Introduction: the so-called adversities in the initial stages of life involve exposure to environmental circumstances during childhood or adolescence which require a considerable capacity for psychological, behavioral or neurobiological adaptation and which represent a marked deviation from expected circumstances. Life events are major, rare and unusual life changes that may be beyond an individual's ability to control. Acute stress is crucial for the survival of the individual: subjects are alerted to dangerous or deadly situations and can subsequently respond when the same condition recurs. The problem is when stress becomes chronic, as chronic deleterious experiences exert an important influence on responses to stress, especially in the early stages of life, where it is associated with the development of chronic pain. The basal mechanism is represented by the dysregulation of the hypothalamic-pituitary-adrenal axis, caused by the loss of stress-induced homeostasis.

Result: Hippocampus and Amygdala play a role in inhibiting or stimulating these phenomena. In conditions of Early Life Adversity, the Hippocampus reduces in volume and function, therefore it is unable to exert the inhibitory action on the Axis. On the other hand, the Amygdala increases in volume and activity, with enhanced activation of the Axis. Added to this is a reduction in the volume and activity of the prefrontal cortex with a decline in higher cognitive functions. If the reduction of higher cognitive abilities is associated with an increase in emotionality or fear, we will have a lowering of the pain threshold. There are two phenomena that unbalance the system: increased expression of CRF in the Amygdala and decrease in GC (Glucocorticoid) and BDNF receptors in the Hippocampus (reduced inhibition on the Hypothalamus). The increased function of the Amygdala and the reduced function of the Hippocampus unbalance the system, facilitating the activation of the Axis. During chronic stress, the increase in the number of CRF-producing neurons, the activity of CRF-mRNA in the PVN and the hyperactivity of the noradrenergic system at the locus ceruleus cause central anxiogenic activity and facilitation of peripheral inflammation. In these conditions, mast cells express abundant receptors for CRF, therefore, the massive release of CRF causes a more intense activation of mast cells, with an increase in peripheral nociception.

Conclusions: In conditions of chronic stress, the increase in CRF in the periphery (due to dysregulation of the Axis) results in the massive activation of Mast Cells, followed by sensitization phenomena of the peripheral nerve terminals, with a crucial lowering of the pain threshold.

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