Hyperalgesic Priming in Chronic Widespread Pain: Role of the Stress Axes (360G-Wellcome-320180_Z_24_Z)

Devastating for millions, costing the UK economy >£10 billion annually, chronic pain remains poorly understood. While some individuals appear to be primed to develop chronic pain, how these risk factors predispose remains an enigma. Stress and early life adversity, especially prevalent among lower socioeconomic groups, are major risk factors. Pre-clinical evidence indicates unchecked hypothalamic-pituitary-adrenal / sympathoadrenal stress axis activation, along with the resulting pro-inflammatory immune dysregulation, can induce a form of latent pro-nociceptive plasticity in nociceptors, hyperalgesic priming (priming), preceding persistent pain. This latent state provides an opportunity to prevent chronic pain. Employing microneurography to determine sensory nerve stimulus-response properties, I have developed protocols to quantify plasticity at single afferent resolution. I will combine this cutting-edge in-vivo approach with deep sensory phenotyping, in a mechanistic study, to determine if nociceptors in people with, or at risk of developing, chronic pain are primed. I will also identify key neurohumoral and neuroinflammatory factors associated with stress-axis engagement that contribute to priming. Finally, I will test if nociceptor function can be ‘re- set’ by normalising intracellular pathways on which maintenance of priming depends, providing a pathway for novel therapeutics to treat and prevent chronic pain and its co-morbidities.