| Title: | Long-term male-specific chronic pain via telomere- and p53-mediated spinal cord cellular senescence |
| Journal: | Journal of Clinical Investigation |
| Published: | 15 Apr 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35426375/ |
| DOI: | https://doi.org/10.1172/jci151817 |
| URL: | http://www.jci.org/articles/view/151817/files/pdf |
| Citations: | 35 (28 in last 2 years) as of 8 Aug 2024 |
Publication 12411
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Abstract
Mice with experimental nerve damage can display long-lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53-mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53-positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male-specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male-specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53-specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male-specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.</p>
12 Keywords
- Animals
- Cellular Senescence
- Chronic Pain
- Female
- Hyperalgesia
- Male
- Mice
- Microglia
- Neuralgia
- Spinal Cord
- Telomere
- Tumor Suppressor Protein p53
26 Authors
- Arjun Muralidharan
- Susana G. Sotocinal
- Noosha Yousefpour
- Nur Akkurt
- Lucas V. Lima
- Shannon Tansley
- Marc Parisien
- Chengyang Wang
- Jean-Sebastien Austin
- Boram Ham
- Gabrielle M.G.S. Dutra
- Philippe Rousseau
- Sioui Maldonado-Bouchard
- Teleri Clark
- Sarah F. Rosen
- Mariam R. Majeed
- Olivia Silva
- Rachel Nejade
- Xinyu Li
- Stephania Donayre Pimentel
- Christopher S. Nielsen
- G. Gregory Neely
- Chantal Autexier
- Luda Diatchenko
- Alfredo Ribeiro-da-Silva
- Jeffrey S. Mogil
1 Application
| Application ID | Title |
|---|---|
| 20802 | A replication study of pain interactions with comorbidities |
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