Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence
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
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
View: Text | PDF
Research Article Neuroscience

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

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.

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

×

Figure 1

Relationship between TL and long-lasting allodynia produced by SNI.

Options: View larger image (or click on image) Download as PowerPoint
Relationship between TL and long-lasting allodynia produced by SNI. (A) ...
(A) SNI produces robust and long-lasting decreases in withdrawal thresholds of the ipsilateral (Ipsi.) hind paw compared with the contralateral (Contra.) hind paw and sham‑operated mice. Symbols represent mean ± SEM 50% withdrawal threshold (g); n = 24–38 mice/surgery/time point. Note that separate cohorts of mice were tested at each time point shown; baselines of all cohorts are averaged. (B) Allodynia data analyzed separately by sex (left/blue, males; right/pink, females). Bars represent mean ± SEM change (Δ) in withdrawal thresholds at each time point compared with baseline thresholds; data were transformed because baselines vary by sex. Compare with Supplemental Figure 1. (C) SNI leads to reductions in PBMC TL at 4 and 14 months after surgery in male mice (left) but not female mice (right). Bars represent mean ± SEM TL measured in kb/diploid genome; n = 16–36 mice/surgery/time point. (D) TL reduction at 4 months after SNI surgery is accompanied by lower telomerase enzyme activity in PBMCs. Symbols represent relative telomerase activity (see Methods). (E and F) Lumbar spinal cord FACS-sorted microglia (E) and astrocyte (F) TL data analyzed separately by sex. Bars as in C; n = 3 biological replicate pools/sex/surgery; each pool consisted of spinal cord tissues from n = 4 mice. *P < 0.05, **P < 0.01, ***P < 0.001 compared with other surgery group via t test.