https://www.ncbi.nlm.nih.gov/books/NBK278995/
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Stress constitutes a state of threatened homeostasis triggered by intrinsic or extrinsic adverse forces (stressors) and is counteracted by an intricate repertoire of physiologic and behavioral responses aiming to maintain/reestablish the optimal body equilibrium (eustasis). The adaptive stress response depends upon a highly interconnected neuroendocrine, cellular, and molecular infrastructure, i.e. the stress system. Key components of the stress system are the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), which interact with other vital centers in the central nervous system (CNS) and tissues/organs in the periphery to mobilize a successful adaptive response against the imposed stressor(s). Dysregulation of the stress system (hyper- or hypo-activation) in association with potent and/or chronic stress can markedly disrupt the body homeostasis leading to a state of cacostasis or allostasis, with a spectrum of clinical manifestations. This chapter describes the organization and physiology of the stress system, focusing on its interactions with other CNS centers and endocrine axes, and reviews the existing evidence linking stress to pathophysiologic mechanisms implicated in the development of stress-related diseases affecting the endocrine, metabolic, gastrointestinal, and immune systems. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
All vital physiologic systems of the body are inherently programmed, through rigorous fine-tuning achieved during evolution, to preserve a predefined steady state (homeostasis or eustasis), which is essential for life and well-being [1-3]. This optimal equilibrium is constantly challenged by adverse forces which are intrinsic or extrinsic, real or even perceived, and are described as stressors [1]. Thus, stress is defined as a state of disharmony (cacostasis or allostasis) and is counteracted by an intricate repertoire of physiologic and behavioral responses which aim to maintain/reestablish the threatened homeostasis (adaptive stress response) [1]. This adaptive stress response is mediated by a complex and interconnected neuroendocrine, cellular, and molecular infrastructure which constituents the stress system and is located in both the central nervous system (CNS) and the periphery [1, 2]. The adaptive response of each individual to stress is determined by a multiplicity of genetic, environmental, and developmental factors. Changes in the ability to effectively respond to stressors (e.g. inadequate, excessive and/or prolonged reactions) may lead to disease. Moreover, highly potent and/or chronic stressors can have detrimental effects on a variety of physiologic functions, including growth, metabolism, reproduction, and immune competence, as well as on behavior and personality development. Of note, prenatal life, infancy, childhood, and adolescence are critical periods in the process of forming the matrix of the adaptive stress response, characterized by high plasticity of the stress system and increased vulnerability to stressors.
The stress system receives and integrates a great diversity of neurosensory (i.e. visual, auditory, somatosensory, nociceptive, and visceral), blood-borne, and limbic signals which arrive at the various stress system centers/stations through distinct pathways. Acute stress system activation triggers a cluster of time-limited changes, both behavioral and physical, which are rather consistent in their qualitative presentation and are collectively defined as the stress syndrome [1-4]. Under normal conditions these changes are adaptive and improve the chances of survival. Initially, the stimulation of the stress system components follows a stressor-specific mode; however, as the potency of the stressor(s) increases the specificity of the adaptive response decreases in order to eventually present the relatively nonspecific stress syndrome phenomenology which follows exposure to potent stressors.
Behavioral adaptation includes enhanced arousal, alertness, vigilance, cognition, focused attention, and analgesia, whilst there is concurrent inhibition of vegetative functions, such as feeding and reproduction. In parallel, physical adaptation mediates an adaptive redirection of energy and body resources. As such, increases in the cardiovascular tone, respiratory rate and intermediate metabolism (gluconeogenesis and lipolysis) work in concert to promote this redirection of vital substrates, while energy consuming functions (e.g. digestion, reproduction, growth, and immunity) are temporally suppressed. Thus, oxygen and nutrients are primarily shunted to the CNS and to stressed body site(s) where they are needed the most.
In addition to the adaptive stress response, restraining forces are also activated during stress to prevent a potential excessive response of the various stress system components [1-4]. The ability to timely and precisely develop restraining forces is equally essential for a successful outcome against the imposed stressor(s), since prolonging the mobilized adaptive stress response can turn maladaptive and contribute to the development of disease.
Interestingly, the mobilization of the stress system is often of a magnitude and nature that allows the perception of control by the individual. Under such conditions, stress can be rewarding and pleasant, or even exciting, providing positive stimuli to the individual for emotional and intellectual growth and development [5]. Thus, it is not surprising that the stress system activation during feeding and sexual activity, both sine qua non functions for survival, is primarily linked to pleasure.
Although the entire CNS is directly or indirectly involved in preserving and fine-tuning the overall body homeostasis, specific areas of the brain have critical, distinct roles in orchestrating the stress response. As such, the central components of the stress system are located in the hypothalamus and the brainstem and include the parvocellular corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons of the paraventricular nuclei (PVN) of the hypothalamus, and the CRH neurons of the paragigantocellular and parabranchial nuclei of the medulla, as well as the locus coeruleus (LC) and other catecholaminergic, norepinephrine (NE)-synthesizing cell groups of the medulla and pons (central sympathetic nervous system) [1-4]. The peripheral limps of the hypothalamic-pituitary-adrenal (HPA) axis, together with the efferent sympathetic/adrenomedullary system, constitute the peripheral components of this interconnected system.
The central neurochemical circuitry responsible for the stress system activation forms a highly complex physiological system within the CNS, consisting of both stimulatory and inhibitory networks with multiple sites of interaction which modulate and fine-tune the adaptive stress response [1-4]. The key components of these networks are the hypothalamic CRH and AVP neurons in combination with the central catecholaminergic (LC/NE) neurons (Figure 1). The central stress system activation is based on reciprocal reverberatory neural connections between the PVN CRH and the catecholaminergic LC/NE neurons, with CRH and NE stimulating the secretion of each other through CRH receptor-1 (CRH-R1) and α1-noradrenergic receptors, respectively [6-8]. Of note, autoregulatory ultrashort negative feedback loops exist in both the PVN CRH and the brainstem catecholaminergic neurons [9, 10], with collateral fibers inhibiting CRH and catecholamine secretion respectively, via inhibition of the corresponding presynaptic CRH- and α2-noradrenergic receptors [11]. In addition, multiple other regulatory central pathways exist, since both CRH and catecholaminergic neurons receive stimulatory innervation from the serotoninergic and cholinergic systems [12, 13], and inhibitory input from the gamma-aminobutyric acid (GABA)/benzodiazepine (BZD) and the opioid neuronal systems of the brain [14, 15], as well as by glucocorticoids (the end-product of the HPA axis) [16]. Interestingly, both α2-adrenoceptor and opiate agonists act through separate receptors on neurons in the LC, albeit sharing common post-receptor effector signaling mediated through Gi proteins [17].