The presence of mu-, delta-, and kappa-opioid receptors in human heart tissue

Sobański, Piotr; Krajnik, Małgorzata; Shaqura, Mohammed; Bloch-Bogusławska, Elzbieta; Schäfer, Michael; Mousa, Shaaban A.

doi:10.1007/s00380-013-0456-5

Cited by 65 publications

(43 citation statements)

References 57 publications

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“…As noted above, the opioid receptors μ, κ, and δ are located throughout the brain, but they are also found in the periphery localized primarily to the enteric nervous system of the gut (Holzer, 2009) and less so in the heart (Sobanski et al, 2014). Opioids have a dramatic influence on gut motility with the unwanted side effect of constipation (Holzer, 2009) and can attenuate the sympathetic regulation of cardiac function (Wong and Shan, 2001).…”

Section: Discussionmentioning

confidence: 98%

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

et al. 2016

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Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (μ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high μ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the μ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the μ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other μ opioid agonists.

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Section: Discussionmentioning

confidence: 98%

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

et al. 2016

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“…In experimental models of ischemia reperfusion injury, morphine inhibits the mitochondrial permeability transition pore24 opening through μ and κ myocardial opioid receptors,25, 26 and induced a significant cardioprotective effect 27. Morphine also stimulates the reperfusion injury salvage kinase pathway 24.…”

Section: Discussionmentioning

confidence: 99%

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Bonin

Mewton

Roubille

et al. 2018

JAHA

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BackgroundMorphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST‐segment elevation myocardial infarction followed up for 1 year.Methods and ResultsWe used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST‐segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P=0.15). The all‐cause mortality was 5.3% in the morphine group versus 5.8% in the no‐morphine group (P=0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P=0.52).ConclusionsIn anterior ST‐segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year.

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“…Findings of this study may yet give anatomical evidence for a permanent influence of the cardiac MOR system on cardiac and mitochondrial function under normal and pathological states of the rat heart. These findings cannot directly be transferred to human tissue, however, all three ORs have recently been detected in human hearts post mortem, but have not been detected in mitochondria of human cardiomycytes so far [57].…”

Section: Figmentioning

confidence: 94%

Evidence for MOR on cell membrane, sarcoplasmatic reticulum and mitochondria in left ventricular myocardium in rats

et al. 2015

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Cardiac function is one important determinant to maintain tissue oxygenation and is thus highly regulated. In this context, it is interesting that centrally mediated opioidergic influence on cardiac function has long been known. Only recently, KOR and DOR have been found to be expressed in healthy left ventricular myocardium in rats and colocalized with parts of the excitation-contraction-coupling system. However, several comments in literature exist doubting the existence of MOR in cardiac tissue. We, therefore, aimed to detect MOR in rat left ventricular cardiomyocytes, and to evaluate whether MOR and POMC are regulated during heart failure. After IRB approval, heart failure was induced using a modified infrarenal aortocaval fistula (ACF) in male Wistar rats. All rats of the control and ACF group were characterized by their morphometrics and hemodynamics and the existence of MOR and POMC was investigated by means of radioligand binding, double immunofluorescence confocal analysis, RT-PCR and Western blot. Membrane MOR selective binding sites were detected in the left ventricular myocardium, however, they were lower in abundance than KOR- and DOR-specific binding sites and B max of MOR could not be determined. In left ventricular cardiomyocytes, MOR colocalized with parts of the excitation-coupling mechanism, e.g., Cav1.2 of the cell membrane and invaginated T-tubules as well as the ryanodine receptor of the sarcoplasmatic reticulum. More importantly, MOR strongly colocalized with mitochondria of left ventricular cardiomyocytes. Volume overload was not associated with an altered expression of MOR and POMC on both mRNA and protein level. These findings provide evidence for the existence of MOR on the cell membrane, sarcoplasmatic reticulum and mitochondria in left ventricular cardiomyocytes in rats. However, heart failure does not result in an altered expression of the cardiac MOR-opioid system. Thus, MOR agonist treatment-commonly used in the clinical setting-might directly affect cardiac function, which needs to be evaluated in greater detail in the near future.

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The presence of mu-, delta-, and kappa-opioid receptors in human heart tissue

Cited by 65 publications

References 57 publications

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone

Effect and Safety of Morphine Use in Acute Anterior ST‐Segment Elevation Myocardial Infarction

Evidence for MOR on cell membrane, sarcoplasmatic reticulum and mitochondria in left ventricular myocardium in rats

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