Long-term male-specific chronic pain via telomere- and p53‑mediated spinal cord cellular senescence
Arjun Muralidharan, … , Alfredo Ribeiro-da-Silva, Jeffrey S. Mogil
Arjun Muralidharan, … , Alfredo Ribeiro-da-Silva, Jeffrey S. Mogil
Published April 15, 2022
Citation Information: J Clin Invest. 2022;132(8):e151817. https://doi.org/10.1172/JCI151817.
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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

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Figure 6

Targeted apoptosis of spinal cord p53-positive senescent cells using the peptide FOXO4-DRI reduces SNI allodynia in a sex- and time-dependent manner.

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Targeted apoptosis of spinal cord p53-positive senescent cells using the...
(A and B) Mice of both sexes were tested for mechanical sensitivity and given SNI surgery. Nine months after SNI (A) or 2 weeks after SNI (B), they were tested again, and injected daily as shown by arrows with FOXO4-DRI (10 μg, intrathecally) or vehicle. Symbols represent mean ± SEM withdrawal threshold (g) of the ipsilateral hind paw (no changes were seen at any time point on the contralateral paw) compared with post-SNI testing immediately prior to drug administration (such that positive values represent reversal of mechanical allodynia); n = 5–6 mice/sex/drug/age. *P < 0.05, **P < 0.01, ***P < 0.001 compared with 0 (i.e., post-SNI, pre-drug baseline) via post hoc testing after 2-between, 1-within repeated-measures ANOVA. (C) Effect on senescence pathway and SASP effector gene expression of FOXO4‑DRI treatment in mice 9 months after SNI. Bars represent mean ± SEM (n = 3–6 mice/drug/sex; values shown are averages of 3 technical replicates) relative expression compared with the housekeeping gene, Gapdh, and normalized to the male-vehicle group. *P < 0.05 as indicated via t test following 2-way ANOVA.