**2. Overview of the stress system**

#### **2.1 Historical context**

The concept of stress is as old as medical history itself, dating back at least to the time of Hippocrates who referred both to the suffering associated with disease (pathos) and to the toil (ponos) — the fight of the body to restore itself to normalcy (Hippocrates, 1923) . In more recent history, both Walter Cannon (Cannon, 1939) and Claude Bernard (Bernard, 1949) described the ability of all organisms to maintain a constancy of their internal milieu or homeostasis. 70 years ago Hans Selye, the pioneer of contemporary stress research, first described the General Adaptation Syndrome (GAS) as a chronological development of the

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 189

perceptions of stress by the subject, the extent of control on the stressful stimulus, and the active or passive coping mechanisms in response stress (Benarroch 2006). Stressor-induced activation of the HPA axis and the SAM results in a series of neural and endocrine adaptations known as the "stress response" or "stress cascade." The stress cascade is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge (Miller et al., 2002). The strongest stressors produce specific and nonspecific responses. The specific stress responses alter an individual to the presence of the stressors, which involve neuroendocrine responses such as increased autonomic nervous system activity (Tsigos et al., 2005) (Gold et al., 1998). When faced with excessive stress, whether physical or emotional, a subject's adaptive responses attain a relatively stereotypic nonspecific nature, referred to by Selye as "the general adaptation syndrome." We now know that the adaptive responses have some specificity toward the stressor that generates them, which, however, is progressively lost as the severity of the stressor increases. The adaptive response of an individual to stress is determined by a multiplicity of genetic, environmental and developmental factors (Chrousos et al., 1992) and prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors (Charmandari et al., 2005).

The orchestrated interplay of several neurotransmitter systems in the brain underlies the characteristic phenomenology of behavioral, endocrine, autonomic and immune responses to stress (Chrousos, 1998). Stress mediators such as adrenocorticotropic hormone, adrenaline and noradrenaline are subsequently released in specific patterns, reflecting the degree of HPA, adrenomedullary, and sympathetic nervous system activation (Goldstein et al., 2008). All stress responses are centrally integrated in the paraventricular nucleus (PVN) of the hypothalamus (Herman et al., 1997 and 2008) and the adrenal glands are their major peripheral effectors (Goldstein et al., 2008). Hypophysiotropic CRH neurons of the PVN are well known to serve as the origin of the final common pathway of glucocorticoid secretion. The powerful and far reaching action of these steroids (including effects upon metabolic, inflammatory, immune functions and on mood and behavior) has led to intensive investigation into regulatory mechanisms controlling glucocorticoid secretion (Cullinan et al., 2000). This hypothalamic neurohormone (CRH) plays a central role in the regulation of the HPA-axis, i.e., the final common pathway in the stress response. The activation of CRH neurons, increasing both adrenocorticotropic hormone (ACTH) biosynthesis and the best marker in ACTH which reaches a maximum in the first hour, which cortisol is highest during the second hour of stress (Dobson et al., 2000). ACTH may play a crucial, perhaps direct, role in the regulation of catecholamine biosynthetic enzymes in sympathetic nervous system, especially during stress. CRH-R1 is the most abundant subtype found in the anterior pituitary and is also widely distributed in the brain (Wong et al., 1994). Other possible factors that may regulate CRH1 receptor mRNA expression in the PVN of rats are catecholamine and glucocorticoids. Regarding catecholaminergic regulation, studies show that brainstem hemi section, which damaged the ascending noradrenergic bundle at least, attenuated the immobilization stress-induced increase in CRH1 receptor mRNA ipsilaterally in the PVN. This previous finding may reflect up-regulation of CRH1 receptor mRNA in the PVN by noradrenergic input from brainstem nuclei, such as the locus coerulus (LC), during

**2.3.2 Regulation of the stress response** 

stress (Fig.1)(Makino et al., 2002).

response to stressors when their action is prolonged (Selye, 1936). Therefore as pointed out for the first time by Hans Selye in Nature in 1936, stress or 'noxious agents' initiate a reaction in the body, which he called the 'general adaptation syndrome' (GAS). Selye distinguished three stages that the body passes when responding to stress in the GAS: 1) the first stage is an 'alarm reaction', in which the body prepares itself for 'fight or flight'; 2) the second stage of adaptation (provided the organism survives the first stage), is one in which a resistance to the stress is built; and 3) finally, if the duration of the stress is sufficiently long, the body enters a stage of exhaustion, a sort of aging, due to 'wear and tear'.

#### **2.2 Stress system & homeostasis**

Life exists by maintaining a complex dynamic equilibrium or *homeostasis* that is constantly challenged by intrinsic or extrinsic adverse forces, the *stressors* (Chrousos et al., 1992). Stress has been defined in many ways. To the physicist, the term refers to a force, strain or pressure applied to a system. However, when the stress response is excessive or in appropriate, it disrupts physiological homeostasis and body function and contributes to disease production (Burchfield, 1979). Although the stress response of the body is meant to maintain stability or *homeostasis,* long-term activation of the stress system can have a hazardous or even lethal effect on the body. For example it increases the risk of obesity, heart disease, depression, and a variety of other illnesses (Selye, 1998). According to Hans Sely, mental, psychologic or sociologic and metabolic stressors (Kvetnansky et al., 2009) tall the stable internal environment of the body, that may contribute directly to the production of disease or it can contribute to the development of certain behaviors that increases the risk of disease. The process that counteracts this disruption and maintains homeostasis is termed allostasis. Allostasis activates a wide range of both general and specific physiological systems and behavioral coping mechanisms. The amount of work carried out during allostasis is termed the allostatic load and represents the cost(s) to the animal of responding to the stimulus. Over the past decade, these terms have been introduced to human stress research to differentiate between adaptation, allostasis and the end result, homeostasis, with the aim of producing a measurement of allostatic load that can be used to compare the effects of a wide range of stimuli. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis").

#### **2.3 Stress system: Response & adaptation**

#### **2.3.1 Transient adaptation: Allostasis**

Physiologic systems operate within a dynamic range of steady states and maintain internal balance, or homeostasis, in terms of blood pH and electrolyte concentration. When physical or psychologic stressors challenge the body, there is activation of sympathoadrenal and adrenocortical responses that promote adaptation and survival in the short term. This has been referred to as **allostasis**. For example, during exercise or emotional responses, there is transient activation of the hypothalamic-pituitary-adrenocortical (HPA) and sympathoadernomedulary (SAM) systems, resulting in the elevation of blood pressure, heart rate, and circulating catecholamines and glucocorticoids. The patterns of autonomic, neuroendocrine, and behavioral responses vary with the type of stress, the different

response to stressors when their action is prolonged (Selye, 1936). Therefore as pointed out for the first time by Hans Selye in Nature in 1936, stress or 'noxious agents' initiate a reaction in the body, which he called the 'general adaptation syndrome' (GAS). Selye distinguished three stages that the body passes when responding to stress in the GAS: 1) the first stage is an 'alarm reaction', in which the body prepares itself for 'fight or flight'; 2) the second stage of adaptation (provided the organism survives the first stage), is one in which a resistance to the stress is built; and 3) finally, if the duration of the stress is sufficiently

Life exists by maintaining a complex dynamic equilibrium or *homeostasis* that is constantly challenged by intrinsic or extrinsic adverse forces, the *stressors* (Chrousos et al., 1992). Stress has been defined in many ways. To the physicist, the term refers to a force, strain or pressure applied to a system. However, when the stress response is excessive or in appropriate, it disrupts physiological homeostasis and body function and contributes to disease production (Burchfield, 1979). Although the stress response of the body is meant to maintain stability or *homeostasis,* long-term activation of the stress system can have a hazardous or even lethal effect on the body. For example it increases the risk of obesity, heart disease, depression, and a variety of other illnesses (Selye, 1998). According to Hans Sely, mental, psychologic or sociologic and metabolic stressors (Kvetnansky et al., 2009) tall the stable internal environment of the body, that may contribute directly to the production of disease or it can contribute to the development of certain behaviors that increases the risk of disease. The process that counteracts this disruption and maintains homeostasis is termed allostasis. Allostasis activates a wide range of both general and specific physiological systems and behavioral coping mechanisms. The amount of work carried out during allostasis is termed the allostatic load and represents the cost(s) to the animal of responding to the stimulus. Over the past decade, these terms have been introduced to human stress research to differentiate between adaptation, allostasis and the end result, homeostasis, with the aim of producing a measurement of allostatic load that can be used to compare the effects of a wide range of stimuli. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in

Physiologic systems operate within a dynamic range of steady states and maintain internal balance, or homeostasis, in terms of blood pH and electrolyte concentration. When physical or psychologic stressors challenge the body, there is activation of sympathoadrenal and adrenocortical responses that promote adaptation and survival in the short term. This has been referred to as **allostasis**. For example, during exercise or emotional responses, there is transient activation of the hypothalamic-pituitary-adrenocortical (HPA) and sympathoadernomedulary (SAM) systems, resulting in the elevation of blood pressure, heart rate, and circulating catecholamines and glucocorticoids. The patterns of autonomic, neuroendocrine, and behavioral responses vary with the type of stress, the different

long, the body enters a stage of exhaustion, a sort of aging, due to 'wear and tear'.

**2.2 Stress system & homeostasis** 

the short-run and promote adaptation ("allostasis").

**2.3 Stress system: Response & adaptation** 

**2.3.1 Transient adaptation: Allostasis** 

perceptions of stress by the subject, the extent of control on the stressful stimulus, and the active or passive coping mechanisms in response stress (Benarroch 2006). Stressor-induced activation of the HPA axis and the SAM results in a series of neural and endocrine adaptations known as the "stress response" or "stress cascade." The stress cascade is responsible for allowing the body to make the necessary physiological and metabolic changes required to cope with the demands of a homeostatic challenge (Miller et al., 2002). The strongest stressors produce specific and nonspecific responses. The specific stress responses alter an individual to the presence of the stressors, which involve neuroendocrine responses such as increased autonomic nervous system activity (Tsigos et al., 2005) (Gold et al., 1998). When faced with excessive stress, whether physical or emotional, a subject's adaptive responses attain a relatively stereotypic nonspecific nature, referred to by Selye as "the general adaptation syndrome." We now know that the adaptive responses have some specificity toward the stressor that generates them, which, however, is progressively lost as the severity of the stressor increases. The adaptive response of an individual to stress is determined by a multiplicity of genetic, environmental and developmental factors (Chrousos et al., 1992) and prenatal life, infancy, childhood and adolescence are critical periods characterized by increased vulnerability to stressors (Charmandari et al., 2005).

#### **2.3.2 Regulation of the stress response**

The orchestrated interplay of several neurotransmitter systems in the brain underlies the characteristic phenomenology of behavioral, endocrine, autonomic and immune responses to stress (Chrousos, 1998). Stress mediators such as adrenocorticotropic hormone, adrenaline and noradrenaline are subsequently released in specific patterns, reflecting the degree of HPA, adrenomedullary, and sympathetic nervous system activation (Goldstein et al., 2008). All stress responses are centrally integrated in the paraventricular nucleus (PVN) of the hypothalamus (Herman et al., 1997 and 2008) and the adrenal glands are their major peripheral effectors (Goldstein et al., 2008). Hypophysiotropic CRH neurons of the PVN are well known to serve as the origin of the final common pathway of glucocorticoid secretion. The powerful and far reaching action of these steroids (including effects upon metabolic, inflammatory, immune functions and on mood and behavior) has led to intensive investigation into regulatory mechanisms controlling glucocorticoid secretion (Cullinan et al., 2000). This hypothalamic neurohormone (CRH) plays a central role in the regulation of the HPA-axis, i.e., the final common pathway in the stress response. The activation of CRH neurons, increasing both adrenocorticotropic hormone (ACTH) biosynthesis and the best marker in ACTH which reaches a maximum in the first hour, which cortisol is highest during the second hour of stress (Dobson et al., 2000). ACTH may play a crucial, perhaps direct, role in the regulation of catecholamine biosynthetic enzymes in sympathetic nervous system, especially during stress. CRH-R1 is the most abundant subtype found in the anterior pituitary and is also widely distributed in the brain (Wong et al., 1994). Other possible factors that may regulate CRH1 receptor mRNA expression in the PVN of rats are catecholamine and glucocorticoids. Regarding catecholaminergic regulation, studies show that brainstem hemi section, which damaged the ascending noradrenergic bundle at least, attenuated the immobilization stress-induced increase in CRH1 receptor mRNA ipsilaterally in the PVN. This previous finding may reflect up-regulation of CRH1 receptor mRNA in the PVN by noradrenergic input from brainstem nuclei, such as the locus coerulus (LC), during stress (Fig.1)(Makino et al., 2002).

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 191

adrenal gland enlargement with high levels of corticosterone secretion, atrophy of the immune organs, and gastric ulcers. All three components of this nonspecific stress response are caused by prolonged activation of corticosteroids in the hypothalamic-pituitary-adrenal axis (HPAC), resulting in secretion of stress levels of ACTH and glucocorticoids. In spite of these harmful effects, glucocorticoids in normal levels are necessary for sustaining life (Munck et al., 1984). Here we discuss the key elements of the HPA axis and the

CRH, synthesized in the PVN of the hypothalamus, represents the main driving force controlling HPA axis activation, the major hormone system responsible to maintain

The HPA axis originates from the CRH neurons in the parvocellular subdivision of the PVN of hypothalamus, while the sympathetic nervous system is under the regulation of brainstem locus coeruleus (LC), clustered with noradrenaline neurons. Morphological and immunocytochemical studies have demonstrated that reciprocal projections exist between PVN–CRH neurons and LC–NE neurons, forming a CRH–NE–CRH loop, which plays an important role in the stressful responses (Maier, 2003) (Pacak et al., 1998) (Pacak et al., 1995). Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH) (Tsigos et al., 2002). The gene for CRH is expressed, not only in the brain, but also in extracranial tissues, (Orth, 1992) (Owens et al., 1991) including normal mammalian skin (Slominski et al., 1995) (**a**Slominski et al., 1993) (bSlominski et al., 1993) (Ermak et al., 1997) (Slominski et al., 1998). It has been proposed that an equivalent to the hypothalamicpituitary-adrenal axis functions in mammalian skin, in response to local stress (**a**Slominski

It has been known for several years that the CRH/ POMC skin system fulfils analogous (pro-opiomelanocortin) functions to the HPA stress axis. CRH is the central trigger of HPA axis, and together with related peptides urocortin I–III that are the most important elements of the body response to stress. These elements regulate behavioral, autonomic, endocrine, reproductive, cardiovascular, gastro-intestinal, metabolic and immune systemic functions (Aguilera et al., 2001) (Grammatopoulos et al., 2002). Other actions of CRH include local immunomodulatory (predominantly proinflammatory) effects (Karalis et al., 1991) (Slominski et al., 2003), differing from a central immunosuppressive activity (through the HPA axis) (Chrousos 1995). Moreover, expression of CRH and regulated activity of CRH receptor type 1 (CRH1) can also play an important role in regulation of local stress response in peripheral tissues including skin, gastrointestinal tract or reproductive system. In humans, expression of at least eight variants of CRH1 mRNA (α, β, c, d, e, f, g and h) was detected and alternative splicing was found to be regulated by diverse physiological and

homeostatic balance in response to stressful stimuli (Tsigos et al., 1994).

neuroendocrine response to systemic and local stress.

**3.2.1 HPA axis & CRH: Response to systemic stress** 

**3.2.2 HPA axis & CRH: Response to local stress** 

**3.2 HPA axis-CRH (homeostatic balance)** 

et al., 1996).

Fig. 1. Multiple feedback loops activating CRH systems during chronic stress. Stress initially activates the hypothalamic CRH system (i.e., CRH in the PVN), resulting in the hyper secretion of glucocorticoids from the adrenal gland. In addition, the psychological component of the stressor stimulates the amygdaloid CRH system (i.e., CRH in the central nucleus of the amygdala). Glucocorticoids exert GR-mediated negative feedback effects on the biosynthesis and release of CRH in the PVN and ACTH in the anterior pituitary (AP) directly or indirectly through the brainstem catecholaminergic nuclei such as the LC, resulting in the termination of stress-induced HPA axis activation. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the LC fails to restrain hyper function of the HPA axis. Increased CRH in the PVN also induces a putative ultra short positive feedback effects on its own biosynthesis through up-regulation of PVN CRHr-1. The persistent activation of the HPA axis further up-regulates the amygdaloid CRH system involved in the expression of fear and anxiety, and the amygdala may have stimulatory effects on the HPA axis. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during chronic stress (Makino et al., 2002).

#### **3. Overview of the HPA axis**

#### **3.1 Historical context of HPAC**

In 1936, Hans Selye reported a historic series of studies on severe stress in rats. Exposure to bacterial infection, toxic chemicals, and other life threatening insults consistently caused adrenal gland enlargement with high levels of corticosterone secretion, atrophy of the immune organs, and gastric ulcers. All three components of this nonspecific stress response are caused by prolonged activation of corticosteroids in the hypothalamic-pituitary-adrenal axis (HPAC), resulting in secretion of stress levels of ACTH and glucocorticoids. In spite of these harmful effects, glucocorticoids in normal levels are necessary for sustaining life (Munck et al., 1984). Here we discuss the key elements of the HPA axis and the neuroendocrine response to systemic and local stress.

#### **3.2 HPA axis-CRH (homeostatic balance)**

190 Psoriasis

Fig. 1. Multiple feedback loops activating CRH systems during chronic stress. Stress initially activates the hypothalamic CRH system (i.e., CRH in the PVN), resulting in the hyper secretion of glucocorticoids from the adrenal gland. In addition, the psychological

component of the stressor stimulates the amygdaloid CRH system (i.e., CRH in the central nucleus of the amygdala). Glucocorticoids exert GR-mediated negative feedback effects on the biosynthesis and release of CRH in the PVN and ACTH in the anterior pituitary (AP) directly or indirectly through the brainstem catecholaminergic nuclei such as the LC, resulting in the termination of stress-induced HPA axis activation. In the chronic phase of stress, down-regulation of GR in the PVN and other brain structures such as the LC fails to restrain hyper function of the HPA axis. Increased CRH in the PVN also induces a putative ultra short positive feedback effects on its own biosynthesis through up-regulation of PVN CRHr-1. The persistent activation of the HPA axis further up-regulates the amygdaloid CRH

system involved in the expression of fear and anxiety, and the amygdala may have stimulatory effects on the HPA axis. Thus, the hypothalamic and the amygdaloid CRH systems cooperatively constitute stress-responsive, anxiety-producing neurocircuitry during

In 1936, Hans Selye reported a historic series of studies on severe stress in rats. Exposure to bacterial infection, toxic chemicals, and other life threatening insults consistently caused

chronic stress (Makino et al., 2002).

**3. Overview of the HPA axis 3.1 Historical context of HPAC** 

CRH, synthesized in the PVN of the hypothalamus, represents the main driving force controlling HPA axis activation, the major hormone system responsible to maintain homeostatic balance in response to stressful stimuli (Tsigos et al., 1994).
