4.8 Article

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

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 8, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI151817

Keywords

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Funding

  1. Canadian Institutes of Health Research
  2. Brain Canada
  3. Cancer Council New South Wales
  4. Ronald Melzack Fellowship in Chronic Pain Research from the Louise and Alan Edwards Foundation

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Mice with experimental nerve damage display long-lasting neuropathic pain behavior. Senescence in the spinal cord for 4 months results in the maintenance of pain and a decreased lifespan. Nerve injury increases the number of p53-positive cells in the spinal cord neurons, astrocytes, and microglia, with a male-specific increase observed only in microglia. Repeated administration of a p53-specific substance reverses pain hypersensitivity.
Mice with experimental nerve damage can display long-lasting neuropathic pain behavior. We show here that 4 months 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 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.

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