Aging Promotes Pain Chronification through Changes in PGC-1alpha Expression and Interneuron Dysfunction

衰老通过 PGC-1α 表达的变化和中间神经元功能障碍促进疼痛慢性化

• 批准号: 10250503
• 负责人: Shiqian Shen
• 金额: $ 16.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250503
• 关键词: Adjuvant; Adult; Affect; Age; Aging; American; Animals; Applications Grants; Area; Arthritis; Attention; Behavior; Behavioral Assay; Biogenesis; Biological; C57BL/6 Mouse; Calcium; Centers for Disease Control and Prevention (U.S.); Clinical Research; Data; Diabetes Mellitus; Elderly; Emotional; Exhibits; Functional disorder; Future; Grant; Heart Diseases; Impaired cognition; Impairment; Individual; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Interneuron function; Interneurons; Joints; Malignant Neoplasms; Mediating; Mental Depression; Mitochondria; Molecular; Molecular Biology; Mood Disorders; Morbidity - disease rate; Mus; Neurons; Nociception; Outcome; Pain; Pain Research; Pathogenesis; Population; Pre-Clinical Model; Prevalence; PubMed; Quality of life; Rattus; Reporting; Research; Role; Somatosensory Cortex; Testing; Thermal Hyperalgesias; age group; aged; ankle joint; arthritic pain; calmodulin-dependent protein kinase II; chronic pain; clinically significant; comorbidity; cost; frailty; functional decline; human old age (65+); human very old age (85+); inflammatory pain; innovation; insight; juvenile animal; mechanical allodynia; mortality; mouse model; nociceptive response; novel; pain chronification; pre-clinical; sensor; somatosensory; stem; therapeutic target; translational study; two photon microscopy; young adult

Chronic pain affects millions of Americans and costs more than $635 billion yearly. The burden of chronic pain is heavily tilted toward older adults. For example, the prevalence of chronic pain is 13.2% in adults 25-44 years old, but 33.6% in population >85 years old. Pain in older adults not only negatively impacts quality of life, increases frailty, but also is related with depression and cognitive decline. As such, studying chronic pain in older individuals, particularly the pathogenesis of pain, the mechanisms behind pain chronification, and the comorbid interactions between pain and other aging related issues is urgently warranted. Age, however, has largely been ignored as a biological variable in preclinical pain research. In preliminary studies, we examined if pain in older animals has unique features than that in younger animals. Specifically, we challenged animals with CFA to induce arthritis, and examined nociceptive behavior in 2 months (young), 12 months (adult), and 25 months old (aged) C57BL/6 mice. Results indicate that the same inflammatory insult in ankle joint led to significant mechanical allodynia in all age groups. However, the duration of mechanical allodynia lasted for about 4 weeks, 4 weeks, and 7 weeks, in young, adult, and aged mice respectively. Thermal hyperalgesia in these animals lasted about 3 weeks, 3.5 weeks, and 6 weeks, respectively. We ruled out unresolved joint inflammatory responses as the cause of prolonged nociceptive responses in aged mice. It is therefore likely that aged animals exhibited pain chronification associated with aging. Our lab has previously found that PGC-1, a master regulator of mitochondria biogenesis, is implicated in pain chronification. More intriguingly, preliminary data also indicate that aged mice expressed lower levels of PGC-1 in somatosensory cortex than their younger counterparts. PGC-1 is preferentially expressed in, and critical for the function of, interneurons, whose dysfunction has been associated with functional and cognitive decline in aging. As such, we hypothesize that aging is associated with decreased somatosensory cortex PGC-1 levels, which impairs interneuron function and facilitates pain chronification. We plan to carry out two Specific Aims to test this hypothesis. Aim 1: To examine the impact of age on neuronal activities in pain. Aim 2: To study if pain chronification in aging can be ameliorated by increasing PGC-1 levels in somatosensory cortex S1. Taken together, this R03 GEMMSTAR proposal aims at examining age as a biological variable in pain, particularly in pain chronification associated with aging, in a preclinical model. This is an area that has great clinical significance but has received little research attention to date. This grant is innovative as it combines molecular biology, cutting edge intravital two-photon microscopy, and behavioral assays to examine a key role for PGC-1 and interneuron in aging and pain chronification. Successful execution of this grant will provide novel mechanistic insights into pain chronification associated with aging, to inform future translational and clinical studies.

慢性疼痛影响着数百万美国人，每年花费超过6350亿美元。慢性疼痛的负担

项目成果

Indole-3-Propionic Acid, a Gut Microbiota Metabolite, Protects Against the Development of Postoperative Delirium.

• DOI: 10.1097/sla.0000000000005886
• 发表时间: 2023-12-01
• 期刊: Annals of surgery
• 影响因子: 9

Bioluminescence Imaging with Functional Amyloid Reservoirs in Alzheimer's Disease Models.

• DOI: 10.1021/acs.analchem.3c02358
• 发表时间: 2023-09
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: Jing Yang;Weihua Ding;Biyue Zhu;Sherri Y. Zhen;Shi Kuang;Jun Yang;C. Zhang;Peng Wang

Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography.

• DOI: 10.1021/acs.jmedchem.1c01477
• 发表时间: 2021-10-28
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Lan Y;Bai P;Liu Y;Afshar S;Striar R;Rattray AK;Meyer TN;Langan AG;Posner AM;Shen S;Tanzi RE;Zhang C;Wang C
• 通讯作者: Wang C

Gut Microbiome in Anesthesiology and Pain Medicine.

• DOI: 10.1097/aln.0000000000004204
• 发表时间: 2022-07-01
• 期刊: ANESTHESIOLOGY
• 影响因子: 8.8
• 作者: Minerbi, Amir;Shen, Shiqian
• 通讯作者: Shen, Shiqian

Foramen lacerum impingement of trigeminal nerve root as a rodent model for trigeminal neuralgia.

• DOI: 10.1172/jci.insight.168046
• 发表时间: 2023-06-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Ding, Weihua;Yang, Liuyue;Chen, Qian;Hu, Kun;Liu, Yan;Bao, Eric;Wang, Changning;Mao, Jianren;Shen, Shiqian
• 通讯作者: Shen, Shiqian