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Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

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Science China(Life Sciences) 2024年第1期67卷 67-82页

作者： Chun-Kui Zhang Pan Wang Yuan-Yuan Ji Jian-Shuai Zhao Jun-Xiang Gu Xian-Xia Yan Hong-Wei Fan Ming-Ming Zhang Yu Qiao Xiao-Die Liu Bao-Juan Li Ming-Hui Wang Hai-Long Dong Hao-Hong Li Peng-Cheng Huang Yun-Qing Li Wu-Gang Hou Jin-Lian Li Tao Chen Department of Anatomy and K.K.Leung Brain Research Centre Fourth Military Medical UniversityXi’an 710032China Beijing Institute of Basic Medical Sciences Beijing 100850China Key Laboratory of Ministry of Public Health for Forensic Science Xi’an Jiaotong UniversityXi’an 710061China Department of Anesthesiology Xijing HospitalFourth Military Medical UniversityXi’an 710032China Department of Neurosurgery the Second Affiliated Hospital of Xian Jiaotong UniversityXi’an 710004China School of Biomedical Engineering Fourth Military Medical UniversityXi’an 710032China Affiliated Mental Health Centre and Hangzhou Seventh People’s Hospital Zhejiang University School of MedicineHangzhou 310013China The MOE Frontier Research Center of Brain&Brain-machine Integration Zhejiang University School of Brain Science and Brain MedicineHangzhou 310058China Department of Neurology The First Affiliated Hospital of Nanchang UniversityNanchang 330006China Department of Anatomy School of MedicineNorthwest UniversityXi’an 710069China

chronic pain often develops severe mood changes such as depression.However,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely unexplored.Here we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression resilience.We determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA circuit.Furthermore,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner.Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain.Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

关键词： chronic pain depression lateral habenula ventral tegmental area dopamine susceptibility

Evaluation of the Effectiveness and Efficiency of Extracorporeal Shock Wave Combined with Rehabilitation Training in the Treatment of Muscle Articulation chronic pain

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Journal of Clinical and Nursing Research 2024年第4期8卷 110-115页

作者： Dongchou Han Qiya Feng Yingmei Fu Feijian Zhang Dazhen Chen Junmei Wu The First Affiliated Hospital of Hainan Medical College Haikou 571000Hainan ProvinceChina

Objective: To analyze the effect of combined extracorporeal shock wave and rehabilitation training treatment in patients with muscle articulation chronic pain (MACP). Methods: Ninety-seven MACP patients admitted to our hospital from September 2021 to September 2023 were randomly selected and were divided into Group A (control group, 46 cases, rehabilitation training treatment) and Group B (observation group, 51 cases, extracorporeal shock wave with rehabilitation training treatment), and outcomes of the two groups were compared. Results: The treatment efficiency, post-treatment clinical indexes (upper and lower limb function scores, activities of daily living (ADL) scores, visual analog scale (VAS) scores), and short-form 36 (SF-36) scores of Group B were better than those of Group A (P pain.

关键词： Extracorporeal shock wave Rehabilitation training Musculoskeletal joint chronic pain Treatment effect

Forgiveness and chronic pain: A Cohort Study

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pain Studies and Treatment 2024年第2期12卷 13-20页

作者： Sheena O’Beirne Dominic Harmon Medical School University of Limerick Limerick Ireland

Background: chronic pain is a major public health issue. It is a complex condition comprising biological, social and psychological elements, which can be challenging to manage. Forgiveness is a recognised effective intervention in various health conditions. Research has shown promising results using forgiveness as an intervention in the management of pain. This study aims to examine the relationship between forgiveness and other variables in patients suffering from chronic pain in the setting of a chronic pain clinic. Methods: Institutional ethical approval was granted for this study. Patients attending a chronic pain clinic for the first time were invited to complete a questionnaire comprising a brief socio-demographic survey and questionnaires including the Heartland Forgiveness Scale, Hospital Anxiety and Depression Scale, pain and Anxiety Symptoms Scale and Perceived Injustice. Results: 104 adult patients were included. The mean age was 59 years. Back pain was the most common chronic pain presentation. The Heartland Forgiveness Scale (HFS) was found to have a good internal consistency among the Irish population. This study found that 55% of patients attending the pain clinic were not forgiving. Negative correlations were identified between forgiveness and pain, and forgiveness and injustice. Conclusion: The majority of patients attending a chronic pain clinic were not forgiving as measured on the HFS. There was a negative correlation between forgiveness and pain. The results have shown that forgiveness could be beneficial as a therapeutic intervention among patients attending a chronic pain clinic.

关键词： Forgiveness chronic pain Associations

Complex Regional pain Syndrome: Outpatient pain Management in the chronic Setting: A Case Report

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Open Journal of Anesthesiology 2024年第5期14卷 137-144页

作者： Julie Chege Ngugi Kinyungu ITAV pain Management Medical School University of Nairobi New York USA ITAV pain Management Donald and Barbara Zucker School of Medicine at Hofstra/Northwell New York USA

Background: Complex Regional pain Syndrome (CRPS), previously known as reflex sympathetic dystrophy and causalgia, is a neuropathic pain condition that usually develops after an injury to an extremity. CRPS can be a debilitating condition with high levels of pain and reduced function. Aim: This case report aims to discuss the multimodal approach in the management of a patient who presented with ongoing poorly controlled pain secondary to CRPS from an injury that happened years prior. Case Presentation: A 45-year-old female was involved in a motor vehicle accident where her right leg was injured. She underwent several surgeries and developed CRPS that significantly reduced her mobility and quality of life. She presented to the pain clinic years after her initial injury and a multimodal regimen was started for her resulting in significantly improved function. Conclusion: CRPS can be a severely debilitating condition. While early diagnosis and management are important, ongoing management in the outpatient chronic pain setting is important in maintaining a good level of function.

关键词： chronic Regional pain Syndrome (CRPS) Multimodal Management chronic pain Sequelae

Dissecting the Neural Circuitry for pain Modulation and chronic pain:Insights from Optogenetics

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Neuroscience Bulletin 2022年第4期38卷 440-452页

作者： Fang Guo Yu Du Feng-Hui Qu Shi-Da Lin Zhong Chen Shi-Hong Zhang Department of Pharmacology and Department of Anesthesiology of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhou 310058China Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province College of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China

pain is an unpleasant sensory and emotional experience associated with,or resembling that associated with,actual or potential tissue damage.The processing of pain involves complicated modulation at the levels of the periphery,spinal cord,and brain.The pathogenesis of chronic pain is still not fully understood,which makes the clinical treatment challenging.Optogenetics,which combines optical and genetic technologies,can precisely intervene in the activity of specific groups of neurons and elements of the related circuits.Taking advantage of optogenetics,researchers have achieved a body of new findings that shed light on the cellular and circuit mechanisms of pain transmission,pain modulation,and chronic pain both in the periphery and the central nervous system.In this review,we summarize recent findings in pain research using optogenetic approaches and discuss their significance in understanding the pathogenesis of chronic pain.

关键词： Optogenetics pain transmission pain modulation chronic pain Neural circu

Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression

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Neural Regeneration Research 2024年第10期19卷 2144-2156页

作者： Ying Ma Yue Qiao Xiang Gao Spinal Cord and Brain Injury Research Group Stark Neuroscience Research InstituteIndianapolisINUSA Department of Neurological Surgery Indiana University School of MedicineIndianapolisINUSA Department of Neurology Shengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer's disease. The largescale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

关键词： antidepressants chronic pain depression exercise hippocampal neurogenesis inflammation inhibition neuroinflammation physical activity deficits social isolation spinal cord injury

Chemogenetic and Optogenetic Manipulations of Microglia in chronic pain

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Neuroscience Bulletin 2023年第3期39卷 368-378页

作者： Sebastian Parusel Min-Hee Yi Christine L.Hunt Long-Jun Wu Department of Neurology Mayo ClinicRochesterMN 55905USA Faculty of Psychology and Neuroscience Maastricht UniversityMaastricht MD6200The Netherlands Department of pain Medicine Mayo ClinicJacksonvilleFL 32224USA Department of Neuroscience Mayo ClinicJacksonvilleFL 32224USA Department of Immunology Mayo ClinicRochesterMN 55905USA

chronic pain relief remains an unmet medical need.Current research points to a substantial contribution of glia-neuron interaction in its pathogenesis.Particularly,microglia play a crucial role in the development of chronic pain.To better understand the microglial contribution to chronic pain,specific regional and temporal manipulations of microglia are necessary.Recently,two new approaches have emerged that meet these demands.Chemogenetic tools allow the expression of designer receptors exclusively activated by designer drugs(DREADDs)specifically in microglia.Similarly,optogenetic tools allow for microglial manipulation via the activation of artificially expressed,light-sensitive proteins.Chemo-and optogenetic manipulations of microglia in vivo are powerful in interrogating microglial function in chronic pain.This review summarizes these emerging tools in studying the role of microglia in chronic pain and highlights their potential applications in microglia-related neurological disorders.

关键词： chronic pain Microglia Optogenetics Chemogenetics DREADDs ReaChR

Targeting the nitric oxide/cGMP signaling pathway to treat chronic pain

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Neural Regeneration Research 2023年第5期18卷 996-1003页

作者： Dan-Yang Li Shao-Jie Gao Jia Sun Long-Qing Zhang Jia-Yi Wu Fan-He Song Dai-Qiang Liu Ya-Qun Zhou Wei Mei Department of Anesthesiology and pain Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Nitric oxide(NO)/cyclic guanosine 3′,5′-monophosphate(cGMP) signaling has been shown to act as a mediator involved in pain transmission and processing. In this review, we summarize and discuss the mechanisms of the NO/cGMP signaling pathway involved in chronic pain, including neuropathic pain, bone cancer pain, inflammatory pain, and morphine tolerance. The main process in the NO/cGMP signaling pathway in cells involves NO activating soluble guanylate cyclase, which leads to subsequent production of cGMP. cGMP then activates cGMP-dependent protein kinase(PKG), resulting in the activation of multiple targets such as the opening of ATP-sensitive K+ channels. The activation of NO/cGMP signaling in the spinal cord evidently induces upregulation of downstream molecules, as well as reactive astrogliosis and microglial polarization which participate in the process of chronic pain. In dorsal root ganglion neurons, natriuretic peptide binds to particulate guanylyl cyclase, generating and further activating the cGMP/PKG pathway, and it also contributes to the development of chronic pain. Upregulation of multiple receptors is involved in activation of the NO/cGMP signaling pathway in various pain models. Notably the NO/cGMP signaling pathway induces expression of downstream effectors, exerting both algesic and analgesic effects in neuropathic pain and inflammatory pain. These findings suggest that activation of NO/cGMP signaling plays a constituent role in the development of chronic pain, and this signaling pathway with dual effects is an interesting and promising target for chronic pain therapy.

关键词： bone cancer pain chronic pain cyclic GMP dorsal root ganglion inflammatory pain morphine tolerance neuropathic pain nitric oxide protein kinase G spinal cord

CYP1B1-derived epoxides modulate the TRPA1channel in chronic pain

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Acta Pharmaceutica Sinica B 2023年第1期13卷 68-81页

作者： Lili Sun Jie Zhang Changshan Niu Cassandra E.Deering-Rice Ronald W.Hughen John G.Lamb Katherine Rose Kevin M.Chase Marysol Almestica-Roberts Markel Walter Eric W.Schmidt Alan R.Light Baldomero M.Olivera Christopher A.Reilly Department of Pharmacology and Toxicology Center for Human ToxicologyUniversity of UtahSalt Lake CityUT84112USA Department of Anesthesiology School of MedicineUniversity of UtahSalt Lake CityUT 84112USA Department of Medicinal Chemistry University of UtahSalt Lake CityUT 84112USA School of Biological Sciences University of UtahSalt Lake CityUT 84112USA

pain is often debilitating,and current treatments are neither universally efficacious nor without risks.Transient receptor potential(TRP)ion channels offer alternative targets for pain relief,but little is known about the regulation or identities of endogenous TRP ligands that affect inflammation and pain.Here,transcriptomic and targeted lipidomic analysis of damaged tissue from the mouse spinal nerve ligation(SNL)-induced chronic pain model revealed a time-dependent increase in Cyp1b1 mRNA and a concurrent accumulation of 8,9-epoxyeicosatrienoic acid(EET)and 19,20-EpDPA post injury.Production of 8,9-EET and 19,20-EpDPA by human/mouse CYP1B1 was confirmed in vitro,and 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptidergic dorsal root ganglia(DRG)neurons.TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079,and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1.This latter effect mapped to residues Y933,G939,and S921 of TRPA1.Intra-plantar injection of 19,20-EpDPA induced acute mechanical,but not thermal hypersensitivity in mice,which was also blocked by A967079.Similarly,Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury.These data suggest that manipulation of the CYP1B1-oxylipin-TRPA1 axis might have therapeutic benefit.

关键词： CYPIB1 Spinal nerve ligation Epoxides TRPA1 Calcium imaging Hyperalgesia chronic pain Inflammation