Carbon Monoxide Regulates Stress Axis Responses Context-Dependently, Modulating HPA and SAM Systems

The term stress, defined as any event disrupting organismal homeostasis, activates the hypothalamic–pituitary–adrenal (HPA) axis and sympatho-adrenal-medullary (SAM) system. Acute stress triggers rapid release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol, alongside epinephrine and norepinephrine, facilitating immediate survival. Conversely, chronic stress leads to prolonged HPA axis activation, dysregulating glucocorticoid (GC) secretion, attenuating negative feedback, and causing structural changes in key brain regions like the hippocampus. Understanding these complex regulatory mechanisms is crucial for developing targeted interventions.

This narrative review synthesized existing literature to explore the multifaceted role of carbon monoxide (CO) as a signaling molecule within the stress axis. Researchers examined studies detailing CO's influence on both acute and chronic stress responses, specifically focusing on its interactions with the HPA axis and SAM system. The review aimed to delineate how CO's regulatory effects are contingent upon the physiological context, integrating findings from various experimental models and clinical observations to build a comprehensive understanding of its modulatory actions.

The review posits carbon monoxide (CO) as a crucial, yet context-dependent, endogenous regulator of the stress axis. It highlights that CO's influence on stress responses is not uniform, but rather varies significantly based on whether the stress is acute or chronic, and the specific physiological state of the organism. This dual role suggests that CO can either enhance or mitigate stress-induced neuroendocrine cascades, impacting the release of CRH, ACTH, cortisol, and catecholamines like epinephrine and norepinephrine. The synthesis of evidence indicates CO's involvement in fine-tuning the body's adaptive responses, influencing glucocorticoid secretion patterns and potentially mitigating neuroinflammation associated with prolonged HPA axis activation. The precise mechanisms of CO's interaction with stress-related pathways, including its effects on key brain regions, are central to its regulatory capacity. > CO modulates the HPA axis and SAM system differently, potentially offering adaptive benefits in acute scenarios while contributing to dysregulation under chronic stress conditions.