Publications by authors named "Zhou-Feng Chen"

63 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

dmPFC-vlPAG projection neurons contribute to pain threshold maintenance and antianxiety behaviors.

J Clin Invest 2020 12;130(12):6555-6570

Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, China.

The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we show that lesions in the dmPFC induced an algesic and anxious state. Using multiple tracing methods including a rabies-based transsynaptic tracing method, we outlined an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG). Specific activation of the dmPFC/vlPAG neural pathway by optogenetic manipulation produced analgesic and antianxiety effects in a mouse model of chronic pain. Inhibitory neurons in the dmPFC were specifically activated using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of the GABAA receptor (GABAAR) or mGluR1 were applied to the dmPFC, which produced analgesic and antianxiety effects. In summary, the results of our study suggest that the dmPFC/vlPAG neural pathway might participate in the maintenance of pain thresholds and antianxiety behaviors under normal conditions, while silencing or suppressing the dmPFC/vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.
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http://dx.doi.org/10.1172/JCI127607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685740PMC
December 2020

Image-Forming Visual Basis of Empathy for Pain in Mice.

Neurosci Bull 2020 12 20;36(12):1563-1569. Epub 2020 Jun 20.

Institute for Biomedical Sciences of Pain, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.

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http://dx.doi.org/10.1007/s12264-020-00528-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719150PMC
December 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

Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord.

Sci Rep 2019 11 1;9(1):15804. Epub 2019 Nov 1.

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

It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.
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http://dx.doi.org/10.1038/s41598-019-52316-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825123PMC
November 2019

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

mir-1 inhibits migration of gastric cancer cells.

Front Biosci (Landmark Ed) 2020 01 1;25:452-462. Epub 2020 Jan 1.

Department of Gastroenterology, The First affiliated hospital of Wenzhou medical University, 325000, China.

Gastric cancer is the fourth most common malignancy world-wide that bears a high mortality by invasiveness and metastases. To this end, we examined the role of miR-1 in mobility and migration of gastric cancer cells. miR-1 was down-regulated and Sorcin, which supports invasion, was highly expressed in gastric cancer cell lines as compared to the control. The overexpression of miR-1 significantly inhibited the mobility and migration of gastric cancer cells, while, its knockdown exerted an oppoiste effect. In addition, while overexpression of miR-1 suppressed the expression of Sorcin, the siRNA knockdown of Sorcin significantly counteracted the effect of miR-1 inhibitor on cell invasion and migration of gastric cancer cells. A miR-1 mimic decreased while its inhibitor increased the MMP-7 and VEGF required for invasion. Taken together, the findings support the view that miR-1 controls the mobility and migration of gastric cancer cells and might be a therapeutic target for blocking gastric cancer invasion.
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January 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

Enhancement of Aggression Induced by Isolation Rearing is Associated with a Lack of Central Serotonin.

Neurosci Bull 2019 Oct 11;35(5):841-852. Epub 2019 Apr 11.

State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, 100871, China.

Isolation rearing (IR) enhances aggressive behavior, and the central serotonin (5-hydroxytryptamine, 5-HT) system has been linked to IR-induced aggression. However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2 and Lmx1b, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1b mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1b mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1b mice. Our results link the serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.
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http://dx.doi.org/10.1007/s12264-019-00373-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754493PMC
October 2019

Sedated gastroscopy improves detection of gastric polyps.

Exp Ther Med 2018 Oct 26;16(4):3116-3120. Epub 2018 Jul 26.

Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The detection rate of gastric polyps (GPs) is low, improving the detection rate would be good. The present study aimed to evaluate the role of sedated gastroscopy in GP detection. The data of patients who underwent gastroscopic examination from January 2014 to December 2016 at the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China) were retrospectively reviewed. Endoscopic records of 6,195 patients diagnosed with GPs were analyzed. The GP detection rate was 3.12 and 5.11% in the unsedated and sedated gastroscopy group, respectively (P<0.05). Also after stratification by sex, the GP detection rate was significantly higher in the sedated gastroscopy group (P<0.05). In addition, patients aged ≥20 years in the sedated gastroscopy group had a higher GP detection rate than those in the unsedated gastroscopy group (P<0.05). The incidence of cardiac, gastric fundus, gastric body and multiple-site GPs was significantly different between the two groups (P<0.05). GPs ≤0.5 and >0.5 cm were more common in the sedated gastroscopy group than in the unsedated gastroscopy group (P<0.05). The common pathologic types of GPs were gastric fundus gland (52.27%) and hyperplastic polyps (34.74%). In conclusion, the GP detection rate may be improved by inhibition of gastric muscle cramping with sedation.
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http://dx.doi.org/10.3892/etm.2018.6525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125842PMC
October 2018

The combined effect of non-alcoholic fatty liver disease and metabolic syndrome on colorectal carcinoma mortality: a retrospective in Chinese females.

World J Surg Oncol 2018 Aug 10;16(1):163. Epub 2018 Aug 10.

Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China.

Background: This research aimed to investigate whether metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) had both individual and synergistic effects on the prognosis for female colorectal carcinoma (CRC) patients.

Methods: The relationship between CRC prognosis and NAFLD as well as MetS was evaluated in 764 female participants. Based on the NAFLD level, patients were divided into significant NAFLD (SNAFLD), "moderate" and "severe" level, and non-SNAFLD, "non" and "mild" level. All the patients were categorized into four subgroups according to the status of SNAFLD and MetS and then a comparison of CRC prognosis among those four groups was performed.

Results: NAFLD, SNAFLD, and MetS were independent factors for CRC-specific mortality with the adjustment of age and other confounders. The hazard ratio (HR) of CRC-specific mortality in MetS (+) SNAFLD (+) group was significantly higher than that in other three groups. Relative excess risk of interaction (RERI) was 2.203 with 95% CI ranged from 0.197 to 4.210, attributable proportion (AP) was 0.444 with range from 0.222 to 0.667, and synergy index (SI) of 2.256 with 95% CI from 1.252 to 4.065, indicating SNAFLD and MetS had a significant synergic effect on CRC-specific mortality.

Conclusions: SNAFLD and MetS are independent risk factors for CRC-specific mortality in females. Moreover, those two diseases have a synergistic effect on promoting CRC-specific mortality.
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http://dx.doi.org/10.1186/s12957-018-1461-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086998PMC
August 2018

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

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch.

Cell 2017 Sep 7;171(1):217-228.e13. Epub 2017 Sep 7.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Dermatology, Department of Medicine, 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 Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
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http://dx.doi.org/10.1016/j.cell.2017.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658016PMC
September 2017

Response to Comment on "Molecular and neural basis of contagious itch behavior in mice".

Science 2017 07;357(6347)

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

Liljencrantz report the failure of observing contagious itch behavior using mice injected with histamine as the demonstrators. Analysis of their results shows that the histamine model is limited by inadequate frequency and duration of scratching bouts required for contagious itch test. To streamline the contagious itch test, the screen paradigm is highly recommended.
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http://dx.doi.org/10.1126/science.aan5000DOI Listing
July 2017

REG3A promotes the proliferation, migration, and invasion of gastric cancer cells.

Onco Targets Ther 2017 6;10:2017-2023. Epub 2017 Apr 6.

Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.

The mechanism underlying the metastasis of gastric cancer (GC) cells remains elusive. REG3A is considered an oncogene in various cancers, but in GC its role is unclear. Here, we report that the expression of REG3A was significantly increased in the tumor tissues of patients with GC compared with the matched normal tissues. Knockdown of REG3A induced by specific small interfering RNA (siRNA) significantly repressed the proliferation of GC cells for 24 h or 48 h. Moreover, knockdown of REG3A significantly suppressed the migration, invasion, and adhesion of GC cells in vitro. Furthermore, knockdown of REG3A reduced the phosphorylation of JAK2 and STAT3, and altered the messenger RNA (mRNA) and protein expression levels of E-cadherin, Snail, RhoC, MTA1, MMP-2, and MMP-9. Taken together, REG3A is overexpressed in GC and promotes the proliferation, migration, invasion, and adhesion of GC cells by regulating the JAK2/STAT3 signal pathway. REG3A may be a potential therapeutic target for GC.
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http://dx.doi.org/10.2147/OTT.S131443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388263PMC
April 2017

Spinal Mechanisms of Itch Transmission.

Neurosci Bull 2018 Feb 1;34(1):156-164. Epub 2017 Apr 1.

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

Peripheral itch stimuli are transmitted by sensory neurons to the spinal cord dorsal horn, which then transmits the information to the brain. The molecular and cellular mechanisms within the dorsal horn for itch transmission have only been investigated and identified during the past ten years. This review covers the progress that has been made in identifying the peptide families in sensory neurons and the receptor families in dorsal horn neurons as putative itch transmitters, with a focus on gastrin-releasing peptide (GRP)-GRP receptor signaling. Also discussed are the signaling mechanisms, including opioids, by which various types of itch are transmitted and modulated, as well as the many conflicting results arising from recent studies.
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http://dx.doi.org/10.1007/s12264-017-0125-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799115PMC
February 2018

Molecular and neural basis of contagious itch behavior in mice.

Science 2017 03;355(6329):1072-1076

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

Socially contagious itch is ubiquitous in human society, but whether it exists in rodents is unclear. Using a behavioral paradigm that does not entail prior training or reward, we found that mice scratched after observing a conspecific scratching. Molecular mapping showed increased neuronal activity in the suprachiasmatic nucleus (SCN) of the hypothalamus of mice that displayed contagious scratching. Ablation of gastrin-releasing peptide receptor (GRPR) or GRPR neurons in the SCN abolished contagious scratching behavior, which was recapitulated by chemogenetic inhibition of SCN GRP neurons. Activation of SCN GRP/GRPR neurons evoked scratching behavior. These data demonstrate that GRP-GRPR signaling is necessary and sufficient for transmitting contagious itch information in the SCN. The findings may have implications for our understanding of neural circuits that control socially contagious behaviors.
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http://dx.doi.org/10.1126/science.aak9748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502115PMC
March 2017

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

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

Dorsal raphe neurons signal reward through 5-HT and glutamate.

Neuron 2014 Mar;81(6):1360-1374

National Institute of Biological Sciences, Beijing 102206, China; School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address:

The dorsal raphe nucleus (DRN) in the midbrain is a key center for serotonin (5-hydroxytryptamine; 5-HT)-expressing neurons. Serotonergic neurons in the DRN have been theorized to encode punishment by opposing the reward signaling of dopamine neurons. Here, we show that DRN neurons encode reward, but not punishment, through 5-HT and glutamate. Optogenetic stimulation of DRN Pet-1 neurons reinforces mice to explore the stimulation-coupled spatial region, shifts sucrose preference, drives optical self-stimulation, and directs sensory discrimination learning. DRN Pet-1 neurons increase their firing activity during reward tasks, and this activation can be used to rapidly change neuronal activity patterns in the cortex. Although DRN Pet-1 neurons are often associated with 5-HT, they also release glutamate, and both neurotransmitters contribute to reward signaling. These experiments demonstrate the ability of DRN neurons to organize reward behaviors and might provide insights into the underlying mechanisms of learning facilitation and anhedonia treatment.
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http://dx.doi.org/10.1016/j.neuron.2014.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4411946PMC
March 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

Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch.

J Invest Dermatol 2013 Oct 4;133(10):2489-2492. Epub 2013 Apr 4.

Department of Dermatology, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA; Department of Neurobiology & Anatomy, University Wake Forest School of Medicine, Winston Salem, North Carolina, USA; Department of Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA. Electronic address:

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http://dx.doi.org/10.1038/jid.2013.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737283PMC
October 2013

The transcription factor, Lmx1b, promotes a neuronal glutamate phenotype and suppresses a GABA one in the embryonic trigeminal brainstem complex.

Somatosens Mot Res 2012 7;29(1):1-12. Epub 2012 Mar 7.

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

Achieving an appropriate balance between inhibitory and excitatory neuronal fate is critical for development of effective synaptic transmission. However, the molecular mechanisms dictating such phenotypic outcomes are not well understood, especially in the whisker-to-barrel cortex neuraxis, an oft-used model system for revealing developmental mechanisms. In trigeminal nucleus principalis (PrV), the brainstem link in the whisker-barrel pathway, the transcription factor Lmx1b marks glutamatergic cells. In PrV of Lmx1b knockout mice (-/-), initial specification of glutamatergic vs. GABAergic cell fate is normal until embryonic day 14.5. Subsequently, until the day of birth, glutamatergic markers (e.g., VGLUT2) stain significantly fewer PrV neurons, whereas, GABAergic markers (Pax2 and Gad1) stain significantly more PrV cells, notably in Lmx1b null PrV cells. These changes also occurred in Lmx1b/Bax double-/- mice, where PrV cells are rescued from Lmx1b-/- induced apoptosis; thus, effects upon excitatory/inhibitory cell ratios do not reflect a cell death confound. Electroporation-induced ectopic expression of Lmx1b in an array of sites decreases numbers of neurons that express GABAergic markers, but increases VGLUT2+ cell numbers or stain intensity. Thus, Lmx1b is not involved in the initial specification of glutamatergic cell fate, but is essential for maintaining a glutamatergic phenotype. Other experiments suggest that Lmx1b acts to suppress Pax2, a promoter of GABAergic cell fate, in a cell-autonomous manner, which may be a mechanism for maintaining a functional balance of glutamatergic and GABAergic cell types in development.
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http://dx.doi.org/10.3109/08990220.2011.650869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756596PMC
August 2012

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