Telomeres and spinal cord cellular senescense affect long-term chronic pain and mortality in male but not female mice
Arjun Muralidharan (1, 5), Susana Sotocinal (1), Nur Akkurt (1), Noosha Yousefpour (2), Chengyang Wang (1), Shannon Tansley (1), Jean-Sebastien Austin (1), Alfredo Ribeiro-da-Silva (2), Luda Diatchenko (3, 4) and Jeffrey Mogil (1, 3)
Department of Psychology, McGill University, Montreal, Canada
Department of Pharmacology, McGill University, Montreal, Canada
Department of Anesthesia, McGill University, Montreal, Canada
Faculty of Dentistry, McGill University, Montreal, Canada
Charles Perkins Centre, University of Sydney, New South Wales, Australia
Telomere shortening exerts pathological effects via p53-mediated cellular senescence, a state of cell-cycle arrest known to release various pro-nociceptive mediators. Chronic pain is a robust stressor, and stress has been convincingly shown to produce telomere shortening. Although studies have associated reduced telomere length (TL) with clinical pain sensitivity and implicated cellular senescence in the pathogenesis of diseases that feature pain, no systematic analysis of their interaction has ever been undertaken. Here, we investigated the role of telomeres and cellular senescence in the pathobiology of chronic neuropathic pain. Spared nerve injury (SNI) produced long-lasting pain hypersensitivity and peripheral blood mononuclear cell (PBMC) TL shortening (at 4- and 14-months post-surgery)–effects that were only observed in male mice. These effects occurred more rapidly in older male mice with nerve injury, with PBMC TL inversely correlated with pain hypersensitivity. Further characterisation demonstrated reduced TL in peripheral monocytes/CD8+ T-cells and spinal microglia of male SNI-mice. At 14-months post-SNI, there was a significant increase in the number of senescent cells (SA-β-GAL+) within the lumbar dorsal horn, with male SNI-mice exhibiting ~3-fold higher senescent cells than female SNI-mice. Immunohistochemical characterisation at 14-months post-SNI showed a significant increase in the expression levels of p53+ microglia in the lumbar dorsal horn of male SNI-mice, and intrathecal administration of p53 antagonist (alpha-pifithrin) produced significant reduction of pain hypersensitivity only in male SNI-mice. Transgenic mice lacking the enzyme telomerase (Terc-/-), and thus having shorter telomeres, displayed hypersensitivity to pain in the naïve state as well as following SNI. Finally, male Terc-/- mice with SNI had significantly reduced lifespan compared to all other groups. In summary, our data establish a novel bidirectional, causal and sex-specific relationship between cellular ageing pathways and chronic pain sensitivity, and are the first conclusive evidence that pain, if left untreated, can increase the likelihood of death.