The Neurobiological Stress and Pain Connection: Current Research and Avenues for Future Directions

Abstract

Chronic pain imposes widespread physiological effects across multiple body systems via inflammation and dysregulation. Chronic stress has been proposed to impact pain chronification through parallel processes. Preliminary research has examined hypothalamic-pituitary-adrenal (HPA) axis dysfunction and allostatic load (AL; nervous system "wear and tear"), but several aspects of the neurobiological stress response have yet to be investigated. This study presents a comprehensive review of the literature on the neurobiological connection between stress and pain and the formulation of a theoretical model that proposes new avenues for investigation. Minimal research has specifically examined the neurobiological processes associated with stress and pain. Of the research that has been performed, the majority has focused on the HPA-axis and associated processes (i.e., AL) and functional connectivity in associated brain regions. Elucidated gaps in the literature and potential avenues of investigation into the stress and pain connection should include glial cell activation, telomere attrition, and endocannabinoid functioning. Specifically, in response to injury and damage, glial cells (namely astrocytes and microglia) begin inflammatory reactions that can increase neuronal sensitization, potentially leading to further pain chronification. Early life stress has been shown to increase dysfunction of astrocyte regulation, affecting corticotropin-releasing factors and HPA axis. When telomeres or the caps at the end of DNA strands are under chronic stress, the HPA axis is activated, generating reactive oxygen species, and leading to stress-related inflammatory damage. Of the endocannabinoid system, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) modulate HPA axis activation. Chronic stress has been shown to reduce AEA and increase 2-AG, affecting pain perception and synaptic plasticity. Chronic stress and pain are damaging to the body, but the neurological connection between stress and pain remains poorly understood. We will develop more targeted chronic pain management and prevention interventions by evaluating the relationship between stress and pain from a neurological perspective.