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Cytochrome P45026A1 Contributes to the Maintenance of Neuropathic Pain

Neuroscience Bulletin 2024年第3期40卷 293-309页

作者： De-Li Cao Ling-Jie Ma Bao-Chun Jiang Qiang Gu yong-jing gao Institute of Pain Medicine and Special Environmental Medicine Co-innovation Center of NeuroregenerationNantong UniversityNantong226019China Nantong University Medical School Nantong226001China Department of Pain Management The Affiliated Hospital of Nantong UniversityNantong226001China

The cytochrome P450 proteins(CYP450s)have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases.CYP26A1,a member of the CYP450 family,carries out the oxidative metabolism of retinoic acid(RA),the active metabolite of vitamin A.Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation(SNL).CYP26A1 was mainly expressed in spinal neurons and astrocytes.HPLC analysis displayed that the content of all-trans-RA(at-RA),the substrate of CYP26A1,was reduced in the spinal cord on day 7 after SNL.Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain.Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine(IL-10)production.The RA receptors RARα,RXRβ,and RXRγwere expressed in spinal neurons and glial cells.The promoter of Il-10 has several binding sites for RA receptors,and at-RA directly increased Il-10 mRNA expression in vitro.Finally,intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia.Collectively,the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation.CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.

关键词： CYP26A1 Microglia Astrocytes ERK P38 IL-10 Neuropathic pain

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Astrocytes in Chronic Pain:Cellular and Molecular Mechanisms

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Neuroscience Bulletin 2023年第3期39卷 425-439页

作者： Huan-Jun Lu yong-jing gao Institute of Pain Medicine and Special Environmental Medicine Co-innovation Center of NeuroregenerationNantong UniversityNantong 226019China

Chronic pain is challenging to treat due to the limited therapeutic options and adverse side-effects of therapies.Astrocytes are the most abundant glial cells in the central nervous system and play important roles in different pathological conditions,including chronic pain.Astrocytes regulate nociceptive synaptic transmission and network function via neuron–glia and glia–glia interactions to exaggerate pain signals under chronic pain conditions.It is also becoming clear that astrocytes play active roles in brain regions important for the emotional and memory-related aspects of chronic pain.Therefore,this review presents our current understanding of the roles of astrocytes in chronic pain,how they regulate nociceptive responses,and their cellular and molecular mechanisms of action.

关键词： Astrocyte Microglia Neuron-glia interaction Spinal cord Chronic pain

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CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

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Neuroscience Bulletin 2021年第7期37卷 921-933页

作者： Xiao-Bo Wu Qian Zhu yong-jing gao Institute of Pain Medicine and Special Environmental Medicine Nantong UniversityNantong 226019China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

The medium spiny neurons(MSNs)in the nucleus accumbens(NAc)integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output.Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation(SNL).SNL increased the frequency,but not the amplitude of spontaneous inhibitory postsynaptic currents(sIPSCs),and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs)in the MSNs.SNL also decreased the paired-pulse ratio(PPR)of evoked IPSCs but increased the PPR of evoked EPSCs.Moreover,acute bath application of C–C motif chemokine ligand 2(CCL2)increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs,and especially strengthened the amplitude of N-methyl-D-aspartate receptor(NMDAR)-mediated miniature EPSCs.Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio.Finally,Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression(LTD)in the NAc after SNL.These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.

关键词： E/I balance Synaptic transmission LTD CCL2 CCR2 Nucleus accumbens Neuropathic pain

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Emerging role of Toll-like receptors in the control of pain and itch

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Neuroscience Bulletin 2012年第2期28卷 131-144页

作者： Tong Liu yong-jing gao Ru-Rong Ji Sensory Plasticity Laboratory Pain Research CenterDepartment of AnesthesiologyPerioperative and Pain MedicineBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusetts 02115USA Institute of Nautical Medicine Nantong UniversityNantong 226001China

Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.

关键词： astrocytes microglia Toll-like receptor pain itch danger-associated molecular patterns pathogen-associatedmolecular patterns

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Chemokine Receptor CXCR3 in the Spinal Cord Contributes to Chronic Itch in Mice

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Neuroscience Bulletin 2018年第1期34卷 54-63页

作者： Peng-Bo jing De-Li Cao Si-Si Li Meixuan Zhu Xue-Qiang Bai Xiao-Bo Wu yong-jing gao Pain Research Laboratory Institute of Nautical MedicineJiangsu Key Laboratory of Neuroregeneration Nantong University Co-innovation Center of Neuroregeneration Nantong University

Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis （ACD）. CXCR3 in the spinal cord also con- tributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3-/- mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund＇s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3-/- mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water （AEW）. Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Further- more, touch-elicited itch （alloknesis） after compound 48/80 or AEW treatment was suppressed in Cxcr3-/- mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3-/- mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.

关键词： Chronic itch Alloknesis Dry skin CXCR3 CXCL10 - Spinal cord

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Increased CXCL13 and CXCR5 in Anterior Cingulate Cortex Contributes to Neuropathic Pain-Related Conditioned Place Aversion

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Neuroscience Bulletin 2019年第4期35卷 613-623页

作者： Xiao-Bo Wu Li-Na He Bao-Chun Jiang Xue Wang Ying Lu yong-jing gao Institute of Pain Medicine Institute of Special Environmental Medicine Nantong University Nantong 226019 China Department of Nutrition and Food Hygiene School of Public Health Nantong University Nantong 226019 China Co-innovation Center of Neuroregeneration Nantong University Nantong 226001 China

Pain consists of sensory-discriminative and emotional-affective components.The anterior cingulate cortex(ACC)is a critical brain area in mediating the affective pain.However,the molecular mechanisms involved remain largely unknown.Our recent study indicated that C-X-C motif chemokine 13(CXCL13)and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation(SNL).Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown.Here,we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL.Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic painrelated place avoidance behavior.Furthermore,electrophysiological recording from layer Ⅱ-Ⅲ neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents(sEPSCs),decreased the EPSC paired-pulse ratio,and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio,indicating enhanced glutamatergic synaptic transmission.Finally,superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs.Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmis sion induced by SNL.Collectively,these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.

关键词： CXCL13 CXCR5 Anterior cingulate cortex Neuropathic pain Conditioned place aversion Synaptic transmission

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CXCL10/CXCR3 Signaling in the DRG Exacerbates Neuropathic Pain in Mice

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Neuroscience Bulletin 2021年第3期37卷 339-352页

作者： Yan-Fang Kong Wei-Lin Sha Xiao-Bo Wu Lin-Xia Zhao Ling-Jie Ma yong-jing gao Institute of Pain Medicine Institute of Nautical MedicineNantong UniversityNantong 226019China Co-Innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

Chemokines and receptors have been implicated in the pathogenesis of chronic pain.Here,we report that spinal nerve ligation(SNL)increased CXCR3 expression in dorsal root ganglion(DRG)neurons,and intra-DRG injection of Cxcr3 shRNA attenuated the SNL-induced mechanical allodynia and heat hyperalgesia.SNL also increased the m RNA levels of CXCL9,CXCL10,and CXCL11,whereas only CXCL10 increased the number of action potentials(APs)in DRG neurons.Furthermore,in Cxcr3^(-/-)mice,CXCL10 did not increase the number of APs,and the SNL-induced increase of the numbers of APs in DRG neurons was reduced.Finally,CXCL10 induced the activation of p38 and ERK in ND7-23 neuronal cells and DRG neurons.Pretreatment of DRG neurons with the P38 inhibitor SB203580 decreased the number of APs induced by CXCL10.Our data indicate that CXCR3,activated by CXCL10,mediates p38 and ERK activation in DRG neurons and enhances neuronal excitability,which contributes to the maintenance of neuropathic pain.

关键词： CXCR3 CXCL10 DRG Neuropathic pain Mice

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Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2： Further Insights into Molecular, Synaptic, and Cellular Mechanisms

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Neuroscience Bulletin 2018年第1期34卷 13-21页

作者： Rou-Gang Xie yong-jing gao Chul-Kyu Park Ning Lu Ceng Luo Wen-Ting Wang Sheng-Xi Wu Ru-Rong Ji Department of Neurobiology and Collaborative Innovation Center for Brain Science The Fourth Military Medical University Xi'an 710032 China Department of Anesthesiology Duke University Medical Center Durham NC 27710 USA Pain Research Laboratory Institute of Nautical Medicine Jiangsu Key laboratory of Neuroregeneration Nantong University Nantong 226001 China Department of Physiology College of Medicine Gachon University Incheon 21999 Republic of Korea Institutes of Brain Science and State Key Laboratory of Medical Neurobiology Collaborative Innovation Center for Brain Science Fudan University Shanghai 200032 China Department of Neurobiology Duke University Medical Center Durham NC 27710 USA

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.

关键词： Chemokines C-C motif chemokine ligand 2 （CCL2） Monocyte chemoattractant protein 1 （MCP-1） Neuron-glial interaction

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TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

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Neuroscience Bulletin 2021年第4期37卷 550-562页

作者： Lin-Xia Zhao Ming Jiang Xue-Qiang Bai De-Li Cao Xiao-Bo Wu jing Zhang Jian-Shuang Guo Tong-Tong Chen Juan Wang Hao Wu yong-jing gao Zhi-Jun Zhang Department of Human Anatomy School of MedicineNantong UniversityNantong 226001China Institute of Pain Medicine Institute of Nautical MedicineNantong UniversityNantong 226019China Department of Otolaryngology Head Neck Surgery The Affiliated Hospital of Nantong UniversityNantong 226001China Co-innovation Center of Neuroregeneration Nantong UniversityNantong 226001China

Trigeminal neuropathic pain(TNP)is a significant health problem but the involved mechanism has not been completely elucidated.Toll-like receptors(TLRs)have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain.Here,we show that TLR8 was persistently increased in the trigeminal ganglion(TG)neurons in model of TNP induced by partial infraorbital nerve ligation(pIONL).In addition,deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia,reduced the activation of ERK and p38-MAPK,and decreased the expression of pro-inflammatory cytokines in the TG.Furthermore,intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity.VTX-2337 also increased the intracellular Ca^(2+)concentration,induced the activation of ERK and p38,and increased the expression of pro-inflammatory cytokines in the TG.These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation.Targeting TLR8 signaling may be effective for the treatment of TNP.

关键词： TLR8 ERK p38 Pro-inflammatory cytokine Trigeminal ganglion Trigeminal neuropathic pain Mouse

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Spinal CCL2 Promotes Pain Sensitization by Rapid Enhancement of NMDA-Induced Currents Through the ERK-GluN2B Pathway in Mouse Lamina Ⅱ Neurons

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Neuroscience Bulletin 2020年第11期36卷 1344-1354页

作者： Hui Zhang Sui-Bin Ma yong-jing gao Jun-Ling Xing Hang Xian Zhen-Zhen Li Shu-Ning Shen Sheng-Xi Wu Ceng Luo Rou-Gang Xie Department of Neurobiology Fourth Military Medical UniversityXi'an 710032China Department of Health Statistics Fourth Military Medical UniversityXi'an 710032China Pain Research Laboratory Institute of Nautical MedicineJiangsu Key laboratory of NeuroregenerationNantong UniversityNantong 226001China Department of Radiation Biology Faculty of Preventive MedicineFourth Military Medical UniversityXi'an 710032China Department of Orthopedics Xijing HospitalFourth Military Medical UniversityXi'an 710032China Department of Stomatology No.984 Hospital of the People's Liberation ArmyBeijing 100094China

Previous studies have shown that CCL2(C-C motif chemokine ligand 2)induces chronic pain,but the exact mechanisms are still unknown.Here,we established models to explore the potential mechanisms.Behavioral experiments revealed that an antagonist of extracellular signal-regulated kinase(ERK)inhibited not only CCL2-induced inflammatory pain,but also pain responses induced by complete Freund’s adjuvant.We posed the question of the intracellular signaling cascade involved.Subsequent experiments showed that CCL2 up-regulated the expression of phosphorylated ERK(pERK)and N-methyl D-aspartate receptor[NMDAR]subtype 2B(GluN2B);meanwhile,antagonists of CCR2 and ERK effectively reversed these phenomena.Whole-cell patchclamp recordings revealed that CCL2 enhanced the NMDAR-induced currents via activating the pERK pathway,which was blocked by antagonists of GluN2B and ERK.In summary,we demonstrate that CCL2 directly interacts with CCR2 to enhance NMDAR-induced currents,eventually leading to inflammatory pain mainly through the CCL2-CCR2-pERK-GluN2B pathway.

关键词： C-C motif chemokine ligand 2 Monocyte chemoattractant protein 1 Neuron-glial interaction Extracellular signal-regulated kinase

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