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Objective To investigate the effect of U50488H on postoperative cognitive dysfunction induced by cardiopulmonary bypass (CPB) in rats.Methods Forty-eight adult male Sprague-Dawley rats,weighing 400-450 g,were divided into 3 groups (n=16 each) using a random number table:sham operation group (group S),CPB group and CPB plus U50488H group (group U).CPB was performed for 60 min in group CPB.U50488H 1.5 mg/kg was injected into the left lateral cerebral ventricle at 30 min prior to CPB,and then CPB was performed for 60 min in group U.Eight rats in each group were selected at 1 day after CPB,and venous blood samples were collected for determination of serum S100β protein,interleukin-lbeta (IL-1 β) and tumor necrosis factor-alpha (TNF-α) concentrations (by enzyme-linked immunosorbent assay).Then the rats were sacrificed and right hippocampi were removed for examination of the pathological changes after haematoxylin and eosin staining.Eight rats were selected from each group at 7 days after CPB for assessment of cognitive function.Results Compared with group S,the concentrations of serum S100β protein,IL-1β and TNF-α were significantly increased in group CPB,and the escape latency was prolonged,the number of crossing original platform was reduced,and the swimming distance in target quadrant and time of staying at target quadrant were shortened in CPB and U groups (P＜0.05).Cormpared with group CPB,the concentrations of serum S100β protein,IL-1β and TNF-α were significantly decreased,the escape latency was shortened,the number of crossing original platform was increased,the swimming distance in target quadrant and time of staying at target quadrant were prolonged (P＜0.05),and the pathological changes of hippocampal tissues were significantly attenuated in group U.Conclusion U50488H can mitigate the postoperative cognitive dysfunction induced by CPB in rats.
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Objective To evaluate the effect of oxycodone on migration of human colon cancer cells and the role of μ and κ receptors.Methods The human colon cancer HCT116 cells at the logarithmic growth phase were seeded in 24-well or in 6-well plates at a density of 1 × 106 cells/mnl (0.5 ml/well or 2 ml/well,144 wells in total).The cells were divided into 6 groups (n=24 each) using a random number table:control group (group C),1,5 and 10 μmol/L oxycodone groups (group O1,group O2 and group O3),oxycodone plus μ receptor antagonist CTOP group (group O2+CTOP) and oxycodone plus κ receptor antagonist nor-binaltorphimine group (group O2+BNI).The cells were incubated for 24 h with oxycodone 1,5 and 10 μmol/L in O1,O2 and O3 groups,respectively.The cells were incubated for 24 h with 5 μmol/L oxycodone plus 20 μmol/L CTOP and 5 μmol/L oxycodone plus nor-binahorphimin 20 μmol/L in O2+CTOP and O2+BNI groups,respectively.The invaded and migrated cells were counted,and the levels of Ras homolog gene family member A (RhoA),Rho-associated protein kinase 1 (ROCK1),matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected.Results Compared with group C,the number of invaded and migrated cells was gradually decreased,and the levels of RhoA,ROCK1,MMP-2 and MMP9 were gradually decreased in O1,O2 and O3 groups (P＜0.05),and no significant change was found in the parameters mentioned above in group O2+BNI (P＞0.05).Compared with group O2,the number of invaded and migrated cells was significantly increased,and the levels of RhoA,ROCK1,MMP-2 and MMP9 were increased in group O2 + BNI (P＜0.05),and no significant change was found in the parameters mentioned above in group O2+CTOP (P＞0.05).Conclusion Oxyc odone can inhibit the migration of human colon cancer cells,and the mechanism is totally related to inhibition of RhoA/ROCKl signaling pathway activation after activating κ receptors,but not related to μ receptors.
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Objective To evaluate the role of spinal κ-opioid receptors in remifentanil-induced postoperative central sensitization in a rat model of incisional pain by in vivo electrophysiology.Methods Sixty adult male Sprague-Dawley rats in which intrathecal catheters were successfully implanted,weighing 230-270 g,were divided into 5 groups (n=12 each) using a random number table:control group (group C),incisional pain group (group I),remifentanil group (group R),remifentanil plus incisional pain group (group R+I),and κ-opioid receptor agonist U50488H group (group U).A 1 cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the right hind paw in isofiurane-anesthetized rats to establish the model of incisional pain.Remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg 1 · min-1 in group R.In group R+I,remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg-1 · min 1,and the model of incisional pain was established at the same time.In group U,U50488H 10 μg/10μl was injected intrathecally,30 min later remifentanil was intravenously infused for 1 h at a rate of 10 μg · kg-1 · min-1,and the model of incisional pain was established.Six rats in each group were randomly selected,the mechanical pain threshold (MPT) was measured in bilateral hind paws before implanting intrathecal catheter (T0),before operation (T1),and at 1 h,4 h and 1,2 and 3 clays after operation (T2-6).Six rats in each group were randomly selected to record the C fiber-evoked filed potentials in the spinal dorsal horn from 60 min before administration or operation to 180 min after administration or operation,the long-term potentiation (LTP) induced was also recorded,and the area under the curve (AUC) of C-fiber-evoked field potentials was calculated.Results No LTP was recorded in C,I and U groups,and the LTP was recorded in R and R+I groups.Compared with group C,the MPT in bilateral hind paws at T5,6 was significantly decreased in group R,the MPT in ipsilateral hind paws at T2 6 was decreased in group I,the MPT in ipsilateral hind paws at T2-6 and in contralateral hind paws at T5,6 was decreased in group R+I,the MPT in ipsilateral hind paws at T2-4 was decreased in group U,and the AUC of C-fiber-evoked field potentials was increased in R and R+I groups (P＜0.05).Compared with group Ⅰ,the MPT in ipsilateral hind paws at T4-6 and in contralateral hind paws at T5,6 was significantly decreased,and the AUC of C-fiber-evoked field potentials was increased in group R+I (P＜0.05).Compared with group R+ I,the MPT in ipsilateral hind paws at T2-6 and in contralateral hind paws at T5,6 was significantly increased,and the AUC of C-fiber-evoked field potentials was decreased in group U (P＜0.05).Conclusion The results of in vivo electrophysiology confirm that inhibition of spinal κ-opioid receptor function mav be involved in the mechanism by which remifentanil induces postoperative central sensitization in a rat model of incisional pain.
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Objective To compare the inhibitory effects of Butorphanol and Dezocine on Etomidate-induced myoclo?nus. Methods A total of 150 patients with ASA physical statusⅠorⅡ, aged 40-65 yr, with body mass index (BMI) of 20-25 kg/m2, scheduled for elective operations under general anesthesia, were included in this study. Patients were randomly al?located into three groups (A, B and C) with 50 patients in each group. Group A was given intravenous Butorphanol 15 μg/kg for 30 s, group B was given Dezocine 0.1 mg/kg and group C was given equal volume of saline. After 2 min, etomidate 0.3 mg/kg was administrated to three groups. The occurrence and severity of myoclonus were recorded for 2 min after administration of Etomidate. The mean arterial pressure (MAP), heart rate (HR), pulse oxygen saturation (SpO2) and Bispectral index (BIS) were recorded at the time points before induction (T0), 2 min after the experimental drug treatment (T1), and 2 min after Etomi?date treatment (T2). At the same time, the concentration of serum potassium was determined at T0 and 5 min after endotrache?al intubation (T3) respectively. Results The positive incidences of myoclonus were 12%in group A, 22%in group B and 74%in group C, respectively. Compared with group C, the positive incidence rates of myoclonus and myoclonus scales were significantly lower in group A and group B (P0.05). Compared with T0, there was no significant difference in the potassium concentration between patients without myoclonus (grade 0) and patients with myoclonus (grade 1 and grade 2) at T3 (P>0.05). There was a significant increase in potassium concentration in patients with grade 3 (P0.05). Conclusion Pre-treatment of Butorphanol (15μg/kg) or Dezocine (0.1 mg/kg) can reduce the Etomidate-induced myoclonus. At the same time, both therapies show no different effects on cir?culation and respiration system.
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Objective To evaluate the efficacy of acting κ opioid receptor for prevention of high altitude pulmonary edema (HAPE) in rats.Methods Forty male Sprague-Dawley rats,aged 8 weeks,weighing 250-300 g,were randomly divided into 5 groups (n =8 each) using a random number table:control group (group C),hypobaric hypoxia group (group H),normal saline + hypobaric hypoxia group (group NH),U50488H (a selective kappa-opioid receptor agonist) + hypobaric hypoxia group (group UH),and nor-binaltorphimine (norBNI,a selective kappa-opioid receptor antagonist) + U50488H + hypobaric hypoxia group (group NUH).The rats were put into the hyperbaric chamber and exposed to hypobaric hypoxia (atmospheric pressure 355 mmHg,partial pressure of oxygen 74 mmHg) for 2 days to induce HAPE.At 3 days before HAPE,normal saline 0.5 ml,U50488H 1.25 mg/kg,and nor-BNI 2.0 mg/kg were injected intraperitoneally once a day in NH,UH,and NUH groups,respectively,and in addition U50488H 1.25 mg/kg was injected intraperitoneally 10 min later in NUH group.After 2 h exposure to hypobaric hypoxia,mean pulmonary artery pressure (mPAP) was detected,and arterial blood samples were collected for determination of serum malondialdehyde (MDA) and erythropoietin (EPO) levels.The rats were then sacrificed and lungs were removed for microscopic examination and for determination of the levels of nitric oxide (NO),inducible nitric oxide synthase (iNOS),MDA,superoxide dismutase (SOD),endothelin-1 (ET-1),thromboxane B2 (TXB2),and 6-keto-prostaglandin F1α (6-keto-PGF1α) in lung tissues.Lung water content and TXB2/6-keto-PGF1α ratio was calculated.Results Compared with group C,mPAP,lung water content,ET-1,MDA,TXB2 and 6-keto-PGF1α levels,TXB2/6-ketoPGF1α ratio,and serum MDA and EPO levels were significantly increased,and iNOS,NO and SOD levels were decreased in the other four groups (P ＜ 0.05).Compared with group H,mPAP,lung water content,ET-1,MDA,TXB2 and 6-keto-PGF1α levels,TXB2/6-ketoPGF1α ratio and serum MDA and EPO levels were significantly decreased,and iNOS,NO and SOD levels were increased in UH group (P ＜ 0.05),and no significant changes were found in the indexes mentioned above in NH and NUH groups (P ＞ 0.05).The pathological changes of lung tissues were significantly attenuated in group UH as compared with H group.Conclusion Acting κ opioid receptor can produce prevention for HAPE in rats,and inhibition of lipid peroxidation and correction of the imbalance between vasoconstrictive factors and vasodilative factors may be involved in the mechanism.
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Objective To explore the nechanism of the interaction between K-opioid receptor and ? adrenal receptor. Method The effects of u50 488H on L-type calcium currents in the normal and hypoxic rat ventricular myocytes were studied by using whole-cell patch clamp technique. Results The basal as well as Isoproterenol-stimulated I_ Ca,L were inhibited by U50,488H in a dose-dependent manner in normal rat ventricular myocytes. In the hypoxic rat ventricular myocytes,the inhibitory effect of U50,488H was decreased. U50,488H had no significant effect on Forkolin-stimulated I_ Ca,L . Conclusion The results indicated that the negative modulation of ?-opioid receptor on ?-adrenoceptor was attenuated in the hypoxic ventricular myocytes,and the target of U50,488H on ?-adrenergic system might be situated between ?-adrenoceptor and adenylate cyclase.
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AIM: To investigate the effect and possible mechanisms of interleukin-2 (IL-2) on the cell contractility in cardiomyocytes during hypoxia and reoxygenation.METHODS: Glucose-free Krebs-Henseleit (K-H) solution, gassed with 95% N 2 and 5% CO 2 for hypoxia, were used. The cell contractility were determined after 20 min of hypoxia and 30 min of reoxygenation by the video tracking system. The parameters of cell contractility included peak velocity of cell shortening (+d L /d t max), peak velocity of cell relengthening (-d L /d t max), contraction amplitude (dL) and end-diastolic cell length.RESULTS: It was shown that during hypoxia, the cell contraction was depressed. All the parameters were unable to return to the pre-hypoxia level during reoxygenation. Pretreatment with IL-2 at 2?10 3 U/L attenuated the inhibitory effect of hypoxia/reoxygenation on contractility in single ventricular myocytes. The effect of IL-2 was reduced in the presence of 10 -8 mol/L nor-binaltorphimine (nor-BNI), a selective ?-opioid receptor antagonist. On blockade of protein kinase C with 3?10 -6 mol/L chelerythrine, the effect of IL-2 was significantly attenuated. The effect of IL-2 was also blocked by 10 -4 mol/L 5-hydroxydecanoate (5-HD), a mitochondrial ATP-sensitive potassium (K ATP ) channel blocker. CONCLUSIONS: The results of the present study provide evidence that pretreatment with IL-2 at 2?10 3 U/L attenuates the effect of hypoxia/reoxygenation on cell contraction in the isolated ventricular myocytes. The ?-opioid receptor mediates the effect of IL-2, in which activation of PKC and opening of mitochondrial ATP-sensitive potassium (mito K ATP ) channel are involved.
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To determine the regulatory effect of ? opioid receptor stimulation on ? adrenoceptor signaling and its underlying mechanism, single ventricular myocytes were isolated from the heart of rat subjected to chronic hypoxia for 4 weeks. The electrically induced [Ca 2+ ] i transient were measured using a spectrofluorometric method. RT PCR was used to determine the mRNA of ? opioid receptor, and Western blot was used to determine the Gi and Gs protein. ? adrenoceptor stimulation with isoproterenol increased the amplitude of the electrically induced [Ca 2+ ] i transient in myocytes of normoxic rats. U50488H, a selective ? opioid receptor agonist, significantly inhibited the effect of isoproterenol. In the heart of chronically hypoxic rats, the inhibition of U50488H was blunted. RT PCR revealed no significant change in mRNA of ? opioid receptor. Western blot showed no change in Gi protein. While biologically active Gs small protein decreased significantly. The results indicate that the negative modulation of ? opioid receptor on ? adrenoceptor is attenuated in the heart of chronically hypoxic rat. The decrease in Gs protein may be partially responsible for the attenuation.