiomyocytes cultured under conditions of serum and glucose deprivation (DEPV), the levels of survivin, Bcl-2 and extracellular signal-regulated kinase (ERK) were positively correlated with the anti-apoptotic action of a δ-opioid receptor agonist, [D-Ala2, D-Leu5]-enkephalin acetate (DADLE). By contrast, Bax translocation, mitochondrial membrane damage and reactive oxygen species (ROS) production were inversely correlated with the changes of survivin and Bcl-2. The use of RNA interference (RNAi) targeting survivin increased DEPV-induced cardiomyocyte apoptosis, whereas the anti-apoptotic effect of DADLE was blunted by survivin RNAi. Moreover, survivin transfection and overexpression provided protection against DEPV-induced cardiomyocyte apoptosis. Inhibition of ERK prevented the DADLE-induced decrease in apoptosis and Bax translocation, and increase in survivin and Bcl-2. DADLE-induced increase in survivin was also blunted by phosphoinositol 3-kinase (PI 3-kinase) inhibition. In conclusion, the present study provides the first direct evidence of an anti-apoptotic role of survivin mediating the anti-apoptotic effect of δ-opioid receptor activation in cardiomyocytes. ERK and PI 3-kinase were found to be upstream regulators of survivin. Mitochondrial membranes as well as ROS, Bcl-2 and Bax were also involved in this anti-apoptotic action.

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“…Although ␦-opioid agonists exert potent cardioprotection, it is unclear which type of cardiac cells actually express ␦-opioid receptor (DOR). Despite the receptor-binding study of DOR (11,27,33) and its gene expression in human and animal hearts (2, 28), no clear immunohistochemical evidence has demonstrated in situ DOR expression in cardiac myocytes. The intrinsic cardiac adrenergic (ICA) cell is a neuroendocrine cell that expresses genes and enzyme proteins for epinephrine biosynthesis (5, 9, 10).…”

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confidence: 99%

Mediating δ-opioid-initiated heart protection via the β₂-adrenergic receptor: role of the intrinsic cardiac adrenergic cell

Huang

Wang

Roeske

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Uretsky BF. Mediating ␦-opioid-initiated heart protection via the ␤ 2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell. Am J Physiol Heart Circ Physiol 293: H376-H384, 2007. First published March 16, 2007; doi:10.1152/ajpheart.01195.2006.-Stimulation of cardiac ␤ 2-adrenergic receptor (␤2-AR) or ␦-opioid receptor (DOR) exerts a similar degree of cardioprotection against myocardial ischemia in experimental models. We hypothesized that ␦-opioid-initiated cardioprotection is mediated by the intrinsic cardiac adrenergic (ICA) cell via enhanced epinephrine release. Using immunohistochemical and in situ hybridization methods, we detected in situ tyrosine hydroxylase (TH) mRNA and TH immunoreactivity that was colocalized with DOR immunoreactivity in ICA cells in human and rat hearts. Western blot analysis detected DOR protein in ICA cells isolated from rat ventricular myocytes. ]i transients in a concentration-dependent manner. Such an effect was abolished by the Ca 2ϩ channel blocker nifedipine. HPLC-electrochemical detection demonstrated a 2.4-fold increase in epinephrine release from ICA cells following DPDPE application. The significance of the ICA cell and its epinephrine release in ␦-opioid-initiated cardioprotection was demonstrated in the rat myocardial infarction model and ICA cell-ventricular myocyte coculture. DPDPE administered before coronary artery occlusion or simulated ischemia-reperfusion reduced left ventricular infarct size by 54 Ϯ 15% or myocyte death by 26 Ϯ 4%, respectively. ␤2-AR blockade markedly attenuated ␦-opioid-initiated infarct size-limiting effect and abolished ␦-opioid-initiated myocyte survival protection in rat ICA cell-myocyte coculture. Furthermore, ␦-opioid agonist exerted no myocyte survival protection in the absence of cocultured ICA cells during ischemia-reperfusion. We conclude that ␦-opioid-initiated myocardial infarct size reduction is primarily mediated via endogenous epinephrine/␤2-AR signaling pathway as a result of ICA cell activation.␦-opioid receptor; epinephrine; myocardial ischemia STIMULATION OF ␤ 2 -adrenergic receptor (␤ 2 -AR) before myocardial ischemia confers cardioprotection via infarct size reduction (13, 14) and facilitated ventricular contractile recovery (25) during ischemia-reperfusion in experimental models. Numerous studies indicate that ␦-opioid agonists precondition the heart against ischemia (2,7,19,22,23). The extent of heart protection conferred by ␦-opioids is comparable with that elicited by myocardial ␤ 2 -AR stimulation. It has been suggested that ␦-opioid-initiated cardioprotection is partially mediated by ␤ 2 -AR in the murine heart (20). Although ␦-opioid agonists exert potent cardioprotection, it is unclear which type of cardiac cells actually express ␦-opioid receptor (DOR). Despite the receptor-binding study of DOR (11,27,33) and its gene expression in human and animal hearts (2, 28), no clear immunohistochemical evidence has demonstrated in situ DOR expression in cardiac myocytes. The intrinsic cardiac adrenergic (ICA) ce...

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Expression of Opioid Receptors During Heart Ontogeny in Normotensive and Hypertensive Rats

Cited by 81 publications

References 28 publications

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Survivin mediates the anti-apoptotic effect of δ-opioid receptor stimulation in cardiomyocytes

Mediating δ-opioid-initiated heart protection via the β₂-adrenergic receptor: role of the intrinsic cardiac adrenergic cell

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Expression of Opioid Receptors During Heart Ontogeny in Normotensive and Hypertensive Rats

Cited by 81 publications

References 28 publications

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice

Survivin mediates the anti-apoptotic effect of δ-opioid receptor stimulation in cardiomyocytes

Mediating δ-opioid-initiated heart protection via the β2-adrenergic receptor: role of the intrinsic cardiac adrenergic cell

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Mediating δ-opioid-initiated heart protection via the β₂-adrenergic receptor: role of the intrinsic cardiac adrenergic cell