Publications by authors named "Xue-Jun Xu"

33 Publications

Downregulation of p53 by Insufficient CTCF in CD4 T Cells Is an Important Factor Inducing Acute Graft-Versus-Host Disease.

Front Immunol 2020 29;11:568637. Epub 2020 Sep 29.

Department of Hematology, Xiangya Hospital, Central South University, Changsha, China.

Recent evidence indicates that p53 plays a protective role against various systemic autoimmune diseases by suppressing pro-inflammatory cytokine production and reducing the number of pathogenic T cells. However, whether abnormal p53 expression participates in the development of acute graft-versus-host disease (aGVHD) remains unclear. In this study, we demonstrated that p53 was downregulated in CD4 T cells from patients with aGVHD compared with the non-aGVHD group. Furthermore, we confirmed that low expression of CCCTC-binding factor (CTCF) in CD4 T cells from aGVHD cases is an important factor affecting histone H3K9/K14 hypoacetylation in the promoter and p53 downregulation. Restoring CTCF expression in CD4 T cells from aGVHD patients increased p53 amounts and corrected the imbalance of Th17 cells/Tregs. Taken together, these results provide novel insights into p53 downregulation in CD4 T cells from aGVHD patients.
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http://dx.doi.org/10.3389/fimmu.2020.568637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550539PMC
May 2021

Clinical effects of warmed humidified carbon dioxide insufflation in infants undergoing major laparoscopic surgery.

Medicine (Baltimore) 2019 Jul;98(27):e16151

Department of Pediatric Surgery, Ningbo Women and Children's Hospital, Ningbo, China.

Purpose: Some studies have reported that warmed humidified carbon dioxide (CO2) insufflation in adult laparoscopic surgery could reduce pain and improve the core body temperature (CBT). However, similar studies are lacking in infants. Thus, this study aimed to investigate the clinical effects of warmed, humidified CO2 insufflation in pediatric patients undergoing major laparoscopic surgeries.

Methods: From January 2015 to December 2017, infants who underwent major laparoscopic surgeries in Ningbo Women and Children's Hospital were randomized to Group A (standard CO2 insufflation) or Group B (warmed humidified CO2 insufflation, 35°C, 95% relative humidity). Change in CBT at the end of surgery was the primary outcome. Secondary outcomes included surgery time, intraoperative blood loss, oxygen saturation (SO2), and Face, Legs, Activity, Cry and Consolability (FLACC) scale. These variables were compared between the 2 groups.

Results: Sixty-three infants (38 females, 25 males) were included; 30 patients were in Group A and 33 in Group B. The diseases treated with the laparoscopic approach included congenital megacolon, congenital diaphragmatic hernia, and intestinal malrotation. No deaths were noted. CBT was significantly higher in Group B at the end of surgery (P = .021). The occurrence of postoperative shivering (P = .02), hypothermia (P = .032), bowel movement (P = .044), and hospital stay (P = .038) was significantly different between the 2 groups; Group B had less shivering and hypothermia occurrence after surgery. Moreover, Group B demonstrated a more rapid postoperative recovery of bowel movement and shortened hospital stay than Group A. There was no statistical difference in operative time (P = .162), intraoperative blood loss (P = .541), SO2 (P = .59), and FLACC scale (P = .65) between the 2 groups.

Conclusion: The use of warmed humidified CO2 insufflation in infants undergoing major laparoscopic surgery was helpful for maintaining normothermia and was associated with several positive postoperative outcomes, including less shivering and hypothermia, faster recovery of bowel movement, and shortened hospital stay.
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http://dx.doi.org/10.1097/MD.0000000000016151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635157PMC
July 2019

Pharmacological Characterization of Dezocine, a Potent Analgesic Acting as a κ Partial Agonist and μ Partial Agonist.

Sci Rep 2018 09 20;8(1):14087. Epub 2018 Sep 20.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Science, Shanghai, 201203, China.

Dezocine is becoming dominated in China market for relieving moderate to severe pain. It is believed that Dezocine's clinical efficacy and little chance to provoke adverse events during the therapeutic process are mainly attributed to its partial agonist activity at the μ opioid receptor. In the present work, we comprehensively studied the pharmacological characterization of Dezocine and identified that the analgesic effect of Dezocine was a result of action at both the κ and μ opioid receptors. We firstly found that Dezocine displayed preferential binding to μ opioid receptor over κ and δ opioid receptors. Dezocine, on its own, weakly stimulated G protein activation in cells expressing κ and μ receptors, but in the presence of full κ agonist U50,488 H and μ agonist DAMGO, Dezocine inhibited U50,488H- and DAMGO-mediated G protein activation, indicating that Dezocine was a κ partial agonist and μ partial agonist. Then the in intro results were verified by in vivo studies in mice. We observed that Dezocine-produced antinociception was significantly inhibited by κ antagonist nor-BNI and μ antagonist β-FNA pretreatment, indicating that Dezocine-mediated antinociception was via both the κ and μ opioid receptors. When co-administrating of Dezocine with U50,488 H or morphine, Dezocine was capable of inhibiting U50,488H- or morphine-induced antinociception. Finally, κ receptor activation-associated side effect sedation was investigated. We found that Dezocine displayed limited sedative effect with a ceiling effecting at a moderate dose. Thus, our work led to a better understanding of the analgesic mechanism of action of Dezocine in vivo.
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http://dx.doi.org/10.1038/s41598-018-32568-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148296PMC
September 2018

7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.

Bioorg Med Chem 2018 08 24;26(14):4254-4263. Epub 2018 Jul 24.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address:

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.
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http://dx.doi.org/10.1016/j.bmc.2018.07.020DOI Listing
August 2018

Heteromers of μ opioid and dopamine D receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner.

Br J Pharmacol 2017 Sep 18;174(17):2842-2861. Epub 2017 Jul 18.

Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Collaborative Innovation Center for Brain Science, Shanghai, China.

Background And Purpose: Exposure to opiates induces locomotor sensitization in rodents, which has been proposed to correspond to the compulsive drug-seeking behaviour. Numerous studies have demonstrated that locomotor sensitization can occur in a dopamine transmission-independent manner; however, the underlying mechanisms are unclear.

Experimental Approach: Co-immunoprecipitation, BRET and cross-antagonism assays were used to demonstrate the existence of receptor heterodimers. Function of heterodimers was evaluated by behavioural studies of locomotor sensitization.

Key Results: The dopamine D receptor antagonist SCH23390 antagonized the signalling initiated by stimulation of μ opioid receptors with agonists in transfected cells expressing two receptors and in striatal tissues from wild-type but not D receptor knockout (KO) mice, suggesting that SCH23390 modified μ receptor function via receptor heteromers, as the ability of an antagonist of one of the receptors to inhibit signals originated by stimulation of the partner receptor was a characteristic of receptor heteromers. The existence of μ receptor-D receptor heterodimers was further supported by biochemical and biophysical assays. In vivo, when dopamine release was absent (by destruction of the dopaminergic projection from the ventral tegmental area to the striatum), SCH23390 still significantly inhibited μ receptor agonist-induced behavioural responses in rats. Additionally, we demonstrated that D or μ receptor KO mice and thus unable to form μ receptor-D receptor heterodimers, failed to show locomotor sensitization to morphine.

Conclusion And Implications: Our results suggest that μ receptor-D receptor heterodimers may be involved in the dopamine-independent expression of locomotor sensitization to opiates.
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http://dx.doi.org/10.1111/bph.13908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554314PMC
September 2017

Unscheduled screening tests cannot be termed as surveillance.

Hepatology 2017 09 27;66(3):1001-1002. Epub 2017 Jul 27.

Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, P. R. China.

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http://dx.doi.org/10.1002/hep.29287DOI Listing
September 2017

The Pharmacological Heterogeneity of Nepenthone Analogs in Conferring Highly Selective and Potent κ-Opioid Agonistic Activities.

ACS Chem Neurosci 2017 04 19;8(4):766-776. Epub 2017 Jan 19.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University , Shanghai 201203, China.

To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group. We performed in vitro tests (binding and functional assays) and molecular docking operations on our newly designed compounds. The results of wet-experimental measures and modeled binding structures demonstrate that these new compounds are selective KOR agonists with nanomolar level affinities. Compound 4 from these new derivatives showed the highest affinity (K = 0.4 ± 0.1 nM) and the highest selectivity (μ/κ = 339, δ/κ = 2034) toward KOR. The in vivo tests revealed that compound 4 is able to induce stronger (ED = 2.1 mg/kg) and much longer antinociceptive effect than that of the typical KOR agonist U50488H (ED = 4.4 mg/kg). Therefore, compound 4 can be used as a perfect lead compound for future design of potent analgesics acting through KOR.
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http://dx.doi.org/10.1021/acschemneuro.6b00321DOI Listing
April 2017

MiRNA-22 inhibits oncogene galectin-1 in hepatocellular carcinoma.

Oncotarget 2016 Aug;7(35):57099-57116

Department of Hepatobiliary Surgery Institute, South Western Hospital, Third Military Medical University, Chongqing 400038, China.

Hepatic stellate cells (HSCs) induce immune privilege and promote hepatocellular carcinoma (HCC) by suppressing the immune system. On the other hand, galectin-1 and miRNA-22 (miR-22) are dysregulated in HCC and serve as prognostic indicators for patients. In this study, therefore, we measured galectin-1 and miR-22 expression in HSCs isolated from HCC tissues (Ca-HSCs), and in normal liver tissues (N-HSCs) as a control. We also investigated the apoptosis rate among T cells and the production of cytokines (IFN-γ and IL-10) in HSCs co-cultured with T cells. And we used immunohistochemical staining to tested for correlation between galectin-1 expression, CD3 expression and clinicopathological features in 162 HCC patients. Our results showed that galectin-1 expression was much higher in Ca-HSCs than in N-HSCs. Overexpression of galectin-1 promoted HSC-induced T cell apoptosis and cytokine production (IFN-γ and IL-10), while miR-22 expression inhibited it. Galectin-1 expression correlated negatively with miR-22 expression in HSCs. High galectin-1 and low CD3 expression levels were associated with poor prognosis in HCC patients. These results suggest that the immunosuppressive microenvironment promoted by HSC-derived galectin-1 in HCC can be inhibited by miR-22. Galectin-1 and miR-22 could potentially serve as prognostic markers and therapeutic targets in HCC.
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http://dx.doi.org/10.18632/oncotarget.10981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302976PMC
August 2016

Spectroscopic Study on the Interaction between Naphthalimide-Polyamine Conjugates and Bovine Serum Albumin (BSA).

Molecules 2015 Sep 11;20(9):16491-523. Epub 2015 Sep 11.

The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.

The effect of a naphthalimide pharmacophore coupled with diverse substituents on the interaction between naphthalimide-polyamine conjugates 1-4 and bovine serum albumin (BSA) was studied by UV absorption, fluorescence and circular dichroism (CD) spectroscopy under physiological conditions (pH = 7.4). The observed spectral quenching of BSA by the compounds indicated that they could bind to BSA. Furthermore, caloric fluorescent tests revealed that the quenching mechanisms of compounds 1-3 were basically static type, but that of compound 4 was closer to a classical type. The Ksv values at room temperature for compound-BSA complexes-1-BSA, 2-BSA, 3-BSA and 4-BSA were 1.438 × 10⁴, 3.190 × 10⁴, 5.700 × 10⁴ and 4.745 × 10⁵, respectively, compared with the value of MINS, 2.863 × 10⁴ at Ex = 280 nm. The obtained quenching constant, binding constant and thermodynamic parameter suggested that the binding between compounds 1-4 with BSA protein, significantly affected by the substituted groups on the naphthalene backbone, was formed by hydrogen bonds, and other principle forces mainly consisting of charged and hydrophobic interactions. Based on results from the analysis of synchronous three-dimensional fluorescence and CD spectra, we can conclude that the interaction between compounds 1-4 and BSA protein has little impact on the BSA conformation. Calculated results obtained from in silico molecular simulation showed that compound 1 did not prefer either enzymatic drug sites I or II over the other. However, DSII in BSA was more beneficial than DSI for the binding between compounds 2-4 and BSA protein. The binding between compounds 1-3 and BSA was hydrophobic in nature, compared with the electrostatic interaction between compound 4 and BSA.
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http://dx.doi.org/10.3390/molecules200916491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332075PMC
September 2015

Hydrogen gas inhalation protects against liver ischemia/reperfusion injury by activating the NF-κB signaling pathway.

Exp Ther Med 2015 Jun 26;9(6):2114-2120. Epub 2015 Mar 26.

Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.

Hydrogen has been demonstrated to function as a novel antioxidant and exert therapeutic antioxidant activity in a number of diseases. The present study was designed to investigate the effect of hydrogen inhalation on liver ischemia/reperfusion (I/R) injury in rats. The portal triad to the left lobe and the left middle lobe of the liver were completely occluded for 90 min. This was followed by reperfusion for 180 min. The rats subsequently underwent syngeneic orthotopic liver transplantation. Inhalation of various concentrations (1, 2 and 3%) of hydrogen gas and its administration for different durations (1, 3 and 6 h) immediately prior to the I/R injury allowed the optimal dose and duration of administration to be determined. Liver injury was evaluated through biochemical and histopathological examinations. The expression levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, were measured by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction (qPCR). Liver nuclear factor κB (NF-κB) was detected by qPCR and western blot analysis. Inhalation of hydrogen gas at 2% concentration for 1 h significantly reduced the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, the expression of cytokines, including IL-6, TNF-α, early growth response protein 1 (Egr-1) and IL-1β, and morphological damage. In addition, the mRNA and protein expression levels of NF-κB, heme oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl-2) and zinc finger protein A20 (A20) in rats where only the donors received hydrogen were significantly increased compared with those in rats where both the donor and recipient, or only the recipient received hydrogen. The results indicate that hydrogen inhalation at 2% concentration for 1 h prior to liver transplantation protected the rats from ischemia/reperfusion injury by activation of the NF-κB signaling pathway.
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http://dx.doi.org/10.3892/etm.2015.2385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473536PMC
June 2015

Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel μ opioid receptor ligands.

Acta Pharmacol Sin 2015 Jul 8;36(7):887-94. Epub 2015 Jun 8.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.

Aim: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton.

Methods: Based on a three-dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the μ opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N-phenethylnormorphine was docked to the μ opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics.

Results: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the μ opioid receptor were comparatively studied.

Conclusion: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design.
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http://dx.doi.org/10.1038/aps.2014.171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648120PMC
July 2015

Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists.

Org Biomol Chem 2015 May 21;13(20):5656-73. Epub 2015 Apr 21.

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.
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http://dx.doi.org/10.1039/c5ob00350dDOI Listing
May 2015

Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation.

Acta Pharmacol Sin 2015 May 30;36(5):565-71. Epub 2015 Mar 30.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai 201203, China.

Aim: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH.

Methods: [(3)H]diprenorphine binding and [(35)S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions.

Results: In [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to μ- and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPγS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (-)U50,488H.

Conclusion: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.
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http://dx.doi.org/10.1038/aps.2014.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422940PMC
May 2015

[An oligopeptide improves solubility of paclitaxel by non-covalent interaction].

Yao Xue Xue Bao 2012 Jul;47(7):947-52

Shenyang Pharmaceutical University, Shenyang 110016, China.

Based on the principle of non-covalent interactions between oligopeptides and paclitaxel for improving the solubility of paclitaxel, an oligopeptide, N terminal-W(L)-FFGREKD-C terminal (W8), was designed and the solubilization effect of W8 on paclitaxel was detected through experiments. The binding efficiency and the possible optimal conformation were optimized by molecular docking program. The solubilization effect of W8 on paclitaxel was determined by RP-HPLC. And the solubilization mechanism of oligopeptide to paclitaxel was proposed at molecular level. It was indicated from the docking result that there existed pi-pi interactions and several hydrogen-bond interactions between the oligopeptide and paclitaxel. After being solubilized by the oligopeptide, the aqueous solubility of paclitaxel was increased to 28 times. This study provided basis for further research of the solubilization of paclitaxel by oligopeptide and confirmed a novel approach for the design of safe oligopeptide solubilizing excipient.
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July 2012

[A pilot study on the accuracy of digital model reconstructed by cone beam CT].

Shanghai Kou Qiang Yi Xue 2010 Oct;19(5):456-9

Department of Stomatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310001, China.

Purpose: To study the feasibility of digital model produced by cone beam CT.

Methods: Ten patients seeking orthodontic treatment with congested lower incisors were enrolled in this study. Plaster models of the lower arch were made using routing method. Digital model was reconstructed from these plaster models by NewTom 3G cone beam CT with 6 inch model. Linear measurements including right first premolar width, arch width, arch length, right first incisor width, all incisors and canines width, were done on the lower arch on plaster models with calipers. The same measurements on digital model were made using software Simplant Pro11.04. Linear measurements were repeated one week later on both plaster and digital model. Paired t test was used to determine the difference between the linear measurements on both models. The absolute measurements errors of two models were compared using paired t test. All statistical analysis was performed using SPSS13.0 software package.

Results: The linear measurements of the digital model slightly underestimated the real plaster model, but no significant difference of the linear measurements was seen between the plaster model and the digital model. The value of all of the lower incisors and canines width of plaster models was significantly higher than that of digital model. Mean absolute difference of different measurement of digital model was not significant from that of plaster model.

Conclusion: Digital model using CBCT is feasible for the linear measurement and storage.
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October 2010

Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice.

Acta Pharmacol Sin 2010 Dec 22;31(12):1547-52. Epub 2010 Nov 22.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.

Aim: to investigate the effects of ATPM-ET [(-)-3-N-Ethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice.

Methods: the pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice.

Results: the binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and μ-opioid receptors with K(i) values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED(50) value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05).

Conclusion: ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.
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http://dx.doi.org/10.1038/aps.2010.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002947PMC
December 2010

Serine 363 of the {delta}-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands.

J Cell Sci 2010 Dec 23;123(Pt 24):4259-70. Epub 2010 Nov 23.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Distinct opioid receptor agonists have been proved to induce differential patterns of ERK activation, but the underlying mechanisms remain unclear. Here, we report that Ser363 in the δ-opioid receptor (δOR) determines the different abilities of the δOR agonists DPDPE and TIPP to activate ERK by G-protein- or β-arrestin-dependent pathways. Although both DPDPE and TIPP activated ERK1/2, they showed different temporal, spatial and desensitization patterns of ERK activation. We show that that DPDPE employed G protein as the primary mediator to activate the ERK cascade in an Src-dependent manner, whereas TIPP mainly adopted a β-arrestin1/2-mediated pathway. Moreover, we found that DPDPE gained the capacity to adopt the β-arrestin1/2-mediated pathway upon Ser363 mutation, accompanied by the same pattern of ERK activation as that induced by TIPP. Additionally, we found that TIPP- but not DPDPE-activated ERK could phosphorylate G-protein-coupled receptor kinase-2 and β-arrestin1. However, such functional differences of ERK disappeared with the mutation of Ser363. Therefore, the present study reveals a crucial role for Ser363 in agonist-specific regulation of ERK activation patterns and functions.
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http://dx.doi.org/10.1242/jcs.073742DOI Listing
December 2010

Adenosine A(1) receptor agonist N(6)-cyclohexyl-adenosine induced phosphorylation of delta opioid receptor and desensitization of its signaling.

Acta Pharmacol Sin 2010 Jul 21;31(7):784-90. Epub 2010 Jun 21.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.

Aim: To define the effect of adenosine A(1) receptor (A(1)R) on delta opioid receptor (DOR)-mediated signal transduction.

Methods: CHO cells stably expressing HA-tagged A(1)R and DOR-CFP fusion protein were used. The localization of receptors was observed using confocal microscope. DOR-mediated inhibition of adenylyl cyclase was measured using cyclic AMP assay. Western blots were employed to detect the phosphorylation of Akt and the DOR. The effect of A(1)R agonist N(6)-cyclohexyladenosine (CHA) on DOR down-regulation was assessed using radioligand binding assay.

Results: CHA 1 micromol/L time-dependently attenuated DOR agonist [D-Pen(2,5)]enkephalin (DPDPE)-induced inhibition of intracellular cAMP accumulation with a t(1/2)=2.56 (2.09-3.31) h. Pretreatment with 1 micromol/L CHA for 24 h caused a right shift of the dose-response curve of DPDPE-mediated inhibition of cAMP accumulation, with a significant increase in EC(50) but no change in E(max). Pretreatment with 1 micromol/L CHA for 1 h also induced a significant attenuation of DPDPE-stimulated phosphorylation of Akt. Moreover, CHA time-dependently phosphorylated DOR (Ser363), and this effect was inhibited by A(1)R antagonist 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX) but not by DOR antagonist naloxone. However, CHA failed to produce the down-regulation of DOR, as neither receptor affinity (K(d)) nor receptor density (B(max)) of DOR showed significant change after chronic CHA exposure.

Conclusion: Activation of A(1)R by its agonist caused heterologous desensitization of DOR-mediated inhibition of intracellular cAMP accumulation and phosphorylation of Akt. Activation of A(1)R by its agonist also induced heterologous phosphorylation but not down-regulation of DOR.
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http://dx.doi.org/10.1038/aps.2010.70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007732PMC
July 2010

Paradoxical relationship between RAVE (relative activity versus endocytosis) values of several opioid receptor agonists and their liability to cause dependence.

Acta Pharmacol Sin 2010 Apr 15;31(4):393-8. Epub 2010 Mar 15.

School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Aim: To examine the relationship between the RAVE (relative activity versus endocytosis) values of opiate agonists and their dependence liability by studying several potent analgesics with special profiles in the development of physical and psychological dependence.

Methods: The effects of (-)-cis-(3R,4S,2'R) ohmefentanyl (F9202), (+)-cis-(3R,4S,2'S) ohmefentanyl (F9204), dihydroetorphine (DHE) and morphine on [(35)S]GTP gamma S binding, forskolin-stimulated cAMP accumulation, and receptor internalization were studied in CHO cells stably expressing HA-tagged mu-opioid receptors (CHO-HA-MOR). cAMP overshoot in response to the withdrawal of these compound treatments was also tested.

Results: All four agonists exhibited the same rank order of activity in stimulation of [(35)S]GTP gamma S binding, inhibition of adenylyl cyclase (AC) and induction of receptor internalization: DHE>F9204>F9202>morphine. Based on these findings and the previous in vivo analgesic data obtained from our and other laboratories, the RAVE values of the four agonists were calculated. The rank order of RAVE values was morphine>F9202>F9204>DHE. For the induction of cAMP overshoot, the rank order was F9202>or=morphine>F9204>or=DHE.

Conclusion: Taken in combination with previous findings of these compounds' liability to develop dependence, the present study suggests that the agonist with the highest RAVE value seems to have a relatively greater liability to develop psychological dependence relative to the agonist with the lowest RAVE value. However, the RAVE values of these agonists are not correlated with their probability of developing physical dependence or inducing cAMP overshoot, a cellular hallmark of dependence.
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http://dx.doi.org/10.1038/aps.2010.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007660PMC
April 2010

Highly selective and potent mu opioid ligands by unexpected substituent on morphine skeleton.

Bioorg Med Chem Lett 2010 Jan 29;20(1):418-21. Epub 2009 Jul 29.

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China.

Unexpected substituent on the well-known morphine skeleton is described to be account for highly selective and potent mu opioid ligands, which is strongly connected to substituted aromatic groups on this omitted 8alpha-position.
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http://dx.doi.org/10.1016/j.bmcl.2009.07.119DOI Listing
January 2010

Pharmacological characterization of ATPM [(-)-3-aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a novel mixed kappa-agonist and mu-agonist/-antagonist that attenuates morphine antinociceptive tolerance and heroin self-administration behavior.

J Pharmacol Exp Ther 2009 Apr 9;329(1):306-13. Epub 2009 Jan 9.

School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.
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http://dx.doi.org/10.1124/jpet.108.142802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670601PMC
April 2009

Role of Src in ligand-specific regulation of delta-opioid receptor desensitization and internalization.

J Neurochem 2009 Jan 10;108(1):102-14. Epub 2008 Nov 10.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

The opioid receptors are a member of G protein-coupled receptors that mediate physiological effects of endogenous opioid peptides and structurally distinct opioid alkaloids. Although it is well characterized that there is differential receptor desensitization and internalization properties following activation by distinct agonists, the underlying mechanisms remain elusive. We investigated the signaling events of delta-opioid receptor (deltaOR) initiated by two ligands, DPDPE and TIPP. We found that although both ligands inhibited adenylyl cyclase (AC) and activated ERK1/2, only DPDPE induced desensitization and internalization of the deltaOR. We further found that DPDPE, instead of TIPP, could activate GRK2 by phosphorylating the non-receptor tyrosine kinase Src and translocating it to membrane receptors. Activation of GRK2 led to the phosphorylation of serine residues in the C-terminal tail, which facilitates beta-arrestin1/2 membrane translocation. Meanwhile, we also found that DPDPE promoted beta-arrestin1 dephosphorylation in a Src-dependent manner. Thus, DPDPE appears to strengthen beta-arrestin function by dual regulations: promoting beta-arrestin recruitment and increasing beta-arrestin dephosphorylation at the plasma membrane in a Src-dependent manner. All effects initiated by DPDPE could be abolished or suppressed by PP2, an inhibitor of Src. Morphine, which has been previously shown to be unable to desensitize or internalize deltaOR, also behaved as TIPP in failure to utilize Src to regulate deltaOR signaling. These findings point to the existence of agonist-specific utilization of Src to regulate deltaOR signaling and reveal the molecular events by which Src modulates deltaOR responsiveness.
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http://dx.doi.org/10.1111/j.1471-4159.2008.05740.xDOI Listing
January 2009

LPK-26, a novel kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential.

Eur J Pharmacol 2008 Apr 19;584(2-3):306-11. Epub 2008 Feb 19.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.

Analgesics such as morphine cause many side effects including addiction, but kappa-opioid receptor agonist can produce antinociception without morphine-like side effects. With the aim of developing new and potent analgesics with lower abuse potential, we studied the antinociceptive and physical dependent properties of a derivate of ICI-199441, an analogue of (-)U50,488H, named (2-(3,4-dichloro)-phenyl)-N-methyl-N-[(1S)-1-(2-isopropyl)-2-(1-(3-pyrrolinyl))ethyl] acetamides (LPK-26). LPK-26 showed a high affinity to kappa-opioid receptor with the Ki value of 0.64 nM and the low affinities to micro-opioid receptor and delta-opioid receptor with the Ki values of 1170 nM and >10,000 nM, respectively. It stimulated [(35)S]GTPgammaS binding to G-proteins with an EC50 value of 0.0094 nM. In vivo, LPK-26 was more potent than (-)U50,488H and morphine in analgesia, with the ED50 values of 0.049 mg/kg and 0.0084 mg/kg in hot plat and acetic acid writhing tests, respectively. Moreover, LPK-26 failed to induce physical dependence, but it could suppress naloxone-precipitated jumping in mice when given simultaneously with morphine. Taken together, our results show that LPK-26 is a novel selective kappa-opioid receptor agonist with highly potent antinociception effects and low physical dependence potential. It may be valuable for the development of analgesic and drug that can be used to reduce morphine-induced physical dependence.
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http://dx.doi.org/10.1016/j.ejphar.2008.02.028DOI Listing
April 2008

[Stress distribution in press-fit orthodontic microimplant bone interface].

Shanghai Kou Qiang Yi Xue 2006 Dec;15(6):619-22

Department of Orthodontics,School of Dentistry, Zhejiang University, Hangzhou 310006, Zhejiang Province, China.

Purpose: The goal of this study is to analyse the stress distribution in the press-fit microimplant-bone interface and its indications for immediate loading of orthodontic microimplant.

Methods: Three-dimensional finite element models were created of a 20 mm section of posterior mandible simplified in isosceles trapezoid shape, 30 mm in height, 10mm in upper side width, 14 mm in lower side width,with a single microimplant, 1.2 mm in diameter, 6 mm in length embedded in the bone. The cortical bone thickness was assumed as 1.6 mm. Cortical and cancellous bone were modeled as transversely isotropic and linearly elastic materials. Titanium was modeled as isotropic and linearly elastic material. Perfect bonding was assumed at microimplant- bone interfaces. ANSYS 9.0 finite element analysis software was used to generate the simplified finite element models of the local mandible-implant complex. 0 mm, 0.05 mm and 0.1 mm press-fit were arbitrarily set to the implant-bone interface to mimic the situation of immediate placement of microimplant. Stresses in the microimplant-bone interface were calculated under these "press-fit".

Results: Stresses distributed mainly in the cortical bone interface. At Omm press-fit, the stress was 0 MPa. For 0.05mm press-fit, the stress was 1648 MPa in mesio-distal direction, 1782MPa in occluso-gingival direction;and for 0.1 mm, it reached 2012MPa in mesio-distal direction, 2110MPa in occluso-gingival direction. As the "press-fit" increased, the stresses increased accordingly.

Conclusion: Values of initial stress in the microimplant-bone interface due to press-fit generated by immediately placed microimplant were very high in these limited and simplified three dimensional finite element models. It reminded us that the initial stress be taken into consideration when immediate loading of the microimplant is planned. Supported by Research Fund of Health Bureau of Zhejiang Province (2005B104).
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December 2006

Radiographic and surgical template for placement of orthodontic microimplants in interradicular areas: a technical note.

Int J Oral Maxillofac Implants 2006 Jul-Aug;21(4):629-34

Stomatology Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.

Purpose: In recent years, microimplants have gained popularity in orthodontics. Microimplants are primarily placed in complex sites where critical anatomic structures, such as roots of teeth, may be damaged, so precise surgical planning is required prior to placement. The goal of this report was to introduce a newly developed technique for the placement of microimplants in interradicular areas and evaluate its accuracy.

Materials And Methods: The planned placement site is radiographed using a radiographic template and film holder fabricated by the investigators. The resultant radiograph is clipped and attached to the radiographic template to make a surgical template to guide the placement of the microimplant. Forty-one patients, 15 men and 26 women ranging in age from 21 to 29 years, were enrolled in this study. On 1 side of the arch, this novel technique was used for implant placement, and on the other side, an established method reported by Maino and associates (i.e., the control technique) was used.

Results: A total of 116 microimplants 2 mm wide and 9 mm long were placed interradicularly in 41 patients. Twelve of 58 microimplants were placed unsuccessfully in the control group, versus 2 of 58 in the test group. Statistical analysis showed that there was a significant difference between the 2 techniques in terms of success rate (P < .05).

Discussion: Presurgical diagnosis of bone quantity and transfer of the information to the surgical sites are vital in microimplant placement. Radiographic templates modified for surgical purposes have the advantage of transferring radiographic information directly to the surgical site.

Conclusion: This study, although limited in some respects, demonstrated that microimplant placement can be improved using the newly developed technique described.
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November 2006

Use of a simple intraoral instrument to standardize film alignment and improve image reproducibility.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005 Jul;100(1):99-104

Department of Orthodontics, School of Dentistry, Zhejiang University, Hang Zhou, People's Republic of China.

Objective: A lot of instruments and devices were reported in standardized realignment of intraoral film. However, these instruments either are too cumbersome and time consuming to be used or require extensive fabrication. In this study we described a prototype of a instrument for realignment of intraoral film and evalated its reproducibility.

Study Design: A technique that uses this instrument was compared with a validated method serving as control. An adult human dry skull with full dentition was exposed for measuring the angular errors. Two types of angular errors were calculated.

Results: of the analysis of the alignment error caused by projection of the x-ray beam showed the mean horizontal angulation error (+/-SD) was 1.70 +/- 0.75 degrees and the vertical one was 1.32 +/- 0.44 degrees in the new instrument group, and 1.65 +/- 0.70 degrees and 1.40 +/- 0.61 degrees, respectively, in the control group. Bite block seating error was 2.12 +/- 0.55 degrees in the newly developed instrument and 2.01 +/- 0.49 degrees in the instrument with registration material. Statistical analysis showed no significant difference in the 2 instruments (P > .05).

Conclusion: The prototype of the new instrument reported by the authors can produce almost identical radiographs in vitro with only slight angular errors. Clinical use of the advanced type of the instrument can be expected to show similar results.
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http://dx.doi.org/10.1016/j.tripleo.2004.12.011DOI Listing
July 2005

[Overbite correction with edgewise technique in adult patient].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2004 Jul;33(4):368-9, 374

The Affiliated Stomatological Hospital, College of Medicine, Zhejiang University, Hangzhou 310006, China.

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July 2004

Effects of ohmefentanyl stereoisomers on phosphorylation of cAMP- response element binding protein in cultured rat hippocampal neurons.

Acta Pharmacol Sin 2003 Dec;24(12):1253-8

Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Aim: To define the effects and signal pathways of ohmefentanyl stereoisomers [(-)-cis-(3R,4S,2'R) OMF (F9202), (+)-cis-(3R,4S,2'S) OMF (F9204), and (-)-cis-(3S,4S,2'R) OMF (F9203)] on the phosphorylation of cAMP-response element binding protein (CREB) in cultured rat hippocampal neurons.

Methods: The effects of the three OMF stereoisomers and morphine (Mor) on cAMP accumulation and CREB phosphorylation were monitored by radioimmunoassay and Western blot analysis, respectively.

Results: The three OMF stereoisomers and Mor could all partially inhibit forskolin-stimulated (25 micromol/L, 15 min) cAMP accumulation in a dose-dependent manner and this effect could be reversed by naloxone. F9202, F9204, and Mor could significantly increase CREB phosphorylation from 2.88 to 3.59 folds over control levels after 30-min exposure. This effect was reversed by naloxone, but F9203 failed to increase CREB phosphorylation. KN-62 and staurosporine significantly blocked the opioids- induced CREB phosphorylation, while H-89 and PD 98059 had no effect on the actions.

Conclusion: Mor, F9202, and F9204, which could induce psychological dependence affected via the micro-opioid receptor, stimulated intracellular signal pathways involving Ca2+/calmodulin-dependent protein kinases (CCDPK) and protein kinase C (PKC) pathways, which in turn initiated CREB phosphorylation. F9203, which could not induce dependence, had no effect on CREB phosphorylation in hippocampal neurons. The increased CREB phosphorylation in hippocampal neurons may play a role in opioids dependence.
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December 2003