Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Muralidharan, A; Sotocinal, SG; Yousefpour, N; Akkurt, N; Lima, LV; Tansley, S; Parisien, M; Wang, C; Austin, J-S; Ham, B; Dutra, GM; Rousseau, P; Maldonado-Bouchard, S; Clark, T; Rosen, SF; Majeed, MR; Silva, O; Nejade, R; Li, X; Donayre Pimentel, S; Nielsen, CS; Neely, GG; Autexier, C; Diatchenko, L; Ribeiro-da-Silva, A; Mogil, JS

Published Date

  • April 15, 2022

Published In

Volume / Issue

  • 132 / 8

PubMed ID

  • 35426375

Pubmed Central ID

  • PMC9012275

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI151817

Language

  • eng

Conference Location

  • United States