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与衰老相关的 PGC-1α 减少会促进疼痛慢性化。

Aging-associated decrease of PGC-1α promotes pain chronification.

机构信息

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA.

出版信息

Aging Cell. 2024 Aug;23(8):e14177. doi: 10.1111/acel.14177. Epub 2024 May 17.

DOI:10.1111/acel.14177
PMID:38760908
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11320346/
Abstract

Aging is generally associated with declining somatosensory function, which seems at odds with the high prevalence of chronic pain in older people. This discrepancy is partly related to the high prevalence of degenerative diseases such as osteoarthritis in older people. However, whether aging alters pain processing in the primary somatosensory cortex (S1), and if so, whether it promotes pain chronification is largely unknown. Herein, we report that older mice displayed prolonged nociceptive behavior following nerve injury when compared with mature adult mice. The expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) in S1 was decreased in older mice, whereas PGC-1α haploinsufficiency promoted prolonged nociceptive behavior after nerve injury. Both aging and PGC-1α haploinsufficiency led to abnormal S1 neural dynamics, revealed by intravital two-photon calcium imaging. Manipulating S1 neural dynamics affected nociceptive behavior after nerve injury: chemogenetic inhibition of S1 interneurons aggravated nociceptive behavior in naive mice; chemogenetic activation of S1 interneurons alleviated nociceptive behavior in older mice. More interestingly, adeno-associated virus-mediated expression of PGC-1α in S1 interneurons ameliorated aging-associated chronification of nociceptive behavior as well as aging-related S1 neural dynamic changes. Taken together, our results showed that aging-associated decrease of PGC-1α promotes pain chronification, which might be harnessed to alleviate the burden of chronic pain in older individuals.

摘要

衰老是与感觉功能下降相关的，而老年人慢性疼痛的高发病率似乎与之相悖。这种差异部分与老年人退行性疾病（如骨关节炎）的高发率有关。然而，衰老是如何改变初级体感皮层（S1）的疼痛处理过程，以及是否促进了疼痛的慢性化，在很大程度上尚不清楚。在此，我们报告称，与成熟成年小鼠相比，老年小鼠在神经损伤后表现出更长时间的痛觉行为。S1 中过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）的表达在老年小鼠中降低，而 PGC-1α 单倍不足则促进了神经损伤后的长时间痛觉行为。衰老和 PGC-1α 单倍不足都会导致 S1 神经动力学异常，这可以通过活体双光子钙成像来揭示。操纵 S1 神经动力学会影响神经损伤后的痛觉行为：S1 中间神经元的化学遗传抑制会加重正常小鼠的痛觉行为；S1 中间神经元的化学遗传激活则会减轻老年小鼠的痛觉行为。更有趣的是，腺相关病毒介导的 S1 中间神经元中 PGC-1α 的表达改善了与衰老相关的痛觉行为慢性化以及与衰老相关的 S1 神经动力学变化。总之，我们的研究结果表明，衰老相关的 PGC-1α 减少促进了疼痛的慢性化，这可能被用来减轻老年人慢性疼痛的负担。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/206dd6565832/ACEL-23-e14177-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d2ad3c798938/ACEL-23-e14177-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d116a6e92aba/ACEL-23-e14177-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/ac7ad9babcec/ACEL-23-e14177-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/ae9a0e796f1b/ACEL-23-e14177-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d803bc640b14/ACEL-23-e14177-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/69cc1bc48447/ACEL-23-e14177-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/206dd6565832/ACEL-23-e14177-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d2ad3c798938/ACEL-23-e14177-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d116a6e92aba/ACEL-23-e14177-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/ac7ad9babcec/ACEL-23-e14177-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/ae9a0e796f1b/ACEL-23-e14177-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/d803bc640b14/ACEL-23-e14177-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/69cc1bc48447/ACEL-23-e14177-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/28dc/11320346/206dd6565832/ACEL-23-e14177-g004.jpg

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