Roles of nitric oxide, carbon monoxide, and hydrogen sulfide in the regulation of the hypothalamic-pituitary-adrenal axis.

The importance of stress in modifying human behavior and lifestyle is no longer a matter of debate. Although mild stress enhances the immune response and prevents infections, prolonged stress seems to play pathogenic roles in depression and neurodegenerative disorders. The body has developed an adaptive stress response consisting of cardiovascular, metabolic, and psychological changes, which act in concert to eliminate stressors. One of the major components of this response is the hypothalamic-pituitary-adrenal axis, also known as the stress axis. Over the last 30 years, many studies have documented the integrated stress-axis regulation by neurotransmitters. They have also demonstrated that gaseous neuromodulators, such as NO, CO, and H(2)S, regulate the hypothalamic release of neuropeptides. The specific effects (stimulatory vs. inhibitory) of these gases on the stress axis varies, depending on the type of stress (neurogenic or immuno-inflammatory), its intensity (low or high), and the species studied (rodents or humans). This review examines the complex roles of NO, CO, and H(2)S in modulation of stress-axis activity, with particular emphasis on the regulatory effects they exert at the hypothalamic level.