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

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.