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.

Omics approaches to discover pathophysiological pathways contributing to human pain

“…In addition, more attention is starting to be paid to duration of behaviors in these assays as well as their peak intensity. 54 , 57 , 70 , 75 …”

“…In addition, more attention is starting to be paid to duration of behaviors in these assays as well as their peak intensity. 54,57,70,75 It is important to note that some biological processes can be captured well by one -omics method but not others. The genes of the inflammatory response represent one example.…”

Sex and gender differences in pain: past, present, and future

“…In a second example, using the UK Biobank cohort, a male-specific genetic association with chronic pain-related mortality was found. 133 There is also higher incidence of suicide in men, but whether chronic pain is a risk factor is currently unknown. 91 These studies indicate women experience more pain, and show that pain has a profound impact on men.…”

Mitochondria and sensory processing in inflammatory and neuropathic pain

“…Increased ROS production is a feature of senescence cells, i.e., cells that have entered a non-proliferative state. Cellular senescence is accompanied by a distinct secretory phenotype, senescence-associated secretory phenotype (SASP), which includes a variety of secreted proteins, cytokines and chemokines that can drive chronic inflammation ( 255 , 256 ). Recently, cellular senescence has been identified in nervous tissue in mice with long-lasting (>4 months) neuropathic pain.…”