Figure 1.

(a) Activation of the immune and inflammatory response of any aetiology leads to peripheral production and/or circulation of proinflammatory agents, which, through endocrine or neural afferent signals, stimulate a central nervous system (CNS) inflammatory cascade, cause manifestations of the sickness syndrome and spur the hypothalamic–pituitary–adrenal (HPA) axis at all levels. Note the involvement of NF‐κB, a major proinflammatory transcription factor in both CNS and peripheral inflammation. On the other hand, the activated HPA axis, through its end‐hormone, cortisol, and its receptor (GR), inhibits CNS and peripheral inflammation, as well as its own activity. (b) The presence of increased proinflammatory cytokines and other agents in the vicinity of peripheral somatic and autonomic afferent nerves decreases the pain and fatigue threshold of an individual and hence produces hyperalgesia and fatigue. This is further accentuated by post‐stress hypocortisolism and diminished by cortisol elevations or administration. iCRH, immune corticotropin‐releasing hormone; Sms, somatostatin; TLR, Toll‐like receptor.