Publications by authors named "Yun-Qing Li"

150 Publications

The perceptions of anatomy teachers for different majors during the COVID-19 pandemic: a national Chinese survey.

Med Educ Online 2021 Dec;26(1):1897267

During the spring semester of 2020, medical school anatomists in China were forced by the COVID-19 pandemic to transition from face-to-face educators or part-time online educators to full-time online educators. This nationwide survey was conducted to assess online anatomy education during the pandemic for medical students from nonclinical medicine and clinical medicine majors at medical schools in China via WeChat. The total of 356 responders included 293 responders from clinical medicine and 63 respondents from nonclinical medicine majors (i.e., 21 from preventive medicine, 13 from stomatology, and 29 from traditional Chinese medicine). The survey results showed that several aspects of online anatomy education were quite similar in clinical and nonclinical majors' classes, including theoretical and practical sessions, active learning, assessments and evaluations. However, there were statistically significant differences in class size, implementation of active learning activities prior to the pandemic, and the evaluation of the effectiveness of online learning during the pandemic, between clinical and nonclinical medicine majors. These results indicated that, compared with teachers of anatomy courses in clinical medicine, teachers of nonclinical medicine majors using online learning in medical schools in China had relatively poor preparation for online learning in response to the unforeseen pandemic.
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http://dx.doi.org/10.1080/10872981.2021.1897267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971280PMC
December 2021

Projecting neurons in spinal dorsal horn send collateral projections to dorsal midline/intralaminar thalamic complex and parabrachial nucleus.

Brain Res Bull 2021 Apr 27;169:184-195. Epub 2021 Jan 27.

Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, 710032, China; Department of Anatomy, Basic Medical College, Zhengzhou University, Zhengzhou, 450001, China; Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province, Haikou, China. Electronic address:

Itch is an annoying sensation that always triggers scratching behavior, yet little is known about its transmission pathway in the central nervous system. Parabrachial nucleus (PBN), an essential transmission nucleus in the brainstem, has been proved to be the first relay station in itch sensation. Meanwhile, dorsal midline/intralaminar thalamic complex (dMITC) is proved to be activated with nociceptive stimuli. However, whether the PBN-projecting neurons in spinal dorsal horn (SDH) send collateral projections to dMITC, and whether these projections involve in itch remain unknown. In the present study, a double retrograde tracing method was applied when the tetramethylrhodamine-dextran (TMR) was injected into the dMITC and Fluoro-gold (FG) was injected into the PBN, respectively. Immunofluorescent staining for NeuN, substance P receptor (SPR), substance P (SP), or FOS induced by itch or pain stimulations with TMR and FG were conducted to provide morphological evidence. The results revealed that TMR/FG double-labeled neurons could be predominately observed in superficial laminae and lateral spinal nucleus (LSN) of SDH; Meanwhile, most of the collateral projection neurons expressed SPR and some of them expressed FOS in acute itch model induced by histamine. The present results implicated that some of the SPR-expressing neurons in SDH send collateral projections to the dMITC and PBN in itch transmission, which might be involved in itch related complex affective/emotional processing to the higher brain centers.
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http://dx.doi.org/10.1016/j.brainresbull.2021.01.012DOI Listing
April 2021

Projections from the lateral parabrachial nucleus to the lateral and ventral lateral periaqueductal gray subregions mediate the itching sensation.

Pain 2021 Jan 12. Epub 2021 Jan 12.

Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China Department of Anatomy, Histology and Embryology, ZunYi Medical University, ZunYi 563006, China Cadet Brigade, The Fourth Military Medical University, Xi'an 710032, China Department of Anatomy, Basic Medical College, Zhengzhou University, Zengzhou 450001, China Department of Human Anatomy, College of Basic Medicine, Dali 671000, China.

Abstract: Lateral and ventral lateral subregions of the periaqueductal gray (l/vlPAG) have been proved to be pivotal components in descending circuitry of itch processing, and their effects are related to the subclassification of neurons that were meditated. In the present study, lateral parabrachial nucleus (LPB), one of the most crucial relay stations in the ascending pathway, was taken as the input nucleus to examine the modulatory effect of l/vlPAG neurons that received LPB projections. Anatomical tracing, chemogenetic, optogenetic and local pharmacological approaches were utilized to investigate the participation of the LPB-l/vlPAG pathway in itch and pain sensation in mice. First, morphological evidence for projections from vesicular glutamate transporter-2 (VGluT2)-containing neurons in the LPB to l/vlPAG involved in itch transmission has been provided. Furthermore, chemogenetic and optogenetic activation of the LPB-l/vlPAG pathway resulted in both antipruritic effect and analgesic effect, whereas pharmacogenetic inhibition strengthened nociceptive perception without affecting spontaneous scratching behavior. Finally, in vivo pharmacology was combined with optogenetics which revealed that AMPA receptor-expressing neurons in l/vlPAG might play a more essential role in pathway modulation. These findings provide a novel insight about the connections between two prominent transmit nuclei, LPB and l/vlPAG, in both pruriceptive and nociceptive sensations, and deepen the understanding of l/vlPAG modulatory roles in itch sensation by chosen LPB as source of ascending efferent projections.
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http://dx.doi.org/10.1097/j.pain.0000000000002193DOI Listing
January 2021

Gross Anatomy Education in China during the Covid-19 Pandemic: A National Survey.

Anat Sci Educ 2021 Jan 23;14(1):8-18. Epub 2020 Dec 23.

Department of Histology and Embryology, Key Laboratory for Regenerative Medicine of the Ministry of Education, Medical College, Jinan University, Guangzhou, People's Republic of China.

The Covid-19 pandemic launched the use of online courses in Chinese medical schools during February 2020. To evaluate the state of gross anatomy education in China during the pandemic, a nationwide survey was conducted through convenience sampling by email or respondent invitations on social media. A total of 359 questionnaires were received from the respondents. The first response from a given school was included in the study to represent that school, thus, 77 questionnaires were used for analyses. Schools represented were from all provinces in mainland China as well as Hong Kong and Macao. The survey found that before the pandemic, 74.0% and 33.8% of the 77 schools conducted online theoretical and practical sessions, respectively, on gross anatomy, and 36 (46.8% of 77) had temporarily suspended practical sessions at the time the survey was conducted. Body donation programs were also affected with 26.0% and 27.3% of the 77 schools having suspended donation programs or saw a decreased number of donations. During the pandemic, 40.3% of the 77 schools kept or initiated the implementation of active learning, and online assessment was continued in 49.4% of the 77 medical schools. Another 26 (33.8%) schools initiated online assessment during the pandemic. A total of 359 answers were included for the analysis of the "teachers' perception of the online teaching experience." Over half (51.0%) of the 359 responded teachers were very statisfied or satisfied with the effectiveness of online teaching during the pandemic. A total of 36.2% of these respondents preferred to implement online teaching of theoretical sessions after the pandemic, and 89 (24.8%) teachers were keen to return to traditional face-to-face anatomy education.
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http://dx.doi.org/10.1002/ase.2036DOI Listing
January 2021

A Neural Circuit from Thalamic Paraventricular Nucleus to Central Amygdala for the Facilitation of Neuropathic Pain.

J Neurosci 2020 10 21;40(41):7837-7854. Epub 2020 Sep 21.

Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China

As one of the thalamic midline nuclei, the thalamic paraventricular nucleus (PVT) is considered to be an important signal integration site for many descending and ascending pathways that modulate a variety of behaviors, including feeding, emotions, and drug-seeking. A recent study has demonstrated that the PVT is implicated in the acute visceral pain response, but it is unclear whether the PVT plays a critical role in the central processing of chronic pain. Here, we report that the neurons in the posterior portion of the PVT (pPVT) and their downstream pathway are involved in descending nociceptive facilitation regarding the development of neuropathic pain conditions in male rats. Lesions or inhibition of pPVT neurons alleviated mechanical allodynia induced by spared nerve injury (SNI). The excitability of pPVT-central amygdala (CeA) projection neurons was significantly increased in SNI rats. Importantly, selective optogenetic activation of the pPVT-CeA pathway induced obvious mechanical hypersensitivity in naive rats. In addition, we used rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques to define a novel neuronal circuit in which glutamatergic neurons in the vlPAG were the target of the pPVT-CeA descending facilitation pathway. Our data suggest that this pPVT-CeA-vlPAG circuit mediates central mechanisms of descending pain facilitation underlying persistent pain conditions. Studies have shown that the interactions between the posterior portion of the thalamic paraventricular nucleus (pPVT) and central amygdala (CeA) play a critical role in pain-related emotional regulation. However, most reports have associated this circuit with fear and anxiety behaviors. Here, an integrative approach of behavioral tests, electrophysiology, and immunohistochemistry was used to advance the novel concept that the pPVT-CeA pathway activation facilitates neuropathic pain processing. Using rabies virus (RV)-based and cell-type-specific retrograde transsynaptic tracing techniques, we found that glutamatergic neurons in the vlPAG were the target of the pPVT-CeA pathway. Thus, this study indicates the involvement of a pPVT-CeA-vlPAG pathway in a descending facilitatory mechanism underlying neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2487-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548696PMC
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

Involvement of the Ventrolateral Periaqueductal Gray Matter-Central Medial Thalamic Nucleus-Basolateral Amygdala Pathway in Neuropathic Pain Regulation of Rats.

Front Neuroanat 2020 21;14:32. Epub 2020 Jul 21.

Department of Human Anatomy, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.

The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the ventrolateral periaqueductal gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral test results showed that a CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia 4, 6, and 8 days after spared nerve injury (SNI) surgery, with the symptoms returning after 10 days. Morphological studies revealed that: (1) the CM received afferents from vlPAG and sent efferents to BLA, indicating that an indirect vlPAG-CM-BLA pathway exists; (2) such CM-BLA projections were primarily excitatory glutamatergic neurons as revealed by fluorescence hybridization; (3) the fibers originated from the CM-formed close contacts with both excitatory and inhibitory neurons in the BLA; and (4) BLA-projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers from vlPAG, suggesting that the vlPAG-CM-BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG-CM-BLA indirect pathway was further confirmed using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidence that the indirect vlPAG-CM-BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.
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http://dx.doi.org/10.3389/fnana.2020.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394700PMC
July 2020

Expression and functional characterization of transient receptor potential vanilloid 4 in the dorsal root ganglion and spinal cord of diabetic rats with mechanical allodynia.

Brain Res Bull 2020 09 30;162:30-39. Epub 2020 May 30.

Department of Anatomy, Histology and Embryology & K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical University, Xi'an, China; Department of Human Anatomy, College of Basic Medicine, Dali University, Dali, China. Electronic address:

Diabetic mechanical allodynia (DMA) is a common manifestation in patients with diabetes mellitus, and currently, no effective treatment is available. Transient receptor potential vanilloid 4 (TRPV4) is involved in mechanical hypersensitivity resulting from varying aetiologies in animal, but its expression pattern during DMA and whether it contributes to this condition are still unclear. We investigated the spatial and temporal expression patterns of TRPV4 in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) by qRT-PCR, Western blotting and immunofluorescence assays. The pathophysiological role of TRPV4 in DMA was also investigated by intrathecal application of the TRPV4 selective antagonist HC-067047 or the agonist GSK1016790A. The results showed that both the mRNA and protein levels of TRPV4 were strikingly upregulated on day 14 in the rats with DMA. The increase in TRPV4 was mainly observed in the soma and central processes of calcitonin gene-related peptide (CGRP)- or neurofilament 200 kDa (NF200)-containing DRG neurons. Both single and repetitive intrathecal applications of HC-067047 (400 ng/kg) significantly alleviated mechanical allodynia in the rats with DMA, whereas a single application of GSK1016790A (200 ng/kg) aggravated mechanical allodynia. The present data suggest that TRPV4 undergoes expression changes that are associated with mechanical hypersensitivity in diabetic rats. TRPV4 may be a new molecular target for developing a clinical strategy to treat this intractable neuropathic pain.
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http://dx.doi.org/10.1016/j.brainresbull.2020.05.010DOI Listing
September 2020

Enkephalinergic Circuit Involved in Nociceptive Modulation in the Spinal Dorsal Horn.

Neuroscience 2020 03 7;429:78-91. Epub 2020 Jan 7.

Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, China; Joint Laboratory of Neuroscience at Hainan Medical University and The Fourth Military Medical University, Hainan Medical University, Haikou, China. Electronic address:

Enkephalin (ENK) has been implicated in pain modulation within the spinal dorsal horn (SDH). Revealing the mechanisms underlying ENK analgesia entails the anatomical and functional knowledge of spinal ENK-ergic circuits. Herein, we combined morphological and electrophysiological studies to unravel local ENK-ergic circuitry within the SDH. First, the distribution pattern of spinal ENK-ergic neurons was observed in adult preproenkephalin (PPE)-GFP knock-in mice. Next, the retrograde tracer tetramethylrhodamine (TMR) or horseradish peroxidase (HRP) was injected into the parabrachial nucleus (PBN) in PPE-GFP mice. Immunofluorescent staining showed I-isolectin B4 (IB4) labeled non-peptidergic afferents were in close apposition to TMR-labeled PBN-projecting neurons within lamina I as well as PPE-immunoreactivity (-ir) neurons within lamina II. Some TMR-labeled neurons were simultaneously in close association with both IB4 and PPE-ir terminals. Synaptic connections of these components were further confirmed by electron microscopy. Finally, TMR was injected into the PBN in adult C57BL/6 mice. Whole-cell patch recordings showed that δ-opioid receptor (DOR) agonist, [D-Pen]-enkephalin (DPDPE, 1 µM), significantly reduced the frequency of miniature excitatory postsynaptic current (mEPSC) and decreased the activity of TMR-labeled neurons. In conclusion, spinal ENKergic neurons receive direct excitatory inputs from primary afferents, which might be directly recruited to release ENK under the condition of noxious stimuli; ENK could inhibit the glutamatergic transmission towards projecting neurons via presynaptic and postsynaptic DORs. These morphological and functional evidence may explain the mechanisms underlying the analgesic effects exerted by ENK within the SDH.
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http://dx.doi.org/10.1016/j.neuroscience.2019.12.020DOI Listing
March 2020

Systemic Injection of Thalidomide Prevent and Attenuate Neuropathic Pain and Alleviate Neuroinflammatory Response in the Spinal Dorsal Horn.

J Pain Res 2019 29;12:3221-3230. Epub 2019 Nov 29.

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

Background And Objective: Thalidomide (Tha) has been shown to exert immunomodulatory and anti-inflammatory properties. Whether Tha can alleviate spinal nerve ligation (SNL)-induced neuropathic pain (NP) is still unclear. This study aimed to investigate the therapeutic effect of Tha on the SNL-induced NP and further explore the potential analgesic mechanisms of Tha.

Methods: The effects of Tha on SNL-induced mechanical allodynia were assessed by pain behavioral testing. The expressions of the astrocyte marker glial fibrillary acidic protein (GFAP) and the microglia marker Iba1 in the spinal dorsal horn were evaluated by immunofluorescence histochemistry. Protein expressions of the tumor necrosis factor alpha (TNF-α) in the spinal dorsal horn were tested by Western blot assay. Data were analyzed using one-way ANOVA or two-way ANOVA.

Results: By the pretreatment with a single intraperitoneal injection, the PWMT in SNL+Tha group was significantly increased from day 1 to day 2 after SNL ( < 0.05 compared with SNL+Veh group). By the posttreatment with a single intraperitoneal injection, the PWMT in SNL+Tha group was also significantly increased from day 3 to day 4 after SNL ( < 0.05 compared with SNL+Veh group). By the posttreatment with multiple intraperitoneal injection, both the PWMT and the PWTL in SNL+Tha group were similarly significantly increased from day 3 to day 14 after SNL ( < 0.05 compared with SNL+Veh group). Furthermore, the GFAP and Iba1 expressions and TNF-α levels of the ipsilateral spinal dorsal horn in SNL+Tha group were significantly weaker from day 3 to day 14 after SNL than those in SNL+Veh group ( < 0.05).

Conclusion: Tha can significantly alleviate NP induced by SNL. The analgesic mechanism may be related to inhibition of astrocyte and microglia activation as well as down-regulation of TNF-α levels in the spinal dorsal horn.
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http://dx.doi.org/10.2147/JPR.S213112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896366PMC
November 2019

Litorilituus lipolyticus sp. nov., isolated from intertidal sand of the Yellow Sea in China, and emended description of Colwellia asteriadis.

Antonie Van Leeuwenhoek 2020 Apr 7;113(4):449-458. Epub 2019 Nov 7.

Department of Pathogenic Biology, Jining Medical University, Jining, 272067, Shandong, People's Republic of China.

A Gram-stain negative, rod-shaped, aerobic, oxidase-positive and catalase-weakly positive bacterial strain with polar or subpolar flagellum, designated RZ04, was isolated from an intertidal sand sample collected from a coastal area of the Yellow Sea, China. The organism was observed to grow optimally at 25 °C and pH 6.5-7.0 with 2% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain RZ04 was closely related to Colwellia asteriadis (similarity 96.9%) and Litorilituus sediminis (similarity 96.8%), and 94.4-96.4% sequence similarities to other type strains of species of the genera belonged to the family Colwelliaceae. The dominant fatty acids of strain RZ04 were determined to be Cω8c, Cω8c, C and summed feature 3 (Cω6c and/or Cω7c), and the predominant isoprenoid quinone was determined to be quinone 8 (Q-8). Phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminophospholipid and four unidentified lipids were determined to be the major constituents of the polar lipids. The genome of strain RZ04 is 4.14 Mbp with a G + C content of 37.4 mol%. A total of 3631 genes are predicted, with 3531 protein-coding genes, 75 RNA genes and 25 pseudogenes. Based on phenotypic, genotypic and phylogenetic analysis, strain RZ04 is considered to represent a novel species in the genus Litorilituus, for which the name Litorilituus lipolyticus is proposed. The type strain is RZ04 (= MCCC 1K03616 = KCTC 62835). An emended description of Colwellia asteriadis is also provided.
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http://dx.doi.org/10.1007/s10482-019-01355-8DOI Listing
April 2020

Nucleus tractus solitarius mediates hyperalgesia induced by chronic pancreatitis in rats.

World J Gastroenterol 2019 Oct;25(40):6077-6093

Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.

Background: Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP). We hypothesized that the nucleus tractus solitarius (NTS), a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn, plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP.

Aim: To investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis.

Methods: CP was induced by the intraductal injection of trinitrobenzene sulfonic acid (TNBS) in rats. Pancreatic hyperalgesia was assessed by referred somatic pain filament assay. Neural activation of the NTS was indicated by immunohistochemical staining for Fos. Basic synaptic transmission within the NTS was assessed by electrophysiological recordings. Expression of vesicular glutamate transporters (VGluTs), N-methyl-D-aspartate receptor subtype 2B (NR2B), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1 (GluR1) was analyzed by immunoblotting. Membrane insertion of NR2B and GluR1 was evaluated by electron microscopy. The regulatory role of the NTS in visceral hypersensitivity was detected pharmacological approach and chemogenetics in CP rats.

Results: TNBS treatment significantly increased the number of Fos-expressing neurons within the caudal NTS. The excitatory synaptic transmission was substantially potentiated within the caudal NTS in CP rats (frequency: 5.87 ± 1.12 Hz in CP rats 2.55 ± 0.44 Hz in sham rats, < 0.01; amplitude: 19.60 ± 1.39 pA in CP rats 14.71 ± 1.07 pA in sham rats; < 0.01). CP rats showed upregulated expression of VGluT2, and increased phosphorylation and postsynaptic trafficking of NR2B and GluR1 within the caudal NTS. Blocking excitatory synaptic transmission the AMPAR antagonist CNQX and the NMDAR antagonist AP-5 microinjection reversed visceral hypersensitivity in CP rats (abdominal withdraw threshold: 7.00 ± 1.02 g in CNQX group, 8.00 ± 0.81 g in AP-5 group and 1.10 ± 0.27 g in saline group, < 0.001). Inhibiting the excitability of NTS neurons chemogenetics also significantly attenuated pancreatic hyperalgesia (abdominal withdraw threshold: 13.67 ± 2.55 g in Gi group, 2.00 ± 1.37 g in Gq group, and 2.36 ± 0.67 g in mCherry group, < 0.01).

Conclusion: Our findings suggest that enhanced excitatory transmission within the caudal NTS contributes to pancreatic pain and emphasize the NTS as a pivotal hub for the processing of pancreatic afferents, which provide novel insights into the central sensitization of painful CP.
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http://dx.doi.org/10.3748/wjg.v25.i40.6077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824279PMC
October 2019

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

Anterior insular cortex mediates hyperalgesia induced by chronic pancreatitis in rats.

Mol Brain 2019 09 4;12(1):76. Epub 2019 Sep 4.

Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, Fourth Military Medical University, No. 169, West Chang-le Road, Xi'an, 710032, China.

Central sensitization plays a pivotal role in the maintenance of chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. This study was designed to examine the role of anterior insular cortex (aIC) in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). Abdomen hyperalgesia and anxiety were assessed by von Frey filament and open field tests, respectively. Two weeks after surgery, the activation of aIC was indicated by FOS immunohistochemical staining and electrophysiological recordings. Expressions of VGluT1, NMDAR subunit NR2B and AMPAR subunit GluR1 were analyzed by immunoblottings. The regulatory roles of aIC in hyperalgesia and pain-related anxiety were detected via pharmacological approach and chemogenetics in CP rats. Our results showed that TNBS treatment resulted in long-term hyperalgesia and anxiety-like behavior in rats. CP rats exhibited increased FOS expression and potentiated excitatory synaptic transmission within aIC. CP rats also showed up-regulated expression of VGluT1, and increased membrane trafficking and phosphorylation of NR2B and GluR1 within aIC. Blocking excitatory synaptic transmission significantly attenuated abdomen mechanical hyperalgesia. Specifically inhibiting the excitability of insular pyramidal cells reduced both abdomen hyperalgesia and pain-related anxiety. In conclusion, our findings emphasize a key role for aIC in hyperalgesia and anxiety of painful CP, providing a novel insight into cortical modulation of painful CP and shedding light on aIC as a potential target for neuromodulation interventions in the treatment of CP.
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http://dx.doi.org/10.1186/s13041-019-0497-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727343PMC
September 2019

Bone marrow mesenchymal stem cell-derived exosome uptake and retrograde transport can occur at peripheral nerve endings.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):2918-2929

a Human Anatomical Department and United Laboratory for Neurosciences, Hainan Medical University , Haikou , China.

We investigated the occurrence of mesenchymal stem cell (MSC)-derived exosome uptake and retrograde transport at peripheral nerve endings using bone marrow MSCs (bMSCs) transduced with recombinant CD63-green fluorescent protein (GFP) lentiviral plasmid. GFP was used to track the release of bMSC-derived exosomes and the uptake and transport at peripheral nerve terminals, the dorsal root ganglion (DRG), and the spinal cord. cell culture and injection of a CD63-GFP exosome suspension into the right gastrocnemius muscle of an rat model were also performed. Fluorescence microscopy of co-cultured CD63-GFP exosomes and SH-SY5Y or BV2 cell lines and primary cultured DRG cells in a separate experiment demonstrated exosome uptake into DRG neurons and glia. Moreover, we observed both retrograde axoplasmic transport and hematogenous transport of exosomes injected into rat models at the DRG and the ipsilateral side of the anterior horn of the spinal cord using fluorescence microscopy, immunohistochemistry, and Western blot analyses. In conclusion, we showed that exosome uptake at peripheral nerve endings and retrograde transport of exosomes to DRG neurons and spinal cord motor neurons in the anterior horn can occur. In addition, our findings propose a novel drug delivery approach for treating neuronal diseases.
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http://dx.doi.org/10.1080/21691401.2019.1640713DOI Listing
December 2019

Flavivirga rizhaonensis sp. nov., a marine bacterium isolated from intertidal sand.

Antonie Van Leeuwenhoek 2019 Nov 19;112(11):1645-1653. Epub 2019 Jun 19.

Department of Pathogenic Biology, Jining Medical University, Jining, 272067, Shandong, People's Republic of China.

A bacterial strain designated RZ03 was isolated from an intertidal sand sample from the Yellow Sea in China and characterised using a polyphasic taxonomic approach. Cells of strain RZ03 were observed to be Gram-stain negative, aerobic, and oxidase and catalase positive rods showing gliding motility and forming yellow colonies. Growth was found to occur at 7-30 °C (optimum, 25 °C), at pH 5.5-9.5 (optimum, pH 6.5-7.0) and with 0.5-5% NaCl (optimum, 1.5-2%). Phylogenetic analysis based on 16S rRNA gene sequences indicates that strain RZ03 clusters within members of the genus Flavivirga of the family Flavobacteriaceae and is closely related to the type strains Flavivirga amylovorans JCM 17112 and Flavivirga jejuensis JCM 17113 (97.9% and 97.5% similarity, respectively). The predominant cellular fatty acids are iso-C, iso-C G, iso-C 3-OH and iso-C 3-OH and the major respiratory quinone is MK-6. Polar lipids include phosphatidylethanolamine, three unidentified aminolipids, an unidentified phospholipid and four unidentified lipids. The genome of strain RZ03 is 4.88 Mbp with a G+C content of 32.2 mol%. A total of 4152 genes are predicted, with 4052 protein-coding genes, 51 RNA genes and 49 pseudogenes. This polyphasic study suggests that strain RZ03 represents a novel species in the genus Flavivirga, for which the name Flavivirga rizhaonensis is proposed. The type strain is RZ03(= KCTC 62833 = MCCC 1K03615).
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http://dx.doi.org/10.1007/s10482-019-01291-7DOI Listing
November 2019

Collateral Projections from the Medullary Dorsal Horn to the Ventral Posteromedial Thalamic Nucleus and the Parafascicular Thalamic Nucleus in the Rat.

Neuroscience 2019 07 7;410:293-304. Epub 2019 May 7.

Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China; Joint Laboratory of Neuroscience at Hainan Medical University and The Fourth Military Medical University, Hainan Medical University, Haikou 571199, China. Electronic address:

Medullary dorsal horn (MDH), the homolog of spinal dorsal horn, plays essential roles in processing of nociceptive signals from orofacial region toward higher centers, such as the ventral posteromedial thalamic nucleus (VPM) and parafascicular thalamic nucleus (Pf), which belong to the sensory-discriminative and affective aspects of pain transmission systems at the thalamic level, respectively. In the present study, in order to provide morphological evidence for whether neurons in the MDH send collateral projections to the VPM and Pf, a retrograde double tracing method combined with immunofluorescence staining for substance P (SP), SP receptor (SPR) and Fos protein was used. Fluoro-gold (FG) was injected into the VPM and the tetramethylrhodamine-dextran (TMR) was injected into the Pf. The result revealed that both FG- and TMR-labeled projection neurons were observed throughout the entire extent of the MDH, while the FG/TMR double-labeled neurons were mainly located in laminae I and III. It was also found that some of the FG/TMR double-labeled neurons within lamina I expressed SPR and were in close contact with SP-immunoreactive (SP-ir) terminals. After formalin injection into the orofacial region, 41.4% and 34.3% of the FG/TMR double-labeled neurons expressed Fos protein in laminae I and III, respectively. The present results provided morphological evidence for that some SPR-expressing neurons within the MDH send collateral projections to both VPM and Pf and might be involved in sensory-discriminative and affective aspects of acute orofacial nociceptive information transmission.
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http://dx.doi.org/10.1016/j.neuroscience.2019.04.050DOI Listing
July 2019

Serotoninergic projection from dorsal raphe nucleus to insular cortex is involved in acute itch sensation processing in mice.

Brain Res 2019 07 27;1715:224-234. Epub 2019 Mar 27.

Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, China; Department of Anatomy, Histology and Embryology & K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China; Joint Laboratory of Neuroscience at Hainan Medical University and The Fourth Military Medical University, Hainan Medical University, Haikou 571199, China. Electronic address:

Previous studies have demonstrated that both dorsal raphe nucleus (DR) and insular cortex (IC) are critical for somatic sensory information transmission and regulation, especially for pain, and neurons in the DR send projection fibers to the IC. However, whether these ascending connections are involved in the processing of itch sensation remains unknown. In order to provide evidence for that, fluoro-gold (FG) retrograde tracing combined with immunofluorescent histochemical staining was performed for revealing the chemical nature of the projection neurons and the FOS expression induced by acute itch stimulation via intradermal histamine or chloroquine injection in the mouse. Both FOS- and p-ERK-containing neurons were increased in the DR and IC in the acute itch mice compared to those in the sham group. After FG was injected into the IC, FG-labeled retrograde neuronal cell bodies were observed in the whole extent of the brainstem, especially in the DR. About 81% of the total number of FG-labeled neurons in the DR showed serotonin (5-HT)-immunopositive staining. About 32% FG-labeled 5-HT-ergic neurons within DR expressed FOS in chroloquine-induced acute itch, whereas only 6% FG-labeled 5-HT-ergic neurons within DR expressed FOS in histamine-induced acute itch. These results provide morphological evidence for that there are 5-HT-ergic projections from the DR to IC which might be involved in the sensory information processing of acute itch. These results are helpful for understanding functional roles of 5-HT-ergic ascending projection under the condition of acute itch.
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http://dx.doi.org/10.1016/j.brainres.2019.03.031DOI Listing
July 2019

A Role of YlBud8 in the Regulation of Cell Separation in the Yeast .

J Microbiol Biotechnol 2019 Jan;29(1):141-150

Department of Pathogenic Biology, Jining Medical University, Shandong 272067, China.

The spatial landmark protein Bud8 plays a crucial role in bipolar budding in the budding yeast . The unconventional yeast can also bud in a bipolar pattern, but is evolutionarily distant from . It encodes the protein YALI0F12738p, which shares the highest amino acid sequence homology with Bud8, sharing a conserved transmembrane domain at the C-terminus. Therefore, we named it YlBud8. Deletion of YlBud8 in causes cellular separation defects, resulting in budded cells remaining linked with one another as cell chains or multiple buds from a single cell, which suggests that YlBud8 may play an important role in cell separation, which is distinct from the function of Bud8 in . We also show that the YlBud8-GFP fusion protein is located at the cell membrane and enriched in the bud cortex, which would be consistent with a role in the regulation of cell separation. The coiled-coil domain at the N-terminus of YlBud8 is important to the correct localization and function of YlBud8, as truncated proteins that do not contain the coiled-coil domain cannot rescue the defects observed in YlΔ. This finding suggests that a new signaling pathway controlled by YlBud8 via regulation of cell separation may exist in .
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http://dx.doi.org/10.4014/jmb.1807.07050DOI Listing
January 2019

Vesicular glutamate transporter isoforms: The essential players in the somatosensory systems.

Prog Neurobiol 2018 12 28;171:72-89. Epub 2018 Sep 28.

Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China. Electronic address:

In nervous system, glutamate transmission is crucial for centripetal conveyance and cortical perception of sensory signals of different modalities, which necessitates vesicular glutamate transporters 1-3 (VGLUT 1-3), the three homologous membrane-bound protein isoforms, to load glutamate into the presysnaptic vesicles. These VGLUTs, especially VGLUT1 and VGLUT2, selectively label and define functionally distinct neuronal subpopulations at each relay level of the neural hierarchies comprising spinal and trigeminal sensory systems. In this review, by scrutinizing each structure of the organism's fundamental hierarchies including dorsal root/trigeminal ganglia, spinal dorsal horn/trigeminal sensory nuclear complex, somatosensory thalamic nuclei and primary somatosensory cortex, we summarize and characterize in detail within each relay the neuronal clusters expressing distinct VGLUT protein/transcript isoforms, with respect to their regional distribution features (complementary distribution in some structures), axonal terminations/peripheral innervations and physiological functions. Equally important, the distribution pattern and characteristics of VGLUT1/VGLUT2 axon terminals within these structures are also epitomized. Finally, the correlation of a particular VGLUT isoform and its physiological role, disclosed thus far largely via studying the peripheral receptors, is generalized by referring to reports on global and conditioned VGLUT-knockout mice. Also, researches on VGLUTs relating to future direction are tentatively proposed, such as unveiling the elusive differences between distinct VGLUTs in mechanism and/or pharmacokinetics at ionic/molecular level, and developing VGLUT-based pain killers.
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http://dx.doi.org/10.1016/j.pneurobio.2018.09.006DOI Listing
December 2018

Identification of COL1A1 as an invasion‑related gene in malignant astrocytoma.

Int J Oncol 2018 Dec 21;53(6):2542-2554. Epub 2018 Sep 21.

National Demonstration Center for Experimental Basic Medical Science Education, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China.

Malignant astrocytoma (MA) is the most common and severe type of brain tumor. A greater understanding of the underlying mechanisms responsible for the development of MA would be beneficial for the development of targeted molecular therapies. In the present study, the upregulated differentially expressed genes (DEGs) in MA were obtained from the Gene Expression Omnibus database using R/Bioconductor software. DEGs in different World Health Organization classifications were compared using the Venny tool and 15 genes, including collagen type I α1 chain (COL1A1) and laminin subunit γ1 (LAMC1), were revealed to be involved in the malignant progression of MA. In addition, the upregulated DEGs in MA were evaluated using functional annotations of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes with the Database for Annotation, Visualization, and Integrated Discovery tool. The results indicated that invasion‑associated enrichment was observed in 'extracellular matrix' (ECM), 'cell adhesion' and 'phosphoinositide 3‑kinase‑protein kinase B signaling pathway'. Subsequently, the analysis of the protein‑protein interactions was performed using STRING and Cytoscape software, which revealed that the ECM component was the invasion‑associated module and its corresponding genes included COL1A1, LAMC1 and fibronectin 1. Finally, survival Kaplan‑Meier estimate was conducted using cBioportal online, which demonstrated that COL1A1 expression affected the survival of and recurrence in patients with MA. Moreover, the results of in vitro Transwell assay and western blot analysis revealed that the depleted levels of COL1A1 also decreased the expression of several proteins associated with cell invasion, including phosphorylated‑signal transducer and activator of transcription 3, matrix metalloproteinase (MMP)‑2, MMP‑9 and nuclear factor‑κB. On the whole, the present study identified the invasion‑related target genes and the associated potential pathways in MA. The results indicated that COL1A1 may be a candidate biomarker for the prognosis and treatment of MA.
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http://dx.doi.org/10.3892/ijo.2018.4568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203155PMC
December 2018

Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.

Front Pharmacol 2018 15;9:509. Epub 2018 May 15.

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

The easily developed morphine tolerance in bone cancer pain (BCP) significantly hindered its clinical use. Increasing evidence suggests that histone deacetylases (HDACs) regulate analgesic tolerance subsequent to continuous opioid exposure. However, whether HDACs contribute to morphine tolerance in the pathogenesis of BCP is still unknown. In the current study, we explored the possible engagement of HDACs in morphine tolerance during the pathogenesis of BCP. After intra-tibia tumor cell inoculation (TCI), we found that the increased expression of HDACs was negatively correlated with the decreased expression of MOR in the DRG following TCI. The paw withdrawal threshold (PWT) and percentage maximum possible effects (MPEs) decreased rapidly in TCI rats when morphine was used alone. In contrast, the concomitant use of SAHA and morphine significantly elevated the PWT and MPEs of TCI rats compared to morphine alone. Additionally, we found that SAHA administration significantly elevated MOR expression in the DRG of TCI rats with or without morphine treatment. Moreover, the TCI-induced increase in the co-expression of MOR and HDAC1 in neurons was significantly decreased after SAHA administration. These results suggest that HDACs are correlated with the downregulation of MOR in the DRG during the pathogenesis of BCP. Inhibition of HDACs using SAHA can be used to attenuate morphine tolerance in BCP.
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http://dx.doi.org/10.3389/fphar.2018.00509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962808PMC
May 2018

Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex.

Nat Commun 2018 05 14;9(1):1886. Epub 2018 May 14.

Center for Neuron and Disease, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, 710054, China.

Spinal sensory transmission is under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain. Descending modulation from the brainstem rostral ventromedial medulla (RVM) has been the most studied, whereas little is known about direct corticospinal modulation. Here, we found that stimulation in the anterior cingulate cortex (ACC) potentiated spinal excitatory synaptic transmission and this modulation is independent of the RVM. Peripheral nerve injury enhanced the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury. Finally, using optogenetics, we showed that selective activation of ACC-spinal cord projecting neurons caused behavioral pain sensitization, while inhibiting the projection induced analgesic effects. Our results provide strong evidence that ACC stimulation facilitates spinal sensory excitatory transmission by a RVM-independent manner, and that such top-down facilitation may contribute to the process of chronic neuropathic pain.
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http://dx.doi.org/10.1038/s41467-018-04309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951839PMC
May 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

VGLUT1 or VGLUT2 mRNA-positive neurons in spinal trigeminal nucleus provide collateral projections to both the thalamus and the parabrachial nucleus in rats.

Mol Brain 2018 04 12;11(1):22. Epub 2018 Apr 12.

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

The trigemino-thalamic (T-T) and trigemino-parabrachial (T-P) pathways are strongly implicated in the sensory-discriminative and affective/emotional aspects of orofacial pain, respectively. These T-T and T-P projection fibers originate from the spinal trigeminal nucleus (Vsp). We previously determined that many vesicular glutamate transporter (VGLUT1 and/or VGLUT2) mRNA-positive neurons were distributed in the Vsp of the adult rat, and most of these neurons sent their axons to the thalamus or cerebellum. However, whether VGLUT1 or VGLUT2 mRNA-positive projection neurons exist that send their axons to both the thalamus and the parabrachial nucleus (PBN) has not been reported. Thus, in the present study, dual retrograde tract tracing was used in combination with fluorescence in situ hybridization (FISH) for VGLUT1 or VGLUT2 mRNA to identify the existence of VGLUT1 or VGLUT2 mRNA neurons that send collateral projections to both the thalamus and the PBN. Neurons in the Vsp that send collateral projections to both the thalamus and the PBN were mainly VGLUT2 mRNA-positive, with a proportion of 90.3%, 93.0% and 85.4% in the oral (Vo), interpolar (Vi) and caudal (Vc) subnucleus of the Vsp, respectively. Moreover, approximately 34.0% of the collateral projection neurons in the Vc showed Fos immunopositivity after injection of formalin into the lip, and parts of calcitonin gene-related peptide (CGRP)-immunopositive axonal varicosities were in direct contact with the Vc collateral projection neurons. These results indicate that most collateral projection neurons in the Vsp, particularly in the Vc, which express mainly VGLUT2, may relay orofacial nociceptive information directly to the thalamus and PBN via axon collaterals.
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http://dx.doi.org/10.1186/s13041-018-0362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897998PMC
April 2018

8-O-Acetyl Shanzhiside Methylester From Lamiophlomis Rotata Reduces Neuropathic Pain by Inhibiting the ERK/TNF-α Pathway in Spinal Astrocytes.

Front Cell Neurosci 2018 8;12:54. Epub 2018 Mar 8.

Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

(; Benth.) Kudo is an effective traditional herb in the clinical treatment of chronic pain syndromes in China. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in , possesses potent immunosuppressive activities and favorable analgesic effects. This study was proposed to compare the analgesic effects of 8-OaS with those of lidocaine and ketamine in a spinal nerve ligation (SNL) model by behavioral tests, and then investigated its effects upon the expression of spinal glial fibrillary acidic protein (GFAP), phosphorylated extracellular regulated protein kinases (pERK) and tumor necrosis factor-alpha (TNF-α) via immunofluorescence staining and western blot analyses. The data showed consecutive intrathecal injection of 8-OaS for 2 weeks brought about remarkable palliation of neuropathic pain (NP), possessing similar anti-allodynia effects with those of lidocaine and ketamine. Two weeks after surgery, pERK within the spinal dorsal horn was mainly expressed in astrocytes more than neurons and microglia, and 8-OaS inhibited spinal astrocytic activation and TNF-α expression. Finally, co-treatment of 8-OaS and PD98059 (an Extracellular signal-regulated kinase, ERK inhibitor) did not lead to remarkable increase in pain relief or TNF-α expression comparing to rats treated with 8-OaS or PD98059 alone. In conclusion, the anti-nociceptive effects of 8-OaS in the condition of NP relied on the inhibition of SNL-induced astrocyte activation, probably via the down-regulation of the ERK/TNF-α pathway.
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http://dx.doi.org/10.3389/fncel.2018.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852333PMC
March 2018

Endomorphin-2 Inhibits the Activity of the Spinoparabrachial Projection Neuron through Presynaptic Mechanisms in the Spinal Dorsal Horn in Rats.

Neurosignals 2018;26(1):43-57. Epub 2018 Mar 15.

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

Background/aims: Spinal dorsal horn (SDH) is one of the most important regions for analgesia produced by endomorphin-2 (EM2), which has a higher affinity and specificity for the µ-opioid receptor (MOR) than morphine. Many studies have focused on substantia gelatinosa (SG, lamina II) neurons to elucidate the cellular basis for its antinociceptive effects. However, the complicated types and local circuits of interneurons in the SG make it difficult to understand the real effects of EM2. Therefore, in the present study, we examined the effects of EM2 on projection neurons (PNs) in lamina I.

Methods: Tracing, immunofluoresence, and immunoelectron methods were used to examine the morphological connections between EM2-immunoreactive (-ir) terminals and PNs. By using in vitro whole cell patch clamp recording technique, we investigated the functional effects of EM2 on PNs.

Results: EM2-ir afferent terminals directly contacted PNs projecting to the parabrachial nucleus in lamina I. Their synaptic connections were further confirmed by immunoelectron microscopy, most of which were asymmetric synapses. It was found that EM2 had a strong inhibitory effect on the frequency, but not amplitude, of the spontaneous excitatory postsynaptic current (sEPSC) of the spinoparabrachial PNs in lamina I, which could be reversed by MOR antagonist CTOP. However, their spontaneous inhibitory postsynaptic current (sIPSC) and intrinsic properties were not changed after EM2 application.

Conclusion: Applying EM2 to the SDH could produce analgesia through inhibiting the activities of the spinoparabrachial PNs in lamina I by reducing presynaptic neurotransmitters release from the primary afferent terminals.
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http://dx.doi.org/10.1159/000488275DOI Listing
March 2018

A UPLC-MS/MS method for simultaneous determination of five flavonoids from Stellera chamaejasme L. in rat plasma and its application to a pharmacokinetic study.

Biomed Chromatogr 2018 Jun 12;32(6):e4189. Epub 2018 Feb 12.

Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.

Stellera chamaejasme L. has been used as a traditional Chinese medicine for the treatment of scabies, tinea, stubborn skin ulcers, chronic tracheitis, cancer and tuberculosis. A sensitive and selective ultra-high liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of five flavonoids (stelleranol, chamaechromone, neochamaejasmin A, chamaejasmine and isochamaejasmin) of S. chamaejasme L. in rat plasma. Chromatographic separation was accomplished on an Agilent Poroshell 120 EC-C column (2.1 × 100 mm, 2.7 μm) with gradient elution at a flow rate of 0.4 mL/min and the total analysis time was 7 min. The analytes were detected using multiple reaction monitoring in positive ionization mode. The samples were prepared by liquid-liquid extraction with ethyl acetate. The UPLC-MS/MS method was validated for specificity, linearity, sensitivity, accuracy and precision, recovery, matrix effect and stability. The validated method exhibited good linearity (r ≥ 0.9956), and the lower limits of quantification ranged from 0.51 to 0.64 ng/mL for five flavonoids. The intra- and inter-day precision were both <10.2%, and the accuracy ranged from -11.79 to 9.21%. This method was successfully applied to a pharmacokinetic study of five flavonoids in rats after oral administration of ethyl acetate extract of S. chamaejasme L.
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http://dx.doi.org/10.1002/bmc.4189DOI Listing
June 2018

Histone deacetylase 2 is involved in µ‑opioid receptor suppression in the spinal dorsal horn in a rat model of chronic pancreatitis pain.

Mol Med Rep 2018 Feb 11;17(2):2803-2810. Epub 2017 Dec 11.

Department of Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.

Chronic pain occurs in ~85-90% of chronic pancreatitis (CP) patients. However, as the pathogenesis of CP pain remains to be fully understood, the current therapies for CP pain remain inadequate. Emerging evidence has suggested that the epigenetic modulations of genes are involved in chronic pain. In the present study, intrapancreatic trinitrobenzene sulfonic acid infusions were used to establish a CP model in rats. Mechanical allodynia was measured with von Frey filaments. Immunofluorescent staining analysis was used to observe the expression changes of histone deacetylase 2 (HDAC2) and µ‑opioid receptor (MOR), and intrathecal administration of the selective HDAC2 inhibitor AR‑42 was used to assess the underlying mechanisms. The expression levels of c‑Jun N‑terminal kinase (JNK) in the thoracic spinal cord were detected by western blotting, and the mRNA expression levels of interleukin (IL)1‑β, IL‑6 and tumor necrosis factor (TNF)‑α were detected by reverse transcription‑quantitative polymerase chain reaction. The results demonstrated that HDAC2 expression was upregulated during the course of CP induction, while MOR activity in the thoracic spinal dorsal horn was significantly suppressed. Intrathecal infusion of AR‑42 significantly attenuated CP‑induced mechanical allodynia, with rescued MOR activity. Additionally, HDAC2 facilitated the release of inflammatory cytokines, including IL‑1β, IL‑6 and TNF‑α. These results suggested that the underlying mechanisms of HDAC2 regulating MOR activity under CP induction may occur via promoting the release of inflammatory cytokines, thus activating the JNK signaling pathway. The present study suggested that the epigenetic‑regulated disturbance of MOR is dependent on the endogenous analgesia system in CP, which may a provide novel therapeutic strategy for treating pain in CP.
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http://dx.doi.org/10.3892/mmr.2017.8245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783494PMC
February 2018

The synergistic effect of treatment with triptolide and MK-801 in the rat neuropathic pain model.

Mol Pain 2017 Jan-Dec;13:1744806917746564. Epub 2017 Nov 22.

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

Triptolide (T10), an active component of Tripterygium wilfordii Hook F, is reported to have potent anti-inflammatory and analgesic effects. Additionally, MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, can reduce glutamate toxicity and has a significant analgesic effect on chronic pain. In this study, we tested the possible synergistic analgesic ability by intrathecal administration of T10 and MK-801 for the treatment of neuropathic pain. Single T10 (3, 10, or 30 µg/kg), MK-801 (10, 30, or 90 µg/kg), or a combination of them were intrathecally administrated in rats with spinal nerve ligation. We found that single administration of T10 caused a slow-acting but long-term analgesic effect, while single administration of MK-801 caused a fast-acting but short-term effect. Administration of their combination showed obviously synergic analgesia and the 1:3 ratio of T10 to MK-801 reached the peak effect. Furthermore, application of T10 and/or MK-801 significantly inhibited the activation of microglia and astrocyte and phosphorylation of STAT and NR2B in the spinal dorsal horn induced by chronic neuropathic pain. Our data suggest that the combination of T10 and MK-801 may be a potentially novel strategy for treatment of neuropathic pain.
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http://dx.doi.org/10.1177/1744806917746564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734437PMC
July 2018