Tissue damage produces pain, pain produces stress, and stress reallocates systemic and cellular metabolic resources to meet the demands for energy and biomass created by injury. The elements of this sequence are usually studied in separation, yet they constitute a single adaptive response: there is no pain devoid of stress. Painful stimuli activate the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, increasing circulating catecholamines and glucocorticoids; painful injury can also recruit the renin–angiotensin–aldosterone system.
Together, these signals mobilize glucose and lipids, preserve vascular volume and perfusion, redirect energy away from dispensable functions, and support immune defense, inflammation, and tissue repair. Corticosterone in rodents and cortisol in humans are critical components of this coordinated endocrine and metabolic response to injury. The central nervous system participates throughout: it processes nociceptive input and transforms it into autonomic and endocrine outputs while undergoing metabolic reallocation of its own.
These systemic and neural adaptations likely meet the energetic and biosynthetic demands imposed by enhanced neural activity, neuroplasticity, immune defense, and tissue repair. Stress should therefore be viewed not as an external factor that aggravates or facilitates pain, but as an integral component of the pain response and of the metabolic work required to sustain it. This is a preview of subscription content, access via your institution Receive 13 print issues and online access We are sorry, but there is no personal subscription option available for your country.
Prices may be subject to local taxes which are calculated during checkout Coutens B, Bouchet CA, Gvon I, Patti LC, De Anda Gamboa CM, Jewett DC, et al. Glucocorticoid–endocannabinoid crosstalk in the ventrolateral periaqueductal gray (vlPAG) promotes pain resolution. Neuropsychopharmacology. 2026. https://doi.org/10.1038/s41386-026-02529-5.
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