Despite the fact that many research articles have been written about stress and stress-related diseases, no scientifically accepted definition of stress exists. Selye introduced and popularized stress as a medical and scientific idea. He did not deny the existence of stressor-specific response patterns; however, he emphasized that such responses did not constitute stress, only the shared nonspecific component. In this review we focus mainly on the similarities and differences between the neuroendocrine responses (especially the sympathoadrenal and the sympathoneuronal systems and the hypothalamo-pituitary-adrenocortical axis) among various stressors and a strategy for testing Selye's doctrine of nonspecificity. In our experiments, we used five different stressors: immobilization, hemorrhage, cold exposure, pain, or hypoglycemia. With the exception of immobilization stress, these stressors also differed in their intensities. Our results showed marked heterogeneity of neuroendocrine responses to various stressors and that each stressor has a neurochemical "signature." By examining changes of Fos immunoreactivity in various brain regions upon exposure to different stressors, we also attempted to map central stressor-specific neuroendocrine pathways. We believe the existence of stressor-specific pathways and circuits is a clear step forward in the study of the pathogenesis of stress-related disorders and their proper treatment. Finally, we define stress as a state of threatened homeostasis (physical or perceived treat to homeostasis). During stress, an adaptive compensatory specific response of the organism is activated to sustain homeostasis. The adaptive response reflects the activation of specific central circuits and is genetically and constitutionally programmed and constantly modulated by environmental factors.

Selye defined stress as the nonspecific response of the body to any demand. Stressors elicit both pituitary-adrenocortical and sympathoadrenomedullary responses. One can test Selye’s concept by comparing magnitudes of responses at different stress intensities and assuming that the magnitudes vary with stress intensity, with the prediction that, at different stress intensities, ratios of increments neuroendocrine responses should be the same. We measured arterial plasma ACTH, norepinephrine, and epinephrine in conscious rats after hemorrhage, intravenous insulin, subctaneous formaldehyde solution, cold, or immobilization. Relative to ACTH increments, cold evoked large norepinephrine responses, insulin large epinephrine responses, and hemorrhage small norepinephrine and epinephrine responses, whereas immobilization elicited large increases in levels of all three compounds. The ACTH response to 25% hemorrhage exceeded five times that to 10%, and the epinephrine response to 25% hemorrhage was two times that to 10%. The ACTH response to 4% formaldehyde solution was two times that to 1%, and the epinephrine response to 4% formaldehyde solution exceeded four times that to 1%. These results are inconsistent with Selye’s doctrine of nonspecificity and the existence of a unitary “stress syndrome,” and they are more consistent with the concept that each stressor has its own central neurochemical and peripheral neuroendocrine “signature.”