The Experts below are selected from a list of 24522 Experts worldwide ranked by ideXlab platform
Ruiping Xiao - One of the best experts on this subject based on the ideXlab platform.
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cross talk of Opioid Peptide receptor and β adrenergic receptor signalling in the heart
Cardiovascular Research, 2004Co-Authors: Ruiping Xiao, Salvatore Pepe, Edward G Lakatta, Olivier W V Van Den BrinkAbstract:Opioid Peptide receptor (OPR) and β-adrenergic receptor (β-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical Gi/Go-coupled receptors and activated by Opioid Peptides derived from the endorphin, dynorphin and enkephalin families, whereas β-AR stimulated by catecholamines is the model system for Gs-coupled receptors. While it is widely accepted that β-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous Opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, Opioid Peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation–contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of Gi-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with β-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the β-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between β-AR and OPR and its potential physiological and pathophysiological relevance in the heart.
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cross talk between Opioid Peptide and adrenergic receptor signaling in isolated rat heart
Circulation, 1997Co-Authors: Salvatore Pepe, Ruiping Xiao, C M Hohl, Ruth A Altschuld, Edward G LakattaAbstract:Background Cardiac myocyte sarcolemma contains both catecholamine and Opioid Peptide receptors (OPRs). Opioid Peptides are coreleased with catecholamines from nerve terminals in the heart. We investigated whether OPR stimulation influences the effects of β-adrenergic receptor (β-AR) stimulation in the isolated, isovolumic rat heart and whether the mechanism of such an interaction involves both β-AR subtypes or an alteration in β-AR–mediated increase in cAMP. Methods and Results Norepinephrine (NE, 10−7 mol/L) increased peak left ventricular systolic pressure (LVSP) and cAMP more than twofold compared with controls. The δ-OPR agonist leucine-enkephalin (LE, 10−8 mol/L) markedly inhibited the β1-AR–induced positive inotropic effect and increase in cAMP but alone had no effect on basal LVSP or basal cAMP levels. The OPR antagonist naloxone 10−8 mol/L added to LE+NE perfusate reversed the LE-induced decrease in cAMP and LVSP even though naloxone alone had no effect on LVSP and cAMP levels. LE could not counte...
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Opioid Peptide receptor stimulation reverses beta adrenergic effects in rat heart cells
American Journal of Physiology-heart and Circulatory Physiology, 1997Co-Authors: Ruiping Xiao, Salvatore Pepe, Harold A Spurgeon, Maurizio C Capogrossi, Edward G LakattaAbstract:Opioid Peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-Opioid Peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an Opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.
Heike L Rittner - One of the best experts on this subject based on the ideXlab platform.
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cxcl10 controls inflammatory pain via Opioid Peptide containing macrophages in electroacupuncture
PLOS ONE, 2014Co-Authors: Ying Wang, Dagmar Hackel, Shaaban A Mousa, Alexander Brack, Rebekka Gehringer, Heike L RittnerAbstract:Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct Opioid-containing neutrophils in the inflamed tissue and stimulate Opioid Peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of Opioid Peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-Opioid Peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of Opioid Peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered Opioid-mediated antinociception and increase Opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating Opioid Peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of Opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.
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recruitment of Opioid Peptide containing neutrophils is independent of formyl Peptide receptors
Journal of Neuroimmunology, 2011Co-Authors: A Stolz, Dagmar Hackel, Heike L Rittner, Shaaban A Mousa, Alexander BrackAbstract:Abstract In complete Freund's adjuvans (CFA) inflammation Opioid containing neutrophils release Opioid Peptides upon stimulation and mediate peripheral analgesia. Neutrophil migration is regulated partially by chemokines, but other mediators e.g. formyl Peptides could also contribute. In vitro , formyl Peptides but not Mycobacterium butyricum (CFA component) induced migration of neutrophils. In contrast, local formyl Peptide injection did not induce leukocyte recruitment in vivo due to insufficient up-regulation of adhesion molecule expression. Furthermore, leukocyte recruitment and peripheral Opioid-mediated analgesia were unaffected by systemic formyl Peptide receptor blockade in CFA inflammation. Thus, while formyl Peptides do not regulate migration they directly stimulate Opioid Peptide release.
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antinociception by neutrophil derived Opioid Peptides in noninflamed tissue role of hypertonicity and the perineurium
Brain Behavior and Immunity, 2009Co-Authors: Heike L Rittner, Dagmar Hackel, Shaaban A Mousa, Michael Schafer, Christoph Stein, Reine-solange Yamdeu, Alexander BrackAbstract:Abstract Inflammatory pain can be controlled by intraplantar Opioid injection or by secretion of endogenous Opioid Peptides from leukocytes in inflamed rat paws. Antinociception requires binding of Opioid Peptides to Opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic Opioid Peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic Opioid Peptides (i.e. Met-Enkephalin and β-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of Opioid Peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered Opioid Peptide release from neutrophils in vitro , nociceptive thresholds were unchanged in vivo . In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and Opioid Peptide release from neutrophils. These inhibitory effects were fully reversible by washout . In vivo , return to normotonicity occurred within 30 min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced Opioid Peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous Opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for Opioid Peptide access and (ii) Opioid Peptide release from neutrophils involving p38 MAPK.
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mycobacteria attenuate nociceptive responses by formyl Peptide receptor triggered Opioid Peptide release from neutrophils
PLOS Pathogens, 2009Co-Authors: Dagmar Hackel, Heike L Rittner, Shaaban A Mousa, Philipp Voigt, Andrea Stolz, Dominika Labuz, Michael Schafer, Michael SchaeferAbstract:In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include Opioid Peptides which are secreted by neutrophils at the site of inflammation, leading to activation of Opioid receptors on peripheral sensory neurons. In humans, local Opioids and Opioid Peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl Peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to Opioid Peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of Opioid receptor antagonists or anti-Opioid Peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, Opioid Peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl Peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid Peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced Opioid Peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of Opioid Peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia.
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Antinociception by neutrophil-derived Opioid Peptides in noninflamed tissue—Role of hypertonicity and the perineurium
Brain Behavior and Immunity, 2009Co-Authors: Heike L Rittner, Dagmar Hackel, Shaaban A Mousa, Michael Schafer, Christoph Stein, Reine-solange Yamdeu, A. BrackAbstract:Abstract Inflammatory pain can be controlled by intraplantar Opioid injection or by secretion of endogenous Opioid Peptides from leukocytes in inflamed rat paws. Antinociception requires binding of Opioid Peptides to Opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic Opioid Peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic Opioid Peptides (i.e. Met-Enkephalin and β-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of Opioid Peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered Opioid Peptide release from neutrophils in vitro , nociceptive thresholds were unchanged in vivo . In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and Opioid Peptide release from neutrophils. These inhibitory effects were fully reversible by washout . In vivo , return to normotonicity occurred within 30 min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced Opioid Peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous Opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for Opioid Peptide access and (ii) Opioid Peptide release from neutrophils involving p38 MAPK.
Salvatore Pepe - One of the best experts on this subject based on the ideXlab platform.
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cross talk of Opioid Peptide receptor and β adrenergic receptor signalling in the heart
Cardiovascular Research, 2004Co-Authors: Ruiping Xiao, Salvatore Pepe, Edward G Lakatta, Olivier W V Van Den BrinkAbstract:Opioid Peptide receptor (OPR) and β-adrenergic receptor (β-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical Gi/Go-coupled receptors and activated by Opioid Peptides derived from the endorphin, dynorphin and enkephalin families, whereas β-AR stimulated by catecholamines is the model system for Gs-coupled receptors. While it is widely accepted that β-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous Opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, Opioid Peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation–contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of Gi-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with β-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the β-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between β-AR and OPR and its potential physiological and pathophysiological relevance in the heart.
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cross talk between Opioid Peptide and adrenergic receptor signaling in isolated rat heart
Circulation, 1997Co-Authors: Salvatore Pepe, Ruiping Xiao, C M Hohl, Ruth A Altschuld, Edward G LakattaAbstract:Background Cardiac myocyte sarcolemma contains both catecholamine and Opioid Peptide receptors (OPRs). Opioid Peptides are coreleased with catecholamines from nerve terminals in the heart. We investigated whether OPR stimulation influences the effects of β-adrenergic receptor (β-AR) stimulation in the isolated, isovolumic rat heart and whether the mechanism of such an interaction involves both β-AR subtypes or an alteration in β-AR–mediated increase in cAMP. Methods and Results Norepinephrine (NE, 10−7 mol/L) increased peak left ventricular systolic pressure (LVSP) and cAMP more than twofold compared with controls. The δ-OPR agonist leucine-enkephalin (LE, 10−8 mol/L) markedly inhibited the β1-AR–induced positive inotropic effect and increase in cAMP but alone had no effect on basal LVSP or basal cAMP levels. The OPR antagonist naloxone 10−8 mol/L added to LE+NE perfusate reversed the LE-induced decrease in cAMP and LVSP even though naloxone alone had no effect on LVSP and cAMP levels. LE could not counte...
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Opioid Peptide receptor stimulation reverses beta adrenergic effects in rat heart cells
American Journal of Physiology-heart and Circulatory Physiology, 1997Co-Authors: Ruiping Xiao, Salvatore Pepe, Harold A Spurgeon, Maurizio C Capogrossi, Edward G LakattaAbstract:Opioid Peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-Opioid Peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an Opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.
Edward G Lakatta - One of the best experts on this subject based on the ideXlab platform.
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cross talk of Opioid Peptide receptor and β adrenergic receptor signalling in the heart
Cardiovascular Research, 2004Co-Authors: Ruiping Xiao, Salvatore Pepe, Edward G Lakatta, Olivier W V Van Den BrinkAbstract:Opioid Peptide receptor (OPR) and β-adrenergic receptor (β-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical Gi/Go-coupled receptors and activated by Opioid Peptides derived from the endorphin, dynorphin and enkephalin families, whereas β-AR stimulated by catecholamines is the model system for Gs-coupled receptors. While it is widely accepted that β-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous Opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, Opioid Peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation–contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of Gi-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with β-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the β-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between β-AR and OPR and its potential physiological and pathophysiological relevance in the heart.
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cross talk between Opioid Peptide and adrenergic receptor signaling in isolated rat heart
Circulation, 1997Co-Authors: Salvatore Pepe, Ruiping Xiao, C M Hohl, Ruth A Altschuld, Edward G LakattaAbstract:Background Cardiac myocyte sarcolemma contains both catecholamine and Opioid Peptide receptors (OPRs). Opioid Peptides are coreleased with catecholamines from nerve terminals in the heart. We investigated whether OPR stimulation influences the effects of β-adrenergic receptor (β-AR) stimulation in the isolated, isovolumic rat heart and whether the mechanism of such an interaction involves both β-AR subtypes or an alteration in β-AR–mediated increase in cAMP. Methods and Results Norepinephrine (NE, 10−7 mol/L) increased peak left ventricular systolic pressure (LVSP) and cAMP more than twofold compared with controls. The δ-OPR agonist leucine-enkephalin (LE, 10−8 mol/L) markedly inhibited the β1-AR–induced positive inotropic effect and increase in cAMP but alone had no effect on basal LVSP or basal cAMP levels. The OPR antagonist naloxone 10−8 mol/L added to LE+NE perfusate reversed the LE-induced decrease in cAMP and LVSP even though naloxone alone had no effect on LVSP and cAMP levels. LE could not counte...
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Opioid Peptide receptor stimulation reverses beta adrenergic effects in rat heart cells
American Journal of Physiology-heart and Circulatory Physiology, 1997Co-Authors: Ruiping Xiao, Salvatore Pepe, Harold A Spurgeon, Maurizio C Capogrossi, Edward G LakattaAbstract:Opioid Peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-Opioid Peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an Opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.
Christoph Stein - One of the best experts on this subject based on the ideXlab platform.
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inflammatory linked changes in cpg island methylation of three Opioid Peptide genes in a rat model for pain
PLOS ONE, 2018Co-Authors: Charlotte Louise Justine Jacobi, Christoph SteinAbstract:Expression of the Opioid Peptide genes proopiomelanocortin (Pomc), proenkephalin (Penk), and prodynorphin (Pdyn), in immune cells plays a key role in endogenous pain control. In a rat model of painful unilateral paw inflammation, we isolated cells from popliteal lymph nodes and evaluated the role of CpG island C5-methylation on the transcriptional activation of those genes. Using methylated DNA immunoprecipitation, we sorted gDNA into methylated (me) and non-me fractions and then determined the CpG island methylation status of each fraction via quantitative Real Time-PCR (qRT-PCR). In silico analysis by MethPrimer software identified one CpG island in Pdyn and three each in Pomc and Penk. No substantial changes in C5-methylation of any gene were observed. In conclusion, the CpG island methylation status does not seem to be a key regulator of Opioid gene activation in immune cells during peripheral tissue inflammation.
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Opioid receptors and Opioid Peptide producing leukocytes in inflammatory pain basic and therapeutic aspects
Brain Behavior and Immunity, 2010Co-Authors: Melanie Buschdienstfertig, Christoph SteinAbstract:This review summarizes recent findings on neuro-immune mechanisms underlying Opioid-mediated inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms by immune cell-derived Opioid Peptides. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generators of impulses relaying nociceptive information towards the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. This is in part achieved by endogenously released immune cell-derived Opioid Peptides within inflamed tissue. In addition, exogenous Opioid receptor ligands that selectively modulate primary afferent function and do not cross the blood-brain barrier, avoid centrally mediated untoward side effects of conventional analgesics (e.g., Opioids, anticonvulsants). This article discusses peripheral Opioid receptors and their signaling pathways, Opioid Peptide-producing/secreting inflammatory cells and arising therapeutic perspectives.
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antinociception by neutrophil derived Opioid Peptides in noninflamed tissue role of hypertonicity and the perineurium
Brain Behavior and Immunity, 2009Co-Authors: Heike L Rittner, Dagmar Hackel, Shaaban A Mousa, Michael Schafer, Christoph Stein, Reine-solange Yamdeu, Alexander BrackAbstract:Abstract Inflammatory pain can be controlled by intraplantar Opioid injection or by secretion of endogenous Opioid Peptides from leukocytes in inflamed rat paws. Antinociception requires binding of Opioid Peptides to Opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic Opioid Peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic Opioid Peptides (i.e. Met-Enkephalin and β-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of Opioid Peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered Opioid Peptide release from neutrophils in vitro , nociceptive thresholds were unchanged in vivo . In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and Opioid Peptide release from neutrophils. These inhibitory effects were fully reversible by washout . In vivo , return to normotonicity occurred within 30 min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced Opioid Peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous Opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for Opioid Peptide access and (ii) Opioid Peptide release from neutrophils involving p38 MAPK.
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Antinociception by neutrophil-derived Opioid Peptides in noninflamed tissue—Role of hypertonicity and the perineurium
Brain Behavior and Immunity, 2009Co-Authors: Heike L Rittner, Dagmar Hackel, Shaaban A Mousa, Michael Schafer, Christoph Stein, Reine-solange Yamdeu, A. BrackAbstract:Abstract Inflammatory pain can be controlled by intraplantar Opioid injection or by secretion of endogenous Opioid Peptides from leukocytes in inflamed rat paws. Antinociception requires binding of Opioid Peptides to Opioid receptors on peripheral sensory nerve terminals. In the absence of inflammation, hydrophilic Opioid Peptides do not penetrate the perineurial barrier and, thus, do not elicit antinociception. This study was designed to examine the conditions under which endogenous, neutrophil-derived hydrophilic Opioid Peptides (i.e. Met-Enkephalin and β-endorphin) can raise nociceptive thresholds in noninflamed tissue in rats. Intraplantar injection of the chemokine CXCL2/3 (macrophage inflammatory protein-2) induced selective neutrophil recruitment without overt signs of inflammation or changes in mechanical nociceptive thresholds (paw pressure threshold). Following intraplantar injection of hypertonic saline, the perineurial barrier was permeable for hours and intraplantar injection of Opioid Peptides increased mechanical nociceptive thresholds. While formyl-Met-Leu-Phe (fMLP) triggered Opioid Peptide release from neutrophils in vitro , nociceptive thresholds were unchanged in vivo . In vitro, hypertonicity interfered with fMLP-induced p38 mitogen activated kinase (MAPK) phosphorylation and Opioid Peptide release from neutrophils. These inhibitory effects were fully reversible by washout . In vivo , return to normotonicity occurred within 30 min while the perineurium remained permeable for hours. Under these conditions, fMLP triggered MAPK phosphorylation and induced Opioid Peptide-mediated increases in nociceptive thresholds in the noninflamed paw. Taken together, antinociception mediated by endogenous Opioids in noninflamed tissue has two important requirements: (i) opening of the perineurial barrier for Opioid Peptide access and (ii) Opioid Peptide release from neutrophils involving p38 MAPK.
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Leukocyte-derived Opioid Peptides and inhibition of pain.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2006Co-Authors: Halina Machelska, Christoph SteinAbstract:In peripheral inflamed tissue interactions between leukocyte-derived Opioid Peptides and Opioid receptors on sensory neurons lead to potent, clinically relevant inhibition of pain. Opioid receptors are present on peripheral terminals of sensory neurons and are upregulated in inflammation. Their endogenous ligands, Opioid Peptides, are synthesized in circulating immune cells, which migrate to injured tissues directed by chemokines and adhesion molecules. Under stressful stimuli or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, catecholamines) leukocytes can secrete Opioids. These Peptides activate peripheral Opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuroPeptides. These effects occur without central Opioid side effects such as depression of breathing, clouding of consciousness, or addiction. Future research should elucidate the selective targeting of Opioid Peptide-containing immune cells to sites of painful tissue injury and the augmentation of Opioid Peptide and receptor synthesis.