The Role of Stress Regulation on Neural Plasticity in Pain Chronification

Abstract

Pain, especially chronic pain, is one of the most common clinical symptoms and has been considered as a worldwide healthcare problem. The transition from acute to chronic pain is accompanied by a chain of alterations in physiology, pathology, and psychology. Increasing clinical studies and complementary animal models have elucidated effects of stress regulation on the pain chronification via investigating activations of the hypothalamic-pituitary-adrenal (HPA) axis and changes in some crucial brain regions, including the amygdala, prefrontal cortex, and hippocampus. Although individuals suffer from acute pain benefit from such physiological alterations, chronic pain is commonly associated with maladaptive responses, like the HPA dysfunction and abnormal brain plasticity. However, the causal relationship among pain chronification, stress regulation, and brain alterations is rarely discussed. To call for more attention on this issue, we review recent findings obtained from clinical populations and animal models, propose an integrated stress model of pain chronification based on the existing models in perspectives of environmental influences and genetic predispositions, and discuss the significance of investigating the role of stress regulation on brain alteration in pain chronification for various clinical applications.

Figure 1

Stress models of chronic pain. (a) The neurotoxic model, from the perspective of environmental influences, conceptualizes that chronic pain intensity or pain duration may lead to the maladaptive stress response, affecting the structure and function of the hippocampal formation and the parahippocampal gyrus (PHG) [32]. (b) The vulnerability model, from the perspective of genetic predispositions, conceptualizes that the small hippocampal volume as a vulnerable factor affects the levels of stress hormones, which in turn lead to enhanced activations of the parahippocampal gyrus and increased persistent pain intensity [32]. (c) The proposed integrated model, from the perspective of the combination of environmental influences and genetic predispositions, conceptualizes that vulnerable factors (e.g., properties of particular brain structures) and environmental factors (e.g., injury) codetermine the levels of basal cortisol, which result in the brain alterations. Thereafter, these physiological responses either return to normal levels with an adaptive manner or initiate a vicious cycle of cortisol dysfunction, brain reorganizations, and persistent pain state.