Angiotensin II induced myocardial hypertrophy in neonatal rats could be attenuated by activated κ-opioid receptor via modulating the calcineurin signal pathways / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe the effect of κ-opioid receptor (κ-OR) stimulation on Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy in vitro cultured myocardial cells from neonatal rats and on calcineurin (CaN) signal pathways.</p><p><b>METHODS</b>Cultured myocardial cells of neonatal rats were divided into control group, CSA (1 µmol/L) group, Ang II (1 µmol/L) group, Ang II (1 µmol/L) + U50488H (1 µmol/L) group, Ang II (1 µmol/L) + CSA (1 µmol/L) group, Ang II (1 µmol/L) + Rp-cAMPS (1 µmol/L) group, Ang II (1 µmol/L) + CSA (1 µmol/L) + U50488H (1 µmol/L) group and Ang II (1 µmol/L) + PTX5 mg/L + U50488H (1 µmol/L) group. The hypertrophic myocytes were induced by Ang II 1µmol/L before κ-OR agonist U50488H 1 µmol/L was administered. The antihypertrophic effect of κ-OR stimulation was observed in the presence of ciclosporine A (CsA) 1 µmol/L, cAMP triethyl-ammonium salt (Rp-cAMPS) 1 µmol/L, and pertussistoxin ( PTX) 5 mg/L. The total protein content was assayed by the method of Lowry. The [Ca²⁺]i was measured by confocal microscope using Fluo-3/AM as flouresecent indicator. The relative expression of CaN was determined by Western blot.</p><p><b>RESULTS</b>(1) The total protein content of Ang II group was significantly higher than that in control group (P<0.01), which could be equally reduced by cotreatment with U50488H, CSA and Rp-cAMPS (P<0.01). Total protein content of the Ang II + PTX + U50488H group and the Ang II group was similar. (2) The [Ca²⁺]i was significantly higher in Ang II group of neonatal rat cardiomyocytes than that in control group (P<0.01), which could be reduced by cotreatment with U50488H, CSA and Rp-cAMPS (P<0.01). [Ca(2+)]i was similar between the Ang II + PTX + U50488H group and the Ang II group. (3) The expression of CaN was significantly higher in Ang II group than that in control group (P<0.01), which could be significantly reduced by cotreatment with U50488H, CSA and Rp-cAMPS (P<0.01). CaN was similar between the Ang II + PTX + U50488H group and the Ang II group.</p><p><b>CONCLUSION</b>κ-opioid receptor activation could attenuate Ang II induced cardiomyocytes hypertrophy via reducing [Ca²⁺]i and downreglating CaN.</p>

κ-opioid receptor agonist U50, 488H attenuates myocardial ischemia-reperfusionvia modulating Toll-like receptor 4/nuclear factor-κB signaling in rat / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe the effects of κ-opioid receptor agonist U50, 488H on myocardial ischemia and reperfusion injury and related mechanism.</p><p><b>METHODS</b>Rats were randomly divided into sham operation, myocardial ischemia and reperfusion(I/R, 30 min ischemia followed by 120 min reperfusion), and MI/R+U50, 488H (1.5 mg/kg) and I/R+U50, 488H+ selective κ-opioid receptor antagonist Nor-BNI (2 mg/kg, n = 8 each). The infarction size and the incidence of ventricular arrhythmias were observed.Real-time PCR and DAB staining were used to define the myocardium Toll-like receptor 4(TLR4) expression. Myeloperoxidase level, TNF-α induction and the expression of NF-κB were also examined in rats.</p><p><b>RESULTS</b>After I/R, the expressions of myocardial TLR4 and NF-κB increased significantly both in ischemia area and area at risk. Compared with I/R, κ-opioid receptor stimulation with U50, 488H significantly attenuated the expressions of TLR4 and NF-κB and reduced myeloperoxidase (MPO) levels, myocardial TNF-α production, myocardial infarct sizes and the incidence of ventricular arrhythmias and arrhythmia score (2.9 ± 0.7 vs. 4.4 ± 0.9, P < 0.05) , above effects of U50, 488H were partly abolished by co-treatment with Nor-BNI.</p><p><b>CONCLUSION</b>These data provide evidence for the first time that κ-opioid receptor stimulation could attenuate myocardial I/R injury via downregulating TLR4/NF-κB signaling in rats.</p>

Effects of Whole Body Irradiation on Morphine, DAMGO, DPDPE, U50,488H and beta-endorphin-Induced Antinociception

Opioid receptors have been pharmacologically classified as micro, delta, kappa and epsilon. We have recently reported that the antinociceptive effect of morphine (a micro-opioid receptor agonist), but not that of beta-endorphin (a novel micro/epsilon-opioid receptor agonist), is attenuated by whole body irradiation (WBI). It is unclear at present whether WBI has differential effects on the antinociceptive effects of micro-, delta-, kappa- and epsilon-opioid receptor agonists. In our current experiments, male ICR mice were exposed to WBI (5Gy) from a 60Co gamma-source and the antinociceptive effects of opioid receptor agonists were assessed two hours later using the hot water (52degrees C) tail-immersion test. Morphine and D-Ala2,N-Me-Phe4,Gly-olenkephalin(DAMGO), [D-Pen2-D-Pen5]enkephalin (DPDPE), trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide (U50,488H), and beta-endorphin were tested as agonists for micro, delta, kappa, and epsilon-opioid receptors, respectively. WBI significantly attenuated the antinociceptive effects of morphine and DAMGO, but increased those of beta-endorphin. The antinociceptive effects of DPDPE and U50,488H were not affected by WBI. In addition, to more preciously understand the differential effects of WBI on micro- and epsilon-opioid receptor agonists, we assessed pretreatment effects of beta-funaltrexamine (beta-FNA, a micro-opioid receptor antagonist) or beta-endorphin1-27 (beta-EP1-27, an epsilon-opioid receptor antagonist), and found that pretreatment with beta-FNA significantly attenuated the antinociceptive effects of morphine and beta-endorphin by WBI. beta-EP1-27 significantly reversed the attenuation of morphine by WBI and significantly attenuated the increased effects of beta-endorphin by WBI. The results demonstrate differential sensitivities of opioid receptors to WBI, especially for micro- and epsilon-opioid receptors.

Kappa-opioid receptor activation during reperfusion limits myocardial infarction via ERK1/2 activation in isolated rat hearts / 대한마취과학회지

BACKGROUND: We investigated whether p42/p44 extracellular signal-regulated kinases (ERK1/2) and/or phosphatidylinositol-3-OH kinase (PI3K)-Akt play a crucial role in cardioprotection by kappa-opioid receptor (KOP) activation. METHODS: Langendorff perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Antagonists of ERK1/2 and PI3K were perfused in hearts treated with the KOP agonist U50488H (U50). Infarct size was measured after 2 h of reperfusion. The phosphorylation states of ERK1/2 and Akt by Western immunoblots were determined. Drugs were perfused for a period of 5 min before and 30 min after reperfusion. RESULTS: Inhibition of ERK1/2 (26.8 +/- 2.9%, P 0.05 vs. U50) completely abrogated the anti-infarct effect of U50488H. Western blot analysis revealed a significant increase in ERK1/2 but not Akt phsophorylation in U50488H-treated hearts as compared to control hearts when measured immediately after reperfusion. CONCLUSIONS: KOP activation effectively reduces myocardial infarction. The anti-infarct effect of U50488H is mediated by the ERK1/2, but not the PI3K-Akt pathway.

Comparing effects of U50488H, prazosin and/or propranolol on cardiac hypertrophy induced by NE in rat / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To demonstrate the inhibitory effect of kappa-opioid receptor activation by U50488H on hypertrophy induced by NE in cultured neonatal rat cardiac myocytes and compare its effect with that of prazosin and propranolol.</p><p><b>METHODS</b>The cellular proliferation was determined with crystal violet staining. The protein content was assayed with Lowry's method. The cardiomyocytes volumes were measured by computer photograph analysis system. The protein synthesis was assayed with [3H]-lencine incorporation method.</p><p><b>RESULTS</b>(1) NE significantly induced the increase of protein content, [3H]-leucine incorporation and cell size without a concomitant increase in cell number in low serum medium. OThese responses were partially suppressed by prazosin or propranolol alone and completely abolished by both in combination. U50488H significantly inhibited the NE-induced increase of protein content, [3H]-leucine incorporation and cell size. The inhibitory effects of U50488H on NE-induced cardiac hypertrophy were greater than either prazosin or propranolol, but comparable to combination of both.</p><p><b>CONCLUSION</b>NE, acting via both alpha1- and beta-adrenergic pathway, stimulates myocyte hypertrophy. Stimulating kappa-opioid receptor significantly inhibits NE-induced cardiac hypertrophy, which may be related with alpha1- and beta1-adrenergic pathway.</p>

Effects of kappa-opioid receptor stimulation on high glucose induced myocardial hypertrophy of neonatal rats / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To observe the effects of kappa-opioid receptor stimulation on high glucose induced myocardial hypertrophy of neonatal rats.</p><p><b>METHODS</b>Using cultured myocardial cells as a model, the protein content was assayed with Lowrys method. The cardiomyocytes volumes were measured by computer photograph analysis system. The level of p-ERK44/42 was determined by Western blot.</p><p><b>RESULTS</b>Compared with the control, U50488H significantly inhibited the protein content and volumes of cultured hypertrophic myocardial cells induced by high glucose. Meanwhile the role of ERK was important.</p><p><b>CONCLUSION</b>The stimulation of kappa-opioid can inhibit myocardial hypertrophy induced by high glucose, which is possibly via attenuating p-ERK.</p>

The study of effects and mechanism of U50, 488H on electrical coupling during ischemia in the perfused isolated rat heart / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To determine the effect of activation of lambda-opioid receptor with U50, 488H, a selective kappa-opioid receptor agonist, on the changes in electrical coupling during prolonged ischemia and to explore the possible mechanism.</p><p><b>METHODS</b>The isolated rat heart was perfused in a Langendorff apparatus. The effect of U50, 488H on electrical coupling parameters including onset of uncoupling, plateau time, slope and fold increase in r(t) was observed in isolated perfused rat heart subjected to global no-flow ischemia. The effect of U50, 488H on connexin 43 (Cx43) expression of ventricular muscle during ischemia was determined by immunohistochemistry.</p><p><b>RESULTS</b>In the prolonged ischemia model, U50, 488H concentration dependently delayed the onset of uncoupling, increased time to plateau, and decreased the maximal rate of uncoupling during ischemia. The effect of U50, 488H on electrical uncoupling parameters during ischemia was abolished by a selective kappa-opioid receptor antagonist nor-BNI or a PKC inhibitor chelerythrine. The amount of Cx43 immunoreactive signal in ventricular muscle was greatly reduced after ischemia. U50, 488H markedly increased Cx43 expression during ischemia and its effect was also attenuated by nor-BNI or chelerythrine.</p><p><b>CONCLUSION</b>These results demonstrated that U50, 488H delayed the onset of uncoupling and plateau time, decreased the maximal rate of uncoupling and increased Cx43 expression of ventricular muscle during ischemia, and these effects of U50, 488H were mediated by kappa-opioid receptor, in which activation of PKC was involved. The effect of U50, 488H on electrical coupling during ischemia was probably correlated with preservation of Cx43 in cardiac muscle.</p>

Cardioprotection by kappa-opioid receptor agonist U50488H is mediated by opioidergic regulation but not by calcium current modulation / 대한마취과학회지

BACKGROUND: Because the kappa-opioid receptor (OR) agonist U50488H stimulates opioidergic regulation and inhibits L-type Ca2+ channels, this study was aimed at assessing the roles of OR and L-type Ca2+ channels on U50488H-induced cardioprotection. METHODS: Langendorff-perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Isolated hearts were treated with U50488H with or without the kappa-OR antagonist nor-binaltorphimine (nor-BNI) or the Ca2+ channels activator BAY K 8644. Infarct size was measured with 2,3,5-triphenyltetrazolium chloride staining. RESULTS: U50488H treatment at reperfusion: (1) significantly reduced infarct size (11.3 +/- 1.3%) compared to control hearts (27.7 +/- 1.1%, P 0.05 vs. U50488H); (2) significantly increased left ventricular developed pressure (65.3 +/- 4.8%) after 2 h of reperfusion compared to control hearts (44.8 +/- 3.6%, P 0.05 vs. control) but not by BAY K 8644 (64.3 +/- 5.6%, P < 0.01 vs. control); and (3) significantly decreased heart rate (P < 0.01 vs. control), an effect that was completely abrogated by both nor-BNI and BAY K 8644. CONCLUSIONS: U50488H significantly limits myocardial infarction and stunning in isolated rat hearts after ischemia-reperfusion induction. The infarct size limitation and contractility improvement observed with U50488H treatment during reperfusion are entirely mediated by OR stimulation and not by Ca2+ channel modulation.

Cardioprotection by kappa-opioid receptor agonist U50488H is mediated by opioidergic regulation but not by calcium current modulation / 대한마취과학회지

BACKGROUND: Because the kappa-opioid receptor (OR) agonist U50488H stimulates opioidergic regulation and inhibits L-type Ca2+ channels, this study was aimed at assessing the roles of OR and L-type Ca2+ channels on U50488H-induced cardioprotection. METHODS: Langendorff-perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Isolated hearts were treated with U50488H with or without the kappa-OR antagonist nor-binaltorphimine (nor-BNI) or the Ca2+ channels activator BAY K 8644. Infarct size was measured with 2,3,5-triphenyltetrazolium chloride staining. RESULTS: U50488H treatment at reperfusion: (1) significantly reduced infarct size (11.3 +/- 1.3%) compared to control hearts (27.7 +/- 1.1%, P 0.05 vs. U50488H); (2) significantly increased left ventricular developed pressure (65.3 +/- 4.8%) after 2 h of reperfusion compared to control hearts (44.8 +/- 3.6%, P 0.05 vs. control) but not by BAY K 8644 (64.3 +/- 5.6%, P < 0.01 vs. control); and (3) significantly decreased heart rate (P < 0.01 vs. control), an effect that was completely abrogated by both nor-BNI and BAY K 8644. CONCLUSIONS: U50488H significantly limits myocardial infarction and stunning in isolated rat hearts after ischemia-reperfusion induction. The infarct size limitation and contractility improvement observed with U50488H treatment during reperfusion are entirely mediated by OR stimulation and not by Ca2+ channel modulation.

Effect of A Kappa-opioid Receptor Agonist U50488H Given at Early Reperfusion Phase in Isolated Rat Hearts / 대한마취과학회지

BACKGROUND: The experiment was performed to determine the role of kappa-opioid receptor (OR) agonist U50488H given at early reperfusion. METHODS: Isolated hearts were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion.Hearts were assigned randomly to one of the three groups:1) Control (n = 9), 2) U50-1 (n = 8); 10micrometer of U50488H, and 3) U50-10 (n = 8); 10micrometer of U50488H.U50488 was perfused for a period of 5 min before and 30 min after reperfusion. RESULTS: U50488H significantly reduced infarct size as a percentage of ischemic area (12.2 +/- 1.9% in U50-1 and 7.2 +/- 1.7% in U50-10, P < 0.001) compared to the control hearts (27.2 +/- 1.2%). After 2 hrs of reperfusion, left ventricular developed pressure was significantly recovered by U50488H (62.6 +/- 5.7% in U50-1 and 68.6 +/- 4.7% in U50-10, P = 0.018 and 0.002, respectively) compared to the control (46.3 +/- 4.4%).Rate-pressure product was improved by 100micrometer U50488H (62.3 +/- 5.5%, P = 0.007) but not by 1micrometer U50488H (50.0 +/- 4.1%) compared to the control (44.7 +/- 4.5%).U50488H significantly increased the + dP/dt(max) (77.9 +/- 5.5% in U50-1 and 78.0 +/- 4.3 in U50-10, P = 0.005 and 0.001 vs. control, respectively).The -dP/dt(min) also improved by 10micrometer U50488H (64.7 +/- 4.8%, P = 0.003) compared to control (47.0 +/- 2.7%). CONCLUSIONS: U50488H given at early reperfusion phase reduces both infarct size and myocardial stunning in isolated rat hearts.

Delayed electrical uncoupling is involved in kappa-opioid receptor activation -induced cardioprotective effect in the isolated rat heart / 中国应用生理学杂志

<p><b>AIM</b>To determine whether activation of kappa-opioid receptor with U50,488H, a selective kappa-opioid receptor agonist, produces any changes in electrical uncoupling during prolonged ischemia and whether these changes in electrical uncoupling is associated with the cardioprotection induced by kappa-opioid receptor activation, and to explore the possible mechanism.</p><p><b>METHODS</b>(1) To observe the effect of U50,488H (10(-7), 10(-6), 3 x10(-6) and 10(-5) mol/L), a selective kappa-opioid receptor agonist, or with a selective kappa-opioid receptor antagonist nor-BNI (5 x 10(-6) mol/L), or with a mitochondrial K(ATP) channel inhibitor 5-HD on myocardium during ischemia/reperfusion in isolated perfused rat heart. Parameters of measurements include hemodynamic data, formazan content, heart rate, coronary flow, and lactate dehydrogenase (LDH). (2) To examine the effect of U50,488H of different concentration on electrical coupling parameters (including onset of uncoupling, plateau time, slope, and fold increase in r1) during 70 min myocardial ischemia in isolated perfused rat heart.</p><p><b>RESULTS</b>(1) Pretreatment with U50,488H concentration dependently increased formazan content and reduced LDH release induced by 30 min of ischemia and 120 min of reperfusion. (2) The onset of electrical uncoupling and plateau time during prolonged ischemia was delayed by kappa-opioid receptor activation with U50,488H. (3) Linear regression analysis shown that the increase in formazan content and decrease in LDH release produced by kappa-opioid receptor activation was associated with delayed electrical uncoupling during prolonged ischemia. (4) The effects of U50,488H on formazan content, LDH release and on electrical coupling were abolished by nor-BNI, or 5-HD.</p><p><b>CONCLUSION</b>This results demonstrate that the onset of electrical uncoupling during prolonged ischemia is delayed by kappa-opioid receptor activation with a selective kappa-opioid receptor agonist U50,488H, and that delayed electrical uncoupling is associated with the cardioprotection induced by kappa-opioid receptor activation with U50,488H. These effects of kappa-opioid receptor activation with U50,488H are mediated by mitochondrial K(ATP) channels.</p>

COX-2 mediates U50488H-induced delayed cardioprotection in isolated rat heart / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To determine whether U50488H, a selective agonist of kappa-opioid receptor, could induce biphasic (early and late) cardioprotection against myocardial ischemia/reperfusion injury and to explore the underlying mechanisms.</p><p><b>METHODS</b>Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 120 min reperfusion and the cardiac function was evaluated.</p><p><b>RESULT</b>Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP) and maximal velocity of contraction and relaxation (+/-dP/dtmax) were improved when U50488H was administered 1 or 24 h before ischemia (P<0.05). Myocardial infarct size, activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in the coronary effluent were lower in the U50488H pretreatment group than those in the control group. Administration of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib abolished the late phase of cardioprotection produced by administration of U50488H 24 h before ischemia. Activities of CK and LDH in the coronary effluent were higher in U50488H and celecoxib co-pretreatment group than those in U50488H group. However, administration of celecoxib did not block the early phase of cardioprotection by 1 h treatment of U50488H before ischemia.</p><p><b>CONCLUSION</b>The late (but not the early) phase of cardioprotection induced by kappa-opioid receptor agonist might be mediated by COX-2.</p>

Interaction between opioid receptor and adrenoceptor signaling in ischemia reperfusion of the isolated rat heart / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the interaction between opioid receptor (OR) stimulation and adrenergic receptor (AR) stimulation in the isolated ischaemia/reperfusion (I-R) rat heart.</p><p><b>METHODS</b>Male Sprague-Dawley rats were used for Langendoff isolated heart perfusion. Myocardial ischemia for 20 min was followed by 30 min of reperfusion, during which the kappa-OR agonist U50488h and beta(1)-AR agonist norepinephrine (NE) were administered.</p><p><b>RESULTS</b>(1) 50488h antagonized the effect of NE in rising left ventricular systolic pressure (LVSP) in the early phase of myocardial ischemia at 10, 20, 30 min of reperfusion. (2) Arrhythmia scores in the I-R+NE+U50488h group were markedly lower than those in the I-R group during the 10 - 20 min reperfusion period. No significant differences in arrhythmia scores were found in either I-R+U50488h or I-R+NE group when compared with I-R group. (3) Compared with the I-R group, U50488h alone or plus NE decreased reperfusion heart rates after myocardial ischemia while NE alone showed no effect.</p><p><b>CONCLUSION</b>It is suggested that the interaction in the signaling pathway between kappa-OR and beta(1)-AR occurred during myocardial I-R of rat heart.</p>

Kappa-opioid receptor stimulation contributes to aortic artery dilation through activation of K(ATP) channel in the rats / 生理学报

To investigate the relaxation effect and underlying mechanism of U50,488H (a selective kappa-opioid receptor agonist) on aorta in the rat, isolated aortic ring was perfused and the tension of the vessel was measured. It was shown: (1) kappa-opioid receptor stimulation with U50,488H relaxed rat aorta dose-dependently; (2) the relaxation effect of U50,488H on aorta was partially endothelium-dependent; (3) the relaxation effect of U50,488H was significantly attenuated in the presence of glybenclamide and glipizide, two ATP-sensitive K(+) channel (K(ATP)) blockers; and (4) the relaxation effect of U50,488H on vessel bore no relationship to muscarinic-receptor, beta-adrenoceptor, prostaglandin and nitric oxide (NO). These results indicate that kappa-opioid receptor stimulation with U50,488H relaxes the aortic artery at least partially via K(ATP) channel in the rat.

Roles of kappa opioid receptors in cardioprotection against ischemia: the signaling mechanisms / 生理学报

There is evidence that the myocytes produce dynorphin and dynorphin-like peptides, which are kappa opioid receptor (kappa-OR) agonists. Activation of kappa-OR, a dominant opioid receptor in the heart, alters the cardiac function in vivo and in vitro. The observations suggest that the endogenous kappa-opioid peptides may act as autocrines or paracrine in regulation of cardiac functions. Myocardial ischemia is a common cause of heart disorders, which is manifested in decreased myocardial performance, arrhythmia and infarct. When myocardial ischemia occurs, the sympathetic discharge increases, which in turn increases the work-load and oxygen consumption. This exacerbates the situation induced by ischemia. One of the mechanisms with which the body protects against ischemia-induced injury/arrhythmia is inhibition of stimulation of beta-adrenoceptor (beta-AR), the receptor mediating the actions of sympathetic stimulation. kappa-Opioids inhibit the beta-AR activation. The inhibition of the beta-AR activation is due to inhibition of Gs-protein and to a lesser extent the adenylyl cyclase of the signaling pathway mediating beta-AR stimulation by a pertussis sensitive G-protein that mediates kappa-OR activation. Another mechanism against ischemia-induced injury is preconditioning, which is defined as prior exposures to ischemia or other insults make the heart more tolerant to subsequent and more severe insults. Protection occurs immediately or 1-3 days after preconditioning. kappa-OR mediates protection of preconditioning with ischemia or metabolic inhibition, one of the consequences of ischemia, in the heart. Activation of kappa-OR by U50488H, a selective kappa-OR agonist (pharmacological preconditioning with U50488H, UP), activates protein kinase C (PKC), opens K(ATP) channels and increases the production of heat shock proteins. Blockade of PKC, or closing of the K(ATP) channels or inhibition of the synthesis of the heat shock protein abolishes the cardioprotection of UP. The findings indicate the important roles of PKC, the K(ATP) channels and the heat shock protein in cardioprotection of UP. In addition, UP also attenuates the Ca(2+) overload, a precipitating cause of cardiac injury, induced by ischemic insults, indicating that UP may confer cardioprotection via at least partly attenuating the Ca(2+) overload. Most interestingly, blockade of the K(ATP) channels with channel blockers, that abolishes the delayed cardioprotection of UP, also attenuates the inhibitory effect of UP on Ca(2+) overload, suggesting that the cardioprotective effect of opening of the K(ATP) channels may be due at least partly to the prevention/attenuation of Ca(2+) overload.

The Effects of Peripheral mu and kappa Opioid Receptor Agonists on the Thermal Injury Induced Hyperalgesia in the Rat / 대한마취과학회지

BACKGROUND: Previous reports have described that the local administration of opioid receptor agonist can attenuate the nociceptive responses induced by a variety of inflammatory states. This study evaluated the effects of mu or kappa opioid receptor agonists peripherally administered at a site of injury on the state of thermal hyperalgesia induced by mild burn injury. METHODS: Thermal injury was induced after briefly anesthetizing with halothane, by applying the left hindpaw to a hot plate (52.5 degree C) for 45 seconds. Paw withdrawal latency of the hindpaw was determined using an underglass thermal stimulus, which allowed the response latency of the injured paw to be obtained. In this work, the mu receptor agonist, morphine (10, 30, 100 microgram), or the kappa receptor agonist, U50,488H (10, 30, 100 microgram), was administered respectively at the injured site on the right hindpaw in rats. To compare the systemic effects of the drug, the same drug was administered at the normal left hindpaw site with mild burn injury. Naloxone (40 microgram/kg) was administered at the injured site or at the normal site to determine the reversibility of the opioid used. RESULTS: Mild burn injury produced thermal hyperalgesia manifested as reduced paw withdrawal latency. Administration of either morphine (10, 30, 100 microgram) or U50,488H (10, 30, 100 microgram) at the injured site attenuated hyperalgesia in a dose-dependent manner. But the administration of drugs at the normal site had no effect on hyperalgesia at the injured site. In addition, naloxone had the effect of morphine and U50,488H reversed significantly. CONCLUSIONS: These results suggest that peripheral mu or kappa opioid receptor administration at an injured site may play an important role in the hyperalgesia induced by mild burn injury.

Inhibitory effects of kappa-opioid receptor stimulation on cultured myocardial cells / 中国应用生理学杂志

<p><b>AIM</b>In order to study the effects of kappa-opioid receptor activation, we used cultured cardiomyocytes to study the inhibitory effects of U50,488H on cellular proliferation, protein content in the presence or absence of nor-binaltorphimine (nor-BNI).</p><p><b>METHODS</b>The cellular proliferation was determined with crystal violet staining and the protein content was assayed with Lowry's method.</p><p><b>RESULTS</b>A kappa-opioid receptor agonist U50,488H at 0.1 micromol/L-10 micromol/L inhibited the cellular proliferation and protein content of cultured myocardial cells in a dose-dependent manner. The inhibitory effects of U50,488H were completely blocked by pretreatment with nor-BNI, a specific kappa-opioid receptor antagonist at 1 micromol/L.</p><p><b>CONCLUSION</b>U50,488H inhibited the cultured myocardial cells' growth. The inhibitory effects of U50,488H are involved in mediating the action of kappa-opioid receptor stimulation.</p>