| First Author | Muralidharan A | Year | 2022 |
| Journal | J Clin Invest | Volume | 132 |
| Issue | 8 | PubMed ID | 35426375 |
| Mgi Jnum | J:323933 | Mgi Id | MGI:7264255 |
| Doi | 10.1172/JCI151817 | Citation | Muralidharan A, et al. (2022) Long-term male-specific chronic pain via telomere- and p53mediated spinal cord cellular senescence. J Clin Invest 132(8):e151817 |
| abstractText | Mice with experimental nerve damage can display longlasting 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 p53mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase malespecific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in malespecific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53specific 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 malespecific 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. |
