Biomedical subjects

Zaijie Jim Wang

Publications and source records attributed to Zaijie Jim Wang.

11 recordsLinked to original sources

PubMed2006

Phosphorylation of neurogranin, protein kinase C, and Ca2+/calmodulin dependent protein kinase II in opioid tolerance and dependence.

Activation of Ca2+/calmodulin dependent protein kinase II (CaMKII) and protein kinase C (PKC) are hallmarks of opioid tolerance and dependence. It is not known if the actions of these two kinases are synchronized by a common mechanism in opioid tolerance and dependence. Neurogranin (Ng), through mechanisms such as phosphorylation, has been previously proposed to regulate the activities of these protein kinases. We examined the phosphorylation status of neurogranin in mice that were made tolerant to opioids by morphine (100 mg/kg, s.c.). Increase in phosphorylation of neurogranin was found both in brains and spinal cords of morphine-treated mice, as compared to the untreated baseline or saline-treated mice. The effect appeared to correlate with the changes in the activities of PKC and CaMKII, and with the development of opioid tolerance and dependence. We have found that neurogranin activity is regulated in opioid tolerance and dependence. Neurogranin may, therefore, provide a potential mechanism interacting with both CaMKII and PKC in opioid tolerance and dependence.

Analgesics, Opioid↗

PubMed2006

Phosphorylation: a molecular switch in opioid tolerance.

Protein phosphorylation is a key posttranslational modification mechanism controlling the conformation and activity of many proteins. Increasing evidence has implicated an essential role of phosphorylation by several major protein kinases in promoting and maintaining opioid tolerance. We review some of the most recent studies on protein kinase C (PKC), cyclic AMP dependent protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase G (PKG), and G protein receptor kinase (GRK). These kinases act as the molecular switches to modulate opioid tolerance. Pharmacological interventions at one or more of the protein kinases and phosphatases may provide valuable strategies to improve opioid analgesia by attenuating tolerance to these drugs.

Animals↗

PubMed2006

Attenuation of opioid tolerance by antisense oligodeoxynucleotides targeting neurogranin.

Neurogranin is capable of regulating protein kinase C and Ca2+/calmodulin-dependent protein kinase II. In this study, we examined the role of neurogranin in opioid tolerance. Increased phosphorylation of neurogranin was found in opioid tolerance. Opioid tolerance was absent in morphine (100 mg/kg)-treated mice that were also pretreated with neurogranin antisense oligodeoxynucleotides (2 microg/day, i.c.v. for 3 days). The behavioral effect correlated with the decreased expression of neurogranin. These data suggest that neurogranin may be critical in the development of opioid tolerance.

Analgesics, Opioid↗

PubMed2006

Reversal of morphine antinociceptive tolerance and dependence by the acute supraspinal inhibition of Ca(2+)/calmodulin-dependent protein kinase II.

Previous studies have suggested that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) can modulate opioid tolerance and dependence via its action on learning and memory. In this study, we examined whether CaMKII could directly regulate opioid tolerance and dependence. CaMKII activity was increased after the treatment with morphine (100 mg/kg s.c. or 75 mg s.c. of morphine/pellet/mouse); the effect exhibited a temporal correction with the development of opioid tolerance and dependence. In mice treated with morphine (100 mg/kg s.c.), morphine tolerance and dependence developed in 2 to 6 h. An acute supraspinal administration of KN93 [2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)], a CaMKII inhibitor, was able to dose-dependently reverse the already-established antinociceptive tolerance to morphine (p < 0.001 for 15-30 nmol; not significant for 5 nmol). KN92 [2-[N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine] (30 nmol i.c.v.), a kinase-inactive analog of KN93, did not affect opioid tolerance. Neither KN92 nor KN93 affected basal nociception or acute morphine antinociception (1-10 nmol i.c.v.). Likewise, dependence on morphine was abolished by the acute administration of KN93, but not KN92, in a dose-dependent manner. Pretreatment of mice with KN93 also prevented the development of morphine tolerance and dependence. The effect of acute CaMKII inhibition was not limited to the particular experimental model, because KN93 also acutely reversed the established opioid tolerance and dependence in mice treated with morphine (75 mg/pellet/mouse s.c.) for 6 days. Taken together, these data strongly support the hypothesis that CaMKII can act as a key and direct factor in promoting opioid tolerance and dependence. Identifying such a direct mechanism may be useful for designing pharmacological treatments for these conditions.

Analgesics, Opioid↗

PubMed2006

Involvement of endothelin in morphine tolerance in neuroblastoma (SH-SY5Y) cells.

Long-term use of morphine in pain management leads to adverse effects, such as development of antinociceptive tolerance. We have previously shown the involvement of central endothelin (ET) mechanisms in morphine analgesia and development of tolerance in vivo. The present study was conducted to investigate the in vitro mechanism of interaction of the ET(A) receptor antagonist, BMS182874, and morphine during acute and chronic morphine tolerance in SH-SY5Y cells. SH-SY5Y cells were exposed to acute and chronic treatment with vehicle, morphine, ET-1, BMS182874, or morphine plus BMS182874. Activation of G-protein-coupled receptors in SH-SY5Y cells was determined using [35S]GTPgammaS binding assays. Acute morphine treatment produced a concentration-dependent increase in GTP binding. Median effective concentration (EC50) values were significantly decreased after acute morphine treament, suggesting sensitization of opioid receptors. Chronic morphine treatment produced a lower maximal response of GTP binding compared with both control (vehicle treated) and acute morphine treatment, indicating uncoupling of G-proteins. Acute and chronic exposure of cells to ET-1 did not affect changes in ET-1-induced GTP binding. BMS182874 treatment alone (acute or chronic) did not produce G-protein activation. However, in cells chronically cotreated with 10 microM morphine and 1 microM BMS182874, morphine-induced GTP stimulation was significantly higher than control (vehicle treated). The EC50 value after control treatment was 414 nM, and was significantly increased in chronically morphine-treated cells (>1000 nM ). However, the EC50 value in cells receiving a chronic treatment of BMS182874 and 63 nM morphine was significantly reduced compared with control (vehicle treated) and chronic morphine treatment. ET(A) antagonists significantly enhance the coupling of G-protein to opioid receptors. Therefore, we propose that restoration of morphine antinociception by ET(A) antagonists in morphine-tolerant animals is likely via a G-protein mediated mechanism.

Analgesics, Opioid↗

PubMed2005

Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance.

Calcium/calmodulin dependent protein kinase II (CaMKII) has been shown to play an important role in the generation and maintenance of opioid tolerance. In this study, trifluoperazine was studied for its effect on morphine tolerance in mice. Acute treatment with trifluoperazine (0.5 mg/kg, i.p.) completely reversed the established antinociceptive tolerance to morphine. Pretreatment with trifluoperazine also significantly attenuated the development of antinociceptive tolerance (p<0.01). Morphine induced a significant up-regulation of supraspinal and spinal CaMKII activity in tolerant mice, which was abolished after the pretreatment or acute treatment with trifluoperazine. These data suggested that trifluoperazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting CaMKII. Since trifluoperazine has been safely used as an antipsychotic drug, we propose that the drug should be studied in humans for the prevention and treatment of opioid tolerance and addiction.

Administration, Oral↗

PubMed2005

Targeted drug delivery crossing cytoplasmic membranes of intended cells via ligand-grafted sterically stabilized liposomes.

In this study, we tested whether sterically stabilized liposomes (SSL) with surface ligands specific for the mu opioid receptor (MOR) can actively target MOR-expressing cells. Dermorphin, a selective MOR agonist, was conjugated to DSPE-PEG(3400) to obtain DSPE-PEG(3400)-dermorphin. Dermorphin-grafted SSL (dermorphin-SSL) was prepared by thin-film rehydration-extrusion and post-insertion method. DSPE-PEG(3400)-dermorphin and dermorphin-SSL retained the affinity to MOR as determined by receptor binding assay using [(3)H]DAMGO, whereas plain SSL without surface ligands showed no binding to the receptor. Cellular uptake of cholesteryl BODIPY encapsulated dermorphin-SSL was studied by microplate spectrofluorometry as well as fluorescent and confocal microscopy. Significant fluorescence signal was observed inside CHO-hMOR cells after the treatment with dermorphin-SSL, indicative of MOR-mediated endocytosis. In contrast, no uptake of dermorphin-SSL was found in naive CHO cells or CHO-hDOR cells that lack MOR. Taken together, these results demonstrate that dermorphin-SSL delivery system is capable of targeting intracellular components of MOR-expressing cells. Such a system may be applied to carry pharmaceutical agents to achieve region-specific delivery of analgesics and/or to attenuate side effects associated with opioids.

Animals↗

PubMed2003

Animal and cellular models of chronic pain.

Chronic pain, especially neuropathic pain and cancer pain, is often not adequately treated by currently available analgesics. Animal models provide pivotal systems for preclinical study of pain. This article reviews some of the most widely used or promising new models for chronic pain. Partial spinal ligation, chronic constriction injury, and L5/L6 spinal nerve ligation represent three of the best characterized rodent models of peripheral neuropathy. Recently, several mouse and rat bone cancer pain models have been reported. Primary or permanent cultures of sensory neurons have been established to study the molecular mechanism of pain, especially for neurotransmitter release and signal transduction. The emerging gene microarray, genomics and proteomics methods may be applied to throughly characterize these cells. Each model is uniquely created with distinct mechanisms, it is therefore essential to report and interpret results in the context of a specific model.

Animals↗

PubMed2003

Reversal of morphine antinociceptive tolerance by acute spinal inhibition of Ca(2+)/calmodulin-dependent protein kinase II.

It has been reported that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) can modulate opioid tolerance via its action on learning and memory. In this study, we examine if CaMKII can directly affect opioid tolerance. We found that spinal CaMKII activity was increased in rats tolerant to morphine. In these rats, acute spinal administration of 2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) (KN93), a CaMKII inhibitor, was able to reverse the already-established antinociceptive tolerance. These results suggest that CaMKII may directly promote opioid tolerance.

Analgesics, Opioid↗

PubMed2002

Bioinformatic analysis of the human mu opioid receptor (OPRM1) splice and polymorphic variants.

Mu opioid receptor (OPRM1), a member of the G-protein coupled receptor superfamily, mediates the analgesic and euphoric effects of opioid drugs. The sequences of OPRM1 cDNA and reported splice variants were used to search the public and Celera genomic databases. The matched sequences were analyzed to assemble an OPRM1 genomic contig. Human OPRM1 gene was estimated to span at least 90 kb in the chromosome 6q24-25 region. Four coding exons are separated by 3 introns. While intron 2 has only 773 bp, these databases for the first time provide the precise length of and other information about long introns 1 and 3, containing 50 and 27 kb, respectively. When a consensus exon/intron splice junction at the end of the coding exon 3 was not utilized, it may have resulted in continuous translation of the exon to yield the splice variant OPRM1A. The study did not identify human orthologs of other OPRM1 variants that had been reported for mouse OPRM1, although several proposed exons were found to be included in mouse genomic clones. Single nucleotide polymorphisms in the OPRM1 gene were also analyzed and summarized, which could provide potential polymorphic markers for molecular genetic studies.

Alternative Splicing↗

PubMedDate not supplied

GABAergic phthalide dimers from Angelica sinensis (Oliv.) Diels.

The methanol extract of Angelica sinensis (Oliv.) Diels roots (Dang Gui) has been shown to exhibit competitive binding to the GABAa receptor, suggesting the presence of GABAergic ligands. Chromatographic fractionation of the methanol extract led to the isolation of two GABAergic dimeric phthalides 1 and 2. Gelispirolide (1) was elucidated as a new phthalide dimer composed of a Z-ligustilide and a Z-butylidenephthalide unit on the basis of spectroscopic approaches including one- and two-dimensional NMR, HRESIMS and HRESIMS-MS. Compound 2 was identified as the known dimeric phthalide, riligustilide, by comparison of its spectroscopic data with literature values. Its dimeric linkage and stereochemistry were ascertained by a single crystal X-ray diffraction experiment. Both dimers 1 and 2 were found to be active in an in vitro GABAa receptor-binding assay with IC50 values of 29 and 24 microM, respectively.

Angelica sinensis↗