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The delta-opioid receptor (DOR),which is a classic analgesic drug widely existed in the central system and peripheral system,is a kind of inhibitory G-protein coupled receptor with seven transmembrane regions.In addition to pain modulation,the opioid receptors are involved in various physiological and pathological activities through gene or cytokines.This review addresses the influence and possible mechanisms of the delta-opioid receptor in ischemic brain injury,analgesia,anti-anxiety and depression,learning and memory,and Parkinson's disease.
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Objective To evaluate the role of δ-opioid receptors in hydromorphone postcondition-ing-induced maintenance of electrophysiological stability during ischemia-reperfusion(I∕R)in isolated rat hearts. Methods Healthy male Sprague-Dawley rats, aged 2-3 months, weighing 280-360 g, were used in this study. The animals were anesthetized with intraperitoneal pentobarbital 60 mg∕kg. Their hearts were immediately removed and perfused in a Langendorff apparatus. Thirty-two isolated hearts were divided into 4 groups after successful preparation of Langendorff perfusion model(n=8 each)using a random number ta-ble: control group(group C), group I∕R, hydromorphone postconditioning group(group HP)and hydro-morphone plus δ-opioid receptor antagonist naltridole postconditioning group(group HNP). In HP and HNP groups, the hearts were perfused for 10 min with K-H solution containing 41 ng∕ml hydromorphone and 41 ng∕ml hydromorphone plus 5 μmol∕L naltridole, respectively, and then with K-H solution for 50 min. At 20 min of stabilization(T0)and 10, 25 and 60 min of reperfusion(T1-2), heart rate(HR), monophasic action potential(MAP)duration at 90% repolarization(MAPD90)of the two layers(endocar-dium, epicardium)of the anterior left ventricular wall were recorded. Transmural dispersion of repolariza-tion(TDR)was calculated. The development of arrhythmia, time for restoration of spontaneous heart beat and duration of arrhythmia were recorded during the period of reperfusion. Results Compared with group C, MAPD90of endocardium at T1-2and MAPD90of epicardium at T1were significantly prolonged in I∕R and HP groups, HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3in group HNP, TDR was significantly enlarged at T1in group I∕R and at T2in group HNP, and TDR was decreased at T3in group HP(P<005). Compared with group I∕R, no significant change was found in arrhythmia score(P>005), the time for restoration of spontaneous heart beat was significantly shortened, and TDR was decreased at T1in HP and HNP groups, duration of arrhythmia was significantly shortened, and MAPD90of endocardium was shortened at T1in group HP, and HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was decreased at T2-3in group HNP(P<005). Compared with group HP, no significant change was found in time for restoration of spon-taneous heart beat, duration of arrhythmia or arrhythmia score(P>005), HR was significantly decreased at T2-3, MAPD90of endocardium and epicardium was prolonged at T1-3, and TDR was increased at T3in group HNP(P<005). Conclusion The mechanism underlying hydromorphone postconditioning-induced maintenance of electrophysiological stability during I∕R is related to activating δ-opioid receptors in isolated rat hearts.
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Objective To evaluate the relationship between delta opioid receptors (DORs) and activity of glycogen synthase kinase-3β (GSK-3β) in the spinal cord during hyperalgesia induced by remifentanil in a rat model of incisional pain (IP).Methods Twenty-four male Sprague-Dawley rats,aged 240-260 g,weighing 2-3 months,were randomly divided into 3 groups (n =8 each) using a random number table:control group (group C),remifentanil+IP group (group R+I) and DOR antagonist naltrindole group (group N).A 1-cm longitudinal incision was made in the plantar surface of the left hindpaw in anesthetized rats.In group C,the equal volume of normal saline was injected intraperitoneally,and normal saline was then infused for 60 min at the same rate.In group R+I,the equal volume of normal saline was injected intraperitoneally,remifentanil was infused for 60 min at 1.2 μg · kg-1 · min-1,and IP was produced immediately after onset of remifentanil infusion.In group N,naltrindole 0.1 mg/kg was injected intraperitoneally,remifentanil was infused for 60 min at 1.2 μg · kg-1 · min-1,and IP was produced immediately after onset of remifentanil infusion.At 24 h before infusion of normal saline or remifentanil and 2,6,24 and 48 h after iv administration (T0-4),the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured.The rats were sacrificed after the last measurement of pain threshold,the lumbar segment (L4-6) of the spinal cord was removed for determination of the expression of GSK-3β,phosphor-GSK-3β (pGSK-3β) (by Western blot) and GSK-3β mRNA (realtime PCR).The ratio of pGSK-3β /GSK-3β was calculated.Results Compared with group C,the MWT was significantly decreased,and the TWL was shortened at T1 4,the expression of GSK-3β,pGSK-3β and GSK-3β mRNA was up-regulated,and pGSK-3β/GSK-3β ratio was decreased in R + I and N groups.Compared with group R + I,thc MWT was significantly incrcased,and the TWL was prolonged at T1-4,the expression of GSK-3β,pGSK-3β and GSK-3β rmRNA was down-regulated,and pGSK-3β/GSK-3β ratio was increased in group N.Conclusion Activation of DOR is involved in enhancement of activity of GSK-3β in the spinal cord during hyperalgesia induced by remifentanil in a rat model of IP.
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Background:Ulcerative colitis(UC)is a chronic and nonspecific intestinal inflammatory disease and its pathogenic mechanism has not yet been clarified. Intestinal mucosal immune function disorder may play a key role in the pathogenesis of UC. Aims:To investigate the effects of Wumeiwan on expressions of δ-opioid receptor(DOR),β-arrestin1 and Bcl-2 in rats with colitis. Methods:Fifty-six Sprague-Dawley rats were randomly divided into model group,Wumeiwan group, mesalazine group and blank group. Rats in model group,Wumeiwan group and mesalazine group were administered intrarectally with 5% TNBS and 50% ethanol to induce experimental colitis. After colitis models were established,rats in Wumeiwan group and mesalazine group were administered intragastrically with Wumeiwan and mesalazine suspension, respectively,and rats in model group and blank group were given intragastrically with 0. 9% NaCl solution,all for 15 days. On day 16,all the rats were sacrificed and colon samples were obtained. Protein and mRNA expressions of DOR,β-arrestin1 and Bcl-2 in colonic tissue were determined by immunohistochemistry and real-time PCR,respectively. Results:The inflammatory injury in colonic tissue of rats with experimental colitis was significantly attenuated when treated with Wumeiwan,Protein and mRNA expressions of DOR,β-arrestin1 and Bcl-2 in colonic tissue of model group were significantly higher than those of blank group(P 0. 05). Conclusions:DOR-β-arrestin1-Bcl-2 signal transduction pathway may play a central role in the pathogenesis of UC. Intervening this signaling pathway may be one of the mechanisms of attenuating UC by Wumeiwan.
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Objective To investigate the effect of brain ischemic preconditioning (IP) combined with traditional Chinese medicine three seven three alcohol saponin (PTS) on proliferation of endogenous neural stem cells and the mRNA expressions of delta opioid receptor (DOR),Bax,Bcl-2 in hippocampus at 7d post middle cerebral artery occlusion (MCAO).Methods The focal-focal ischemic tolerance models were established with twice suture method.80 SD rats were included and randomly divided into 5 groups:sham group,MCAO group,sham+ MCAO group,IP+ MCAO group,PTS+MCAO group (n=16 each).We chose 10 SD rats from each group to evaluate their neurological status,and made BrdU fluorescent immunolabeling.In addition,we chose the other 6 SD rats to detect the expression levels of DOR,Bax and Bcl-2 mRNA in ischemic region in hippocampusby using RT-PCR.Animals were given one set of BrdU injections (on day 6,three times,4h apart,50mg/kg) to label the proliferating cells.The neurological status was assessed by using Zea Longa neurological deficit scores at 7 days following cerebral infarction.Results Zea longa neurologic deficit scores in MCAO group and sham+ MCAO) group had significantly differences with IP+ MCAO group and PTS+ MCAO group respectively at 7d post MCAO(P＜0.01).There was no significant differeuce in Zea-longa neurologic deficit scores between MCAO group versus sham+ MCAO group,and IP+ MCAO group versus PTS+ MCAO group(P＞0.05).The number of BrdU+ ceils in hippocampus had significant differences between IP+ MCAO and PTS+ MCAO groups at 7d post MCAOand three groups of sham,MCAO and sham+ MCAO respectively (P＜0.01).There was no difference in the number of BrdU+ cells between MCAO versus Sham + MCAO groups and IP + MCAO versus PTS+MCAO groups(P＞0.05).DOR and Bcl-2 mRNA expression levels were higher and Bax mRNA expression level was lower in IP+ MCAO group than in MCAO,Sham+ MCAO and PTS+MCAO groups (P＜0.01).There were no significant differences in DOR,Bcl-2 and Bax mRNA expressions among MCAO,Sham + MCAO and PTS + MCAO groups (P＞ 0.05).Conclusions Acute cerebral infarction can induce the proliferation of endogenous neural stem cells in hippocampus in SD rats.IPC can facilitate the proliferation of endogenous neural stem cells in hippocampus afteracute cerebral infarction,improve the symptoms of neurologic dysfunction,increase DOR and Bcl 2 mRNA expressions,and reduce Bax mRNA expression in SD rats.PTS can facilitate the proliferation of endogenous neural stem cells in hippocampus after acute cerebral infarction in SD rats,and improve the symptoms of neurologic dysfunction,but it has no influence on the expressions of DOR,Bcl-2 and Bax mRNA.
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Objective To evaluate the role of δ opioid receptor in the brain injury following asphyxial cardiac arrest-resuscitation in rats.Methods Ninety-six pathogen-free male Sprague-Dawley rats,weighing 300-350 g,were randomly divided into 4 groups (n =24 each):sham operation group (group S),asphyxial cardiac arrest-resuscitation group (group M),δ opioid receptor agonist BW373U86 group (group B) and δ opioid receptor antagonist naltrindole group (group N).Cardiac arrest was induced by clamping the tracheal tube for 8 min.Mechanical ventilation with pure oxygen was performed.Epinephrine 0.02 mg/kg and 5％ NaHCO3 1 mg/kg were injected intravenously as soon as chest compression was started.Appearance of spontaneous breathing and MAP ＞ 50 mm Hg (lasting for more than 10 min) were considered to be signs of successful recovery of spontaneous circulation (ROSC).BW373U86 and naltrindole 1 mg/kg were injected via the femoral vein immediately after ROSC in groups B and N,respectively,while the equal volume of normal saline was given instead in groups S and M.Neurological deficit score (NDS) was evaluated at 3,24 and 72 h after ROSC.The rats were then sacrificed,brains were isolated and the hippocampus was obtained for detection of the expression of brain-derived neurotrophic factor (BDNF)and tyrosine receptor kinase B (TrkB)mRNA by RT-PCR.The histological grading (HG) of neurons and number of survival neurons in hippocampal CA1 region were determined at 72 h after ROSC.Results Compared with group S,the expression of BDNF and TrkB mRNA was significantly up-regulated,HG was increased,and NDS and the number of survival neurons were decreased in groups M,B and N (P ＜ 0.05).Compared with group M,the expression of BDNF and TrkB mRNA was significantly up-regulated in group B,the expression of BDNF and TrkB mRNA was down-regulated in group N,and HG was significantly decreased,and NDS and the number of survival neurons were increased in groups B and N (P ＜ 0.05).NDS was significantly lower,the number of survival neurons was smaller,the expression of BDNF and TrkB mRNA was lower,and HG was higher in group N than in group B (P ＜ 0.05).Conclusion Activation of δ opioid receptor can reduce the brain injury following asphyxial cardiac arrest-resuscitation in rats and the mechanism may be related to up-regulation of BDNF and TrkB after activation of δ opioid receptor.
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Objective To evaluate the role of δ receptor in reduction of hypoxia-reoxygenation (H/R) injury to cardiomyocytes by morphine preconditioning in rats with chronic heart failure.Methods Adult male Sprauge-Dawley rats weighing 220-250 g were used in the study.Chronic heart failure was induced by injection of adriamycin 2 mg/kg via the tail vein once a week for 6 weeks.Their hearts were removed 2 weeks after the last injection and the cardiomyocytes were isolated and cultured.The cells were randomly divided into 5 groups ( n =8 each):control group (group C); H/R group; morphine preconditioning group (group MPC); morphine preconditioning + naloxone (opioid receptor antagonist ) group (group MPC + Naloxone) ; morphine preconditioning + naltrindole ( δ receptor antagonist) group ( MPC + Naltrindole group).The cells were cultured in normal culture atmosphere in group C and were exposed in hypoxic air for 3 h followed by 1 h reoxygenation in the other groups.Morphine preconditioning was performed immediately before hypoxia in group MPC.Naloxone and naltrindole were added before morphine preconditioning in groups MPC + Naloxone and MPC + Natrindole respectively.At 1 h of reoxygenation,the cell viability ( by MTT assay),activities of lactate dehydrogenase ( LDH ) and creatine kinase (CK),and cell apoptosis were detected.The apoptotic rate was calculated.Results The cell viability was significantly lower,and the activities of LDH and CK and apoptotic rate were significantly higher in groups H/R,MPC + Naloxone and MPC + Natrindole than in group C (P ＜ 0.05).The cell viability was significantly higher,and the activities of LDH and CK and apoptotic rate were significantly lower in group MPC than in group H/R ( P ＜ 0.05).Conclusion Morphine preconditioning reduces H/R injury to cardiomyocytes through activating δ receptor in rats with chronic heart failure.
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ObjectiveTo investigate the role of δ-opioid receptor in remifentanil-induced N-methyl-D-aspartate (NMDA) receptor miniature excitatory postsynaptic currents (mEPSCs) in rat spinal dorsal horn neurons.MethodsMale 14-18 d old Wistar rats weighing 50-60 g were used in this study.The animals were anesthetized with intraperitoneal choral hydrate 400 mg/kg and sacrificed.Their lumbar segments of spinal cord (L1-S1 ) were immediately removed and sliced.Twenty-four slices were randomly divided into 4 groups ( n =6 each): control group (group C) ; glycine group (group G) ; remifentanil group (group R) and remifentanil + naltrindole(a δ receptor antagon) (group RN).Slices were cultured in artificial cerebrospinal fluid (ACSF) (group C) or incubated in ACSF containing glycine 0.24 μmol/L (group G) or remifentanil 4 nmol/L (group R) or remifentanil 4 nmol/L+ naltrindole 1 nmol/L (group RN) for 60 min.Whole cell patch clamp technique was used to measure NMDA receptor mEPSCs.ResultsThe amplitude and frequency of mEPSCs were significantly higher in group R than in groups C and RN ( P ＜ 0.01).There were no significant differences in amplitude and frequency of mEPSCs among gorups C,G and RN ( P ＞ 0.05).ConclusionActivation of δ-receptor can enhance NMDA receptor function in spinal dorsal horn neurons in rats which may be the mechanism of remifentanil-induced hyperalgesia.
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Objective To investigate the effect of δ-opioid receptor agonist D-Ala2-D-Leu5-enkephalin (DADLE) on the celluar immune function in septic rats. Methods One hundred and fifty healthy male SD rats weighing 154-198 g were randomly divided into 3 groups (n = 50 each):group Ⅰ sham operation (group S);group Ⅱ sepsis (group SEP) and group Ⅲ DADLE. Sepsis was induced by cecum ligation and punture (CLP) in group Ⅱ and Ⅲ. In group Ⅲ 0.5 rmg/kg DADLE 10 ml/kg was injected intraperitoneally (IP) immediately after CLP operation. Seven day survival rate was calculated. Blood samples were collected from 10 animals at 4, 8 and 12 h after operation (T1-3) respectively in each group for determination of serum TNF-α and IL-10 concentrations by ELISA and changes in T-cell subsets by flow cytometry. Results CLP significantly increased serum TNF-α and IL-10 concentrations and TNF-α/IL-10 ratio at T1-3 and decreased CD4+ and CD4+/CD8+ ratio and increased CD8+ at T3 in group Ⅱ as compared with group S (group Ⅰ). DADLE treatment significantly attenuated the CLP-induced above changes. Seven-day survival rate was significantly higher in DADLE group than in CLP group.Conclusion δ-opioid receptor agonist DADLE can improve the celluar immune function of rats with sepsis and increase the survival rate.
