Publications by authors named "Xian-Yu Liu"

39 Publications

A spinal neural circuitry for converting touch to itch sensation.

Nat Commun 2020 10 8;11(1):5074. Epub 2020 Oct 8.

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2) receive direct Aβ low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2 neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.
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http://dx.doi.org/10.1038/s41467-020-18895-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545208PMC
October 2020

Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors.

Nat Commun 2020 03 13;11(1):1397. Epub 2020 Mar 13.

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Gastrin-releasing peptide (GRP) functions as a neurotransmitter for non-histaminergic itch, but its site of action (sensory neurons vs spinal cord) remains controversial. To determine the role of GRP in sensory neurons, we generated a floxed Grp mouse line. We found that conditional knockout of Grp in sensory neurons results in attenuated non-histaminergic itch, without impairing histamine-induced itch. Using a Grp-Cre knock-in mouse line, we show that the upper epidermis of the skin is exclusively innervated by GRP fibers, whose activation via optogeneics and chemogenetics in the skin evokes itch- but not pain-related scratching or wiping behaviors. In contrast, intersectional genetic ablation of spinal Grp neurons does not affect itch nor pain transmission, demonstrating that spinal Grp neurons are dispensable for itch transmission. These data indicate that GRP is a neuropeptide in sensory neurons for non-histaminergic itch, and GRP sensory neurons are dedicated to itch transmission.
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http://dx.doi.org/10.1038/s41467-020-15230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070094PMC
March 2020

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes.

J Invest Dermatol 2020 08 29;140(8):1524-1532. Epub 2020 Jan 29.

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, USA. Electronic address:

Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis.
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http://dx.doi.org/10.1016/j.jid.2020.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387154PMC
August 2020

NPY2R signaling gates spontaneous and mechanical, but not thermal, pain transmission.

Mol Pain 2019 Jan-Dec;15:1744806919887830

Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.

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http://dx.doi.org/10.1177/1744806919887830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880052PMC
June 2020

Cross-talk between Human Spinal Cord μ-opioid Receptor 1Y Isoform and Gastrin-releasing Peptide Receptor Mediates Opioid-induced Scratching Behavior.

Anesthesiology 2019 08;131(2):381-391

From the Center for the Study of Itch, Departments of Anesthesiology, Psychiatry and Developmental Biology (X.-Y.L., Z.-F.C.) the Division of Obstetric Anesthesiology, Department of Anesthesiology, Barnes Jewish Hospital (Y.G., A.H.), Washington University School of Medicine, St. Louis, Missouri the Mother and Child Anesthesia Unit, Department of Anesthesiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (Y.G.) SpineMore Surgical Associates, St. Louis, Missouri (J.Y.).

Background: Although spinal opioids are safe and effective, pruritus is common and distressing. The authors previously demonstrated in mouse spinal cord that interactions between μ-opioid receptor isoform 1D and gastrin releasing peptide receptor mediate morphine-induced scratch. The C-terminal of 1D inhibits morphine-induced scratch without affecting analgesia. The authors hypothesize that human spinal cord also contains itch-specific μ-opioid receptor isoforms which interact with gastrin releasing peptide receptor.

Methods: Reverse transcription polymerase chain reaction was performed on human spinal cord complimentary DNA from two human cadavers. Calcium responses to morphine (1 μM) were examined using calcium imaging microscopy on human cells (HEK293) coexpressing gastrin releasing peptide receptor and different human μ-opioid receptor isoforms. The authors assessed morphine-induced scratching behavior and thermal analgesia in mice following intrathecal injection of morphine (0.3 nmol) and a transactivator of transcription peptide designed from C-terminal sequences of 1Y isoform (0, 0.1, and 0.4 nmol).

Results: The authors demonstrated 1Y expression in the spinal cord dorsal horn. Morphine administration evoked a calcium response (mean ± SD) (57 ± 13 nM) in cells coexpressing both gastrin releasing peptide receptor and the 1Y isomer. This was blocked by 10 μM naltrexone (0.7 ± 0.4 nM; P < 0.0001), 1 μM gastrin-releasing peptide receptor antagonist (3 ± 2 nM; P < 0.0001), or 200 μM 1Y-peptide (2 + 2 nM; P < 0.0001). In mice, 0.4 nmol 1Y-peptide significantly attenuated morphine-induced scratching behaviors (scratching bouts, vehicle vs. 1Y-peptide) (92 ± 31 vs. 38 ± 29; P = 0.011; n = 6 to 7 mice per group), without affecting morphine antinociception in warm water tail immersion test (% of maximum possible effect) (70 ± 21 vs. 67 ± 22; P = 0.80; n = 6 mice per group).

Conclusions: Human μ-opioid receptor 1Y isomer is a C-terminal splicing variant of Oprm1 gene identified in human spinal cord. Cross-talk between 1Y and gastrin releasing peptide receptor is required for mediating opioid-induced pruritus. Disrupting the cross talk may have implications for therapeutic uncoupling of desired analgesic effects from side effects of opioids.
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http://dx.doi.org/10.1097/ALN.0000000000002776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098053PMC
August 2019

Three and Six Months of Ketogenic Diet for Intractable Childhood Epilepsy: A Systematic Review and Meta-Analysis.

Front Neurol 2019 15;10:244. Epub 2019 Mar 15.

Department of Pediatric Neurology, Children's Hospital of Nanjing Medical University, Nanjing, China.

The ketogenic diet (KD) has been an effective antiepileptic treatment for intractable childhood epilepsy. The appropriate timing to evaluate the effect of KD is 3 months which is still not defined statistically. Therefore, we aim to realistically assess whether spasm remission during the period of 3 months KD can be a prediction index for the therapeutic effect of 6 months treatment. To investigate the duration and effect of the KD therapy for intractable childhood epilepsy, we searched the relevant articles up to May 20, 2018 from PubMed, Cochrane, Embase, Ovid, Web of Science, Google Scholar, and Conference literature. The inclusion criteria were: (i) confirmed cases of intractable childhood epilepsy, (ii) specific 3 and 6 months follow-up time, (iii) classified spasm remission evaluation. The exclusion criteria were: (i) including other therapy, (ii) unspecific follow-up time, (iii) no specific index for seizure reduction. The data extracted by two researchers independently included proportion of KD duration, seizure remission, year of publication, author, study design, and diet varieties. The search strategy included a total of 542 citations, 18 articles were met the criteria with a total of 1,062 patients included in the final analysis. Compared with 3 and 6 months KD treatment, the rate difference of 50% seizure reduction was -0.01(95% CI: -0.09 to 0.06). And 90% seizure reduction was -0.036(95% CI: -0.090 to 0.017) and seizure free was -0.031(95% CI: -0.081 to 0.020). This meta-analysis provides statistical support that a period of 3 months KD can be a prediction index of 6 months duration in term of spasm remission. The 3 months KD can be implemented to evaluate seizure remission timely and provide personalized early support.
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http://dx.doi.org/10.3389/fneur.2019.00244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428709PMC
March 2019

Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

Cell Rep 2018 Apr;23(3):866-877

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated G signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca-independent protein kinase C (PKC)δ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies.
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http://dx.doi.org/10.1016/j.celrep.2018.03.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937707PMC
April 2018

Distinct roles of NMB and GRP in itch transmission.

Sci Rep 2017 11 13;7(1):15466. Epub 2017 Nov 13.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA.

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.
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http://dx.doi.org/10.1038/s41598-017-15756-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684337PMC
November 2017

The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway.

Bosn J Basic Med Sci 2018 Feb 20;18(1):49-54. Epub 2018 Feb 20.

Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.
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http://dx.doi.org/10.17305/bjbms.2017.2044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826674PMC
February 2018

[The Gemological Characteristics of One Kind Turquoise Imitation].

Guang Pu Xue Yu Guang Pu Fen Xi 2016 Aug;36(8):2629-33

It has been a long time that the imitations of turquoise appear in gem market. Pressed dyed carbonate in the early stage and dyed variscite, chalcedony as well as magnesite appeared in succession. These kinds of materials do not have the color and characteristics of natural turquoise. Their physical and optical properties are quite different from natural turquoise. One kind of turquoise imitation newly appears in market is selected to be studied in this paper. The conventional gemological method, infrared absorption spectroscopy and X-ray diffraction were employed to study its mineral compositions, gemological properties and structural characteristics. The results show that: the brecciated structure can be observed and the distribution of the iron wire is very simple on the surface of the sample. Deep blue granules are visible on the surface of blue samples and a few black spots can be observed on the surface of white ones, which are typical indication of pressing process. The blue imitations of turquoise has been stained and pressed. The index of this kind of turquoise imitation range from 1.54 to 1.58, which is lower than that of natural turquoise and it show bluish white fluorescence, which can be used as important evidence to distinguish it with natural turquoise. The data of X-ray diffraction shows the sample mainly consists of enstatite and quartz. The results of infrared absorption spectroscopy show that the absorption spectra of this kind of turquoise imitation is in accordance with the typical absorption peaks of enstatite: the absorption peaks which locates near 1 088 and 799 cm-1 are associated with Si—O, Si—O—Si stretching vibration in quartz; the absorption peaks near 2 947 and 2 882 cm-1 is related with stretching vibration of CH2 of exotic organic resin; the absorption peaks near 1 736 and 1 510 cm-1 are resulted from the bending and stretching vibration of CO and CH2.
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August 2016

Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations.

Sci Signal 2016 07 19;9(437):ra71. Epub 2016 Jul 19.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The transient receptor potential channels (TRPs) respond to chemical irritants and temperature. TRPV1 responds to the itch-inducing endogenous signal histamine, and TRPA1 responds to the itch-inducing chemical chloroquine. We showed that, in sensory neurons, TRPV4 is important for both chloroquine- and histamine-induced itch and that TRPV1 has a role in chloroquine-induced itch. Chloroquine-induced scratching was reduced in mice in which TRPV1 was knocked down or pharmacologically inhibited. Both TRPV4 and TRPV1 were present in some sensory neurons. Pharmacological blockade of either TRPV4 or TRPV1 significantly attenuated the Ca(2+) response of sensory neurons exposed to histamine or chloroquine. Knockout of Trpv1 impaired Ca(2+) responses and reduced scratching behavior evoked by a TRPV4 agonist, whereas knockout of Trpv4 did not alter TRPV1-mediated capsaicin responses. Electrophysiological analysis of human embryonic kidney (HEK) 293 cells coexpressing TRPV4 and TRPV1 revealed that the presence of both channels enhanced the activation kinetics of TRPV4 but not of TRPV1. Biochemical and biophysical studies suggested a close proximity between TRPV4 and TRPV1 in dorsal root ganglion neurons and in cultured cells. Thus, our studies identified TRPV4 as a channel that contributes to both histamine- and chloroquine-induced itch and indicated that the function of TRPV4 in itch signaling involves TRPV1-mediated facilitation. TRP facilitation through the formation of heteromeric complexes could be a prevalent mechanism by which the vast array of somatosensory information is encoded in sensory neurons.
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http://dx.doi.org/10.1126/scisignal.aaf1047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310287PMC
July 2016

Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord.

Mol Pain 2016 11;12. Epub 2016 Apr 11.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA Departments of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA Departments of Psychiatry, Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA Departments of Developmental Biology, Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA

There are substantial disagreements about the expression of gastrin-releasing peptide (GRP) in sensory neurons and whether GRP antibody cross-reacts with substance P (SP). These concerns necessitate a critical revaluation of GRP expression using additional approaches. Here, we show that a widely used GRP antibody specifically recognizes GRP but not SP. In the spinal cord of mice lacking SP (Tac1KO), the expression of not only GRP but also other peptides, notably neuropeptide Y (NPY), is significantly diminished. We detectedGrpmRNA in dorsal root ganglias using reverse transcription polymerase chain reaction, in situ hybridization and RNA-seq. We demonstrated thatGrpmRNA and protein are upregulated in dorsal root ganglias, but not in the spinal cord, of mice with chronic itch. Few GRP(+)immunostaining signals were detected in spinal sections following dorsal rhizotomy and GRP(+)cell bodies were not detected in dissociated dorsal horn neurons. Ultrastructural analysis further shows that substantially more GRPergic fibers form synaptic contacts with gastrin releasing peptide receptor-positive (GRPR(+)) neurons than SPergic fibers. Our comprehensive study demonstrates that a majority of GRPergic fibers are of primary afferent origin. A number of factors such as low copy number ofGrptranscripts, small percentage of cells expressingGrp, and the use of an eGFP GENSAT transgenic as a surrogate for GRP protein have contributed to the controversy. Optimization of experimental procedures facilitates the specific detection of GRP expression in dorsal root ganglia neurons.
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http://dx.doi.org/10.1177/1744806916643724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972254PMC
December 2016

[Study on Vibrational Spectra Characteristics of Gem-Quality Natrolite].

Guang Pu Xue Yu Guang Pu Fen Xi 2015 Aug;35(8):2186-8

Recently, there is a batch of colorless faceted gem-quality natrolite appear in the international jewelry market. In order to provide some information that can help us to distinguish them from the imitations. The infrared spectrometer and Raman spectrometer were employed to study the characteristics of the vibrational spectrum of three natrolite samples in this article. The typical infrared spectra shows that: the absorption region 4000~1200 cm(-1) is induced by stretching vibration of the hydroxyl group, the strong absorption peaks range from 1200~600 cm(-1) are relative with the anti-symmetry and symmetry stretching vibration of tetrahedral T-O bonds (T=Si or Al). The Raman spectra scattering peaks are located in the range of 300~600 and 700~1200 cm(-1). The low intensity Raman scattering spectrum in the range of 300~360 cm(-1) corresponds to the vibration of the water molecules in the crystal. The medium intensity Raman scattering spectrum is assigned to the deformation of SiO4 tetrahedra. The Raman spectra scattering peak at 726 cm(-1) is assigned to the stretching vibration of Al-O; The Si-O stretching vibration displays the Raman spectra scattering peaks at 974, 1038 and 1084 cm(-1).
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August 2015

Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling.

Neuron 2014 Nov 30;84(4):821-34. Epub 2014 Oct 30.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Unlabelled: Central serotonin (5-hydroxytryptophan, 5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5-HT potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Coactivation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca(2+) transients, and action potential firing of GRPR(+) neurons. Immunostaining, biochemical, and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs, and a disruption of crosstalk between 5-HT1A and GRPR may be a useful antipruritic strategy.

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http://dx.doi.org/10.1016/j.neuron.2014.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254557PMC
November 2014

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.

J Neurosci 2014 Sep;34(37):12402-14

Center for the Study of Itch, and Departments of Anesthesiology, Psychiatry, Developmental Biology,

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.
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http://dx.doi.org/10.1523/JNEUROSCI.1709-14.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160775PMC
September 2014

Postnatal maintenance of the 5-Ht1a-Pet1 autoregulatory loop by serotonin in the raphe nuclei of the brainstem.

Mol Brain 2014 Jun 28;7:48. Epub 2014 Jun 28.

Center for the Study of Itch, Washington University School of Medicine, St, Louis 63110, USA.

Background: Despite the importance of 5-HT1A as a major target for the action of several anxiolytics/antidepressant drugs, little is known about its regulation in central serotonin (5-hydroxytryptamine, 5-HT) neurons.

Results: We report that expression of 5-HT1A and the transcription factor Pet1 was impaired in the rostral raphe nuclei of mice lacking tryptophan hydroxylase 2 (Tph2) after birth. The downregulation of Pet1 was recapitulated in 5-Ht1a-/- mice. Using an explant culture system, we show that reduction of Pet1 and 5-HT1A was rescued in Tph2-/- brainstem by exogenous 5-HT. In contrast, 5-HT failed to rescue reduced expression of Pet1 in 5-Ht1a-/- brainstem explant culture.

Conclusions: These results suggest a causal relationship between 5-HT1A and Pet1, and reveal a potential mechanism by which 5-HT1A-Pet1 autoregulatory loop is maintained by 5-HT in a spatiotemporal-specific manner during postnatal development. Our results are relevant to understanding the pathophysiology of certain psychiatric and developmental disorders.
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http://dx.doi.org/10.1186/1756-6606-7-48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086287PMC
June 2014

B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway.

Mol Pain 2014 Jan 18;10. Epub 2014 Jan 18.

Center for the Study of Itch, Washington University School of Medicine Pain Center, St, Louis, MO 63110, USA.

Background: A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968-971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb-/- mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims.

Findings: We were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia.

Conclusions: Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.
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http://dx.doi.org/10.1186/1744-8069-10-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930899PMC
January 2014

Chronic itch development in sensory neurons requires BRAF signaling pathways.

J Clin Invest 2013 Nov;123(11):4769-80

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF(Nav1.8) mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.
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http://dx.doi.org/10.1172/JCI70528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809799PMC
November 2013

Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids.

Cell 2011 Oct;147(2):447-58

Center for the Study of Itch, Washington University School of Medicine Pain Center, St. Louis, MO 63110, USA.

Spinal opioid-induced itch, a prevalent side effect of pain management, has been proposed to result from pain inhibition. We now report that the μ-opioid receptor (MOR) isoform MOR1D is essential for morphine-induced scratching (MIS), whereas the isoform MOR1 is required only for morphine-induced analgesia (MIA). MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, relaying itch information. We show that morphine triggers internalization of both GRPR and MOR1D, whereas GRP specifically triggers GRPR internalization and morphine-independent scratching. Providing potential insight into opioid-induced itch prevention, we demonstrate that molecular and pharmacologic inhibition of PLCβ3 and IP3R3, downstream effectors of GRPR, specifically block MIS but not MIA. In addition, blocking MOR1D-GRPR association attenuates MIS but not MIA. Together, these data suggest that opioid-induced itch is an active process concomitant with but independent of opioid analgesia, occurring via the unidirectional cross-activation of GRPR signaling by MOR1D heterodimerization.
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http://dx.doi.org/10.1016/j.cell.2011.08.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197217PMC
October 2011

Molecular logic circuit based on a multi-state mononuclear platinum(ii) terpyridyl complex.

Phys Chem Chem Phys 2010 Oct 31;12(40):13026-33. Epub 2010 Aug 31.

Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry & Graduate University, the Chinese Academy of Sciences, Beijing 100190, PR China.

A new type of multi-state platinum(ii) terpyridyl acetylide complex: platinum(ii) 4'-(4-dimethylaminophenyl)-2,2' : 6',2''-terpyridyl ferrocenyl acetylide (1), together with its reference complexes: platinum(ii) 4'-(4-methylphenyl)-2,2' : 6',2''-terpyridyl ferrocenyl acetylide (2), platinum(ii) 4'-(4-dimethylaminophenyl)-2,2' : 6',2''-terpyridyl phenyl acetylide (3) and platinum(ii) 4'-(4-methylphenyl)-2,2' : 6',2''-terpyridyl phenyl acetylide (4), are designed and synthesized. UV-vis-NIR absorption and electrochemical studies demonstrate that complex 1 possesses three ordered intraligand charge transfer (ILCT), ligand-to-ligand charge transfer (LLCT) and metal-to-ligand charge transfer (MLCT) states, and the successive modulation of the intramolecular ILCT, LLCT and MLCT states in a single mononuclear platinum(ii) complex 1 is well evidenced by their reference complexes 2-4. More interestingly, a near-infrared absorption band ranging from 720-1000 nm was clearly observed for complexes 1 and 2 upon oxidation of the σ-bonded ferrocene-ethynyl group by Fe(ClO(4))(3), which was tentatively assigned to platinum(ii)-disturbed ligand-to-metal charge transfer (LM'CT) of the ferrocenium group. These promising features allow us to integrate the multiple states to reproduce basic logic operations at the molecular level. A four-state (LLCT, ILCT, MLCT and LM'CT) molecular switch of complex 1 that responds to the stimulation of H(+), Fe(ClO(4))(3) and Zn producing four outputs has been encoded in binary digits. The logic function executed by complex 1 is equivalent to that of a combinational logic circuit integrating seven or eight logic functions as AND, OR, NOT. A three-input-four-output molecular logic circuit has been established.
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http://dx.doi.org/10.1039/c0cp00100gDOI Listing
October 2010

CaMKIIalpha interacts with M4 muscarinic receptors to control receptor and psychomotor function.

EMBO J 2010 Jun 11;29(12):2070-81. Epub 2010 May 11.

Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA.

Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the mammalian brain and are essential for neuronal functions. These receptors are believed to be actively regulated by intracellular signals, although the underlying mechanisms are largely unknown. In this study, we show that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) binds directly and selectively to one of five mAChR subtypes, M4 receptors (M4Rs), at their C-terminal regions of second intracellular loops. This binding relies on Ca(2+) activation of the kinase and leads to the phosphorylation of M4Rs at a specific threonine site (Thr145). Complementary in vivo studies in rat striatal neurons enriched with M4Rs confirm that rising Ca(2+) recruits CaMKIIalpha to M4Rs to potentiate receptor signalling, which controls behavioural sensitivity to dopamine stimulation in an activity-dependent manner. Our data identify a new model of protein-protein interactions. In a Ca(2+)-sensitive manner, CaMKIIalpha regulates M4R efficacy and controls the acetylcholine-dopamine balance in the basal ganglia and also the dynamics of movement.
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http://dx.doi.org/10.1038/emboj.2010.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892372PMC
June 2010

Regulation of dopamine D3 receptors by protein-protein interactions.

Neurosci Bull 2010 Apr;26(2):163-7

Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Saint Luke's Hospital, Kansas City, Missouri 64108, USA.

Galphai/o protein-coupled dopamine D3 receptors (D3Rs) are preferentially expressed in the limbic system, including the nucleus accumbens. This situates the receptor well in the regulation of limbic function and in the pathogenesis of various neuropsychiatric and neurodegenerative disorders. The intracellular domains of the receptor, mainly the large third intracellular loop and the intracellular C-terminal tail, interact with multiple submembranous proteins. These interactions are critical for the control of surface expression of the receptor and the efficacy of receptor signaling. Recently, a synapse-enriched protein kinase, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), has been found to interact with D3R in the above mentioned interaction model. CaMKII directly binds to the N-terminal of the third loop of D3R. This binding is Ca(2+)-dependent and is sustained by the autophosphorylation of the kinase. In rat accumbal neurons, the increase in Ca(2+) level induces the recruitment of CaMKII to D3R, and CaMKII phosphorylates the receptor at a specific serine site. The CaMKII-induced phosphorylation could inhibit the receptor function and further regulate the behavioral response to the psychostimulant cocaine. These findings reveal a prototypic protein association model between a G protein-coupled receptor and CaMKII. Through the dynamic protein-protein interactions, the abundance, turnover cycle, and function of D3R can be regulated by multiple signals and enzymatic proteins.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953790PMC
http://dx.doi.org/10.1007/s12264-010-1016-yDOI Listing
April 2010

Cellular basis of itch sensation.

Science 2009 Sep 6;325(5947):1531-4. Epub 2009 Aug 6.

Departments of Anesthesiology, Psychiatry, and Developmental Biology, Washington University School of Medicine Pain Center, St. Louis, MO 63110, USA.

Itch and pain are two distinct sensations. Although our previous study suggested that gastrin-releasing peptide receptor (GRPR) is an itch-specific gene in the spinal cord, a long-standing question of whether there are separate neuronal pathways for itch and pain remains unsettled. We selectively ablated lamina I neurons expressing GRPR in the spinal cord of mice. These mice showed profound scratching deficits in response to all of the itching (pruritogenic) stimuli tested, irrespective of their histamine dependence. In contrast, pain behaviors were unaffected. Our data also suggest that GRPR+ neurons are different from the spinothalamic tract neurons that have been the focus of the debate. Together, the present study suggests that GRPR+ neurons constitute a long-sought labeled line for itch sensation in the spinal cord.
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http://dx.doi.org/10.1126/science.1174868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786498PMC
September 2009

Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine.

Nat Neurosci 2009 May 6;12(5):602-10. Epub 2009 Apr 6.

Department of Basic Medical Science, University of Missouri Kansas City, USA.

Plastic changes in glutamatergic synapses that lead to endurance of drug craving and addiction are poorly understood. We examined the turnover and trafficking of NMDA receptors and found that chronic exposure to the psychostimulant amphetamine (AMPH) induced selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. This downregulation was a long-lived event and was a result of the destabilization of surface-expressed NR2B caused by accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translated to the modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induced and restoration of NR2B loss prevented behavioral sensitization to AMPH. Our data identify NR2B as an important regulator in the remodeling of excitatory synapses and persistent psychomotor plasticity in response to AMPH.
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http://dx.doi.org/10.1038/nn.2300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749993PMC
May 2009

Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII.

Neuron 2009 Feb;61(3):425-38

Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO 64108, USA.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is central to synaptic transmission. Here we show that synaptic CaMKIIalpha binds to the N-terminal region of the third intracellular loop of the limbic dopamine D3 receptor (D3R). This binding is Ca(2+) sensitive and is sustained by autophosphorylation of CaMKII, providing an unrecognized route for the Ca(2+)-mediated regulation of D3Rs. The interaction of CaMKIIalpha with D3Rs transforms D3Rs into a biochemical substrate of the kinase and promotes the kinase to phosphorylate D3Rs at a selective serine site (S229). In accumbal neurons in vivo, CaMKIIalpha is recruited to D3Rs by rising Ca(2+) to increase the CaMKIIalpha-mediated phosphorylation of D3Rs, thereby transiently inhibiting D3R efficacy. Notably, the D3R inhibition is critical for integrating dopamine signaling to control behavioral sensitivity to the psychostimulant cocaine. Our data identify CaMKIIalpha as a recruitable regulator of dopamine receptor function. By binding and phosphorylating limbic D3Rs, CaMKIIalpha modulates dopamine signaling and psychomotor function in an activity-dependent manner.
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http://dx.doi.org/10.1016/j.neuron.2008.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650276PMC
February 2009

Phosphorylation of group I metabotropic glutamate receptors (mGluR1/5) in vitro and in vivo.

Neuropharmacology 2008 Sep 10;55(4):403-8. Epub 2008 Jun 10.

Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.

Group I metabotropic glutamate receptors (mGluR1 and mGluR5 subtypes) are densely expressed in mammalian brain. They are actively involved in the regulation of normal cellular activity and synaptic plasticity, and are frequently linked to the pathogenesis of various mental illnesses. Like ionotropic glutamate receptors, group I mGluRs are subject to the regulation by protein phosphorylation. Accumulative data demonstrate sufficient phosphorylation of the intracellular mGluR1/5 domains at specific serine/threonine sites by protein kinase C in heterologous cells or neurons, which serves as an important mechanism for regulating the receptor signaling and desensitization. Emerging evidence also shows the significant involvements of G protein-coupled receptor kinases, Ca2+/calmodulin-dependent protein kinase II, tyrosine kinases, and protein phosphatases in controlling the phosphorylation status of group I mGluRs. This review analyzes the recent data concerning group I mGluR phosphorylation and the phosphorylation-dependent regulation of group I mGluR function. Future research directions in this area with newly available high throughput and proteomic approaches are also discussed in the end.
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http://dx.doi.org/10.1016/j.neuropharm.2008.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566896PMC
September 2008

Therapeutic strategies for Parkinson's disease: the ancient meets the future--traditional Chinese herbal medicine, electroacupuncture, gene therapy and stem cells.

Neurochem Res 2008 Oct 11;33(10):1956-63. Epub 2008 Apr 11.

Department of Physiology, Capital Medical University, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing, 100069, People's Republic of China.

In China, it has been estimated that there are more than 2.0 million people suffering from Parkinson's disease, which is currently becoming one of the most common chronic neurodegenerative disorders during recent years. For many years, scientists have struggled to find new therapeutic approaches for this disease. Since 1994, our research group led by Drs. Ji-Sheng Han and Xiao-Min Wang of Neuroscience Research Institute, Peking University has developed several prospective treatment strategies for the disease. These studies cover the traditional Chinese medicine-herbal formula or acupuncture, and modern technologies such as gene therapy or stem cell replacement therapy, and have achieved some original results. It hopes that these data may be beneficial for the research development and for the future clinical utility for treatment of Parkinson's disease.
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http://dx.doi.org/10.1007/s11064-008-9691-zDOI Listing
October 2008

Group I metabotropic glutamate receptor-mediated gene expression in striatal neurons.

Neurochem Res 2008 Oct 20;33(10):1920-4. Epub 2008 Mar 20.

Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.

Group I mGluRs (mGluR1/5) are G-protein-coupled receptors and are abundantly expressed in most of medium spiny projection neurons in the striatum. Recent evidence demonstrates that group I mGluRs are among essential regulators for constitutive and inducible gene expression in host neurons. Upon activation, mGluR1/5 signals activate extracellular signal-regulated kinases (ERKs) which in turn phosphorylate transcription factors such as cAMP response element-binding protein (CREB) and Elk-1, and thereby facilitate immediate early gene and opioid peptide gene expression. The conventional mGluR1/5 signaling cascade (phosphoinositide hydrolysis and intracellular Ca(2+) release) participates in linking mGluR1/5 to ERK. Additionally, the prominent mGluR1/5 adaptor protein Homer contributes to assemble an efficient signaling apparatus connecting mGluR1/5 to gene expression. The mGluR1/5 linkage to transcription also functions in dopamine-stimulated gene expression. Together, the mGluR1/5-mediated gene expression constitutes a transcription-dependent mechanism underlying molecular adaptations and plasticity related to the pathogenesis of various mental illnesses.
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http://dx.doi.org/10.1007/s11064-008-9654-4DOI Listing
October 2008

[Efficacy comparison between morphine sulfate controlled-released tablet and morphine hydrochloride sustained-released tablet in treating cancer pain].

Ai Zheng 2007 Dec;26(12):1357-9

Department of Medical Oncology, Sichuan Provincial Tumor Hospital, Chengdu, Sichuan, 610041, PR China.

Background & Objective: Morphine sulfate controlled-released tablet and morphine hydrochloride sustained-released tablet are preferred medicines for treating moderate-severe cancer pain. There are some differences between the two medicines in their efficacy, metabolism and adverse events. This study was to compare the efficacy and toxicities between morphine sulfate controlled-released tablet and morphine hydrochloride sustained-released tablet in treating moderate-severe cancer pain.

Methods: A total of 121 patients with moderate-severe cancer pain were randomized into two groups: 61 were treated with morphine sulfate controlled-released tablet and 60 were treated with morphine hydrochloride sustained-released tablet. Analgesic efficacy and toxicities of the two medicines were observed.

Results: Of the 61 patients treated with morphine sulfate controlled-released tablet, 12 had moderate pain, 49 had severe pain; the total response rate was 91.80%. Of the 60 patients treated with morphine hydrochloride sustained-released tablet, 13 had moderate pain, 47 had severe pain; the total response rate was 91.67%. There was no significant difference in the efficacy between the two medicines. Digestive system adverse events, including nausea, vomiting and constipation, were more common in morphine hydrochloride sustained-released tablet group than in morphine sulfate controlled-released tablet group (66.66% vs. 34.43%, P<0.05).

Conclusions: Both morphine sulfate controlled-released tablet and morphine hydrochloride sustained-released tablet are safety in treating moderate-severe cancer pain and the toxicities are tolerable. We recommend to take morphine sulfate controlled-released tablet for older patients and the patients with digestive disorders.
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December 2007

Cocaine increases Ras-guanine nucleotide-releasing factor 1 protein expression in the rat striatum in vivo.

Neurosci Lett 2007 Nov 16;427(2):117-21. Epub 2007 Sep 16.

Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.

Psychostimulants activate the Ras-mitogen-activated protein kinase (Ras-MAPK) cascade in the limbic reward circuit and thereby trigger a transcription-dependent mechanism underlying enduring synaptic plasticity related to addictive properties of drugs of abuse. The Ras-specific activator, Ras-guanine nucleotide-releasing factor (Ras-GRF), is predominantly expressed at synapses and is thought to actively regulate Ras-MAPK responses to changing synaptic signals. In this study, a possible influence of cocaine on Ras-GRF gene expression at the protein level in the rat striatum was investigated in vivo. A single systemic injection of cocaine induced an increase in Ras-GRF1 protein levels in both the dorsal (caudoputamen) and ventral (nucleus accumbens) striatum. The increase in Ras-GRF1 proteins was dose-dependent and was a delayed and transient event. In contrast to Ras-GRF1, a closely related Ras-GRF2 showed no change in its protein abundance following cocaine administration. These data identify the Ras activator, Ras-GRF1, although not Ras-GRF2, as a susceptible target to cocaine stimulation in striatal neurons.
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http://dx.doi.org/10.1016/j.neulet.2007.09.010DOI Listing
November 2007