Stress and the stress reaction. Stress-related illnesses. Stress is not always unpleasant Stress is big business! Stress. Stressor

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1 Stress and the stress reaction Stress Stressor Any change/event that either disrupts, or threatens to disrupt homeostasis to an unusual degree. Any change that threatens a negative reward Can be almost any severe disturbance: Stress-related illnesses John Morris Any queries to john.morris@dpag.ox.ac.uk Acute stressors: extreme heat/cold; blood volume depletion by heavy bleeding, dehydration; hypoglycaemia; pain; surgical procedures; toxins from a bacterial infection; severe exercise; sleep deprivation; any psychic stress that causes a fear reaction Chronic stressors may be obvious or more subtle: chronic pain, chronic infection; housing problems, marital problems, financial worries, difficulties at work, commuting etc. The complexity of the human cerebral cortex means that, unlike most animals, some humans may be stressed by situations that do not affect others (e.g. phobias). Stress is not always unpleasant Stress is big business! Stress does not have to be unpleasant; some degree of stress may be very pleasurable - adrenaline buzz

2 Any major stress can trigger a general adaptation stress response. - involves many body systems; largely independent of the stressful stimulus. Normal homeostatic mechanisms function to restore/fine-tune the milieu interne chemistry, temperature, etc. Very system-dependent The stress response is, at least in the short term, counter-homeostatic (counter-regulatory). It raises blood pressure, blood sugar, ventilation, cardiac output etc. PURPOSE: to prepare the body to meet an emergency situation. EVOLVED to allow the individual to survive emergency by physical activity; return to homeostasis when the stress is no longer present. BUT: A physical response is not appropriate to many things that stress humans It involves: a short-term alarm reaction a more long-lasting resistance reaction. If the stress cannot be overcome, exhaustion ensues; can be terminal. The hypothalamus controls and coordinates the stress response via its actions on the autonomic nervous system & endocrine systems. Inputs from: brain stem specific e.g. from nucleus tractus solitarius; pain non-specific e.g. from raphé, locus coeruleus) higher centres hippocampus via fornix; amygdala; orbito-frontal and septal cortex; dorsomedial and midline thalamic nuclei convey potentially stressful information from the external world the internal organs the psyche Acute alarm reaction (fight or flight) Responses - immediate but can be relatively short-lived Mobilise body s resources for immediate physical activity Cause arousal of the cerebral cortex Involves hypothalamic control by activation of: CNS outputs neurohormones controlling pituitary esp. CRH; ADH via respiratory centre (increased rate; depth) via cardiovascular centre (and ANS) (increased CO) arousal reaction; blunting pain perception (endorphin etc) via control of ANS sympathetic nervous system - effects specific to terminals of nerves Sympathetic nerve increased activity, combined with Adrenaline and noradrenaline secretion from the adrenal medulla increases the circulation to muscle, preserves it to vital organs (brain, heart, adrenals, kidneys) increases energy substrates - promotes catabolism but spares glucose for CNS decreases non-essential activities (governed by which receptors the tissues express) adrenal medulla - widespread via adrenaline (cortisol increases A:NA ratio)

3 Adrenal medullary chromaffin cells have massive stores of catecholamine (adrenaline > noradrenaline) Rapid massive increase in adrenaline and noradrenaline as a result of (hypoxic) stress. Note: the very rapid increase and the rapid decrease (adrenaline half-life sec) more adrenaline than noradrenaline is secreted an acute stress depletes only a small fraction of the stored catecholamine NB: Catecholamine secretion controlled by preganglionic symp (ACh) nerves Sympathetic nerves also LOCAL vasodilate adrenal vasculature vasoconstrict splanchnic, skin; kidneys are relatively spared; no constriction in lung, heart, no decrease cerebral blood flow increases ability of the blood to clot preparation for possible bleeding increases sweat production cold sweat, but improves heat loss if exertion; eliminates some wastes increase glycogenolysis by adrenaline (ß); also by reducing insulin and increasing glucagon secretion. The decreased insulin causes reduced use of glucose by muscle and fat; conserves glucose for CNS etc (muscle runs on glucose from muscle glycogen, free fatty acids) decreases secretion from GI tract; decreases GI motility, closes sphincters (α1) Pathology Phaeochromocytoma; tumour secreting catecholamines

4 Resistance reaction - chronic stress reaction If stress is more long-lasting more prolonged effects of the acute (sympathetic) response more chronic effects (N.B. HPA axis cortisol is switched on immediately)(cortisol half life 90 min; acts slowly via transcription) hypothalamo-gh and hypothalamo-tsh-thyroid axis also respond. Feed-forward and negative feedback in control of glucocorticoid secretion Situations, perceptions, phobias HIPPOCAMPUS AMYGDALA CRH AVP CORTEX PERIPHERAL SIGNALS - Temperature - Pain, - Infection (eg. IL-1β) - Hypoglyaemia HYPOTHALAMUS Parvocellular CRH neuron in PVN Sympathetic stimulates JGA of kidney > renin > angiotensin II causes vascular constriction; thirst mineralocorticoid (aldosterone) secretion Na reabsorption > water retention > maintains high BP & counteracts fluid loss increases elimination H + ions (accumulated from increased catabolism) Rapid activation of the hypothalamo-pituitary-adrenal axis CORTICOTROPH PRL, GH, TSH ADRENAL GLAND ACTH GLUCOCORTICOIDS Cortisol secretion in response to operation stress Glucocorticoids: Minor Major accelerate lipid and protein catabolism in liver and peripheral tissues; accelerate gluconeogenesis in liver; increase the sensitivity of blood vessels to vasoconstrictors; prevent increased capillary permeability; maintain the contractility of cardiac muscle; increase erythrocyte production (minor effect; mostly androgens). reduce inflammation - prevent it from becoming disruptive rather than protective; inhibit the production of fibroblasts (which when injured stimulate the inflammatory reaction); inhibit the immune response - by an action which damages lymphocytes.

5 Hypothalamo-pituitary GH axis Hypothalamic GHRH stimulates the release of GH in a prolonged manner (normally it is secreted in short pulses every 4-6h) Prolonged release of GH causes: increases liver breakdown of fats to fatty acids and glycerol increases liver conversion of glycogen to glucose decreases peripheral use of glucose (insulin resistance) Hypothalamo-pituitary-thyroid axis Hypothalamic TRH stimulates the release of TSH and therefore thyroid hormones. When the stress is very prolonged within the hypothalamus CRF, glucocorticoids, opioid peptides reduce GnRH secretion - avoid risk of pregnancy and a further drain on metabolic resources in the hippocampus, glucocorticoids act on GR to modify emotional reactions - induce mild euphoria to diminish psychic effects of the stress. However, if excessive, damage hippocampal neurons: dendrite loss, cell death Normal Prolonged stress Monkey CA1 neurons Thyroid hormones: increase the metabolic rate and the catabolism of glucose, fats & proteins. N.B. in starvation (a particular form of stress) glucocorticoids reduce conversion of T4 to T3 in the liver, blunting the catabolic response. The stress response is variable in extent and effect: varies with diurnal rhythm: in human, morning > evening or at night Exhaustion Sometimes the stress is so great that the body or the CNS cannot cope and a state of counter-productive exhaustion ensues. prolonged mineralocorticoid activity (high levels of glucocorticoid also have this effect because they act on the MR and swamp the protective action of11ßohsd type 2) cause continuing loss of K + (in exchange for Na + ); cells become progressively depleted of K + and may die. effectiveness of the stress response is reduced if pre-existing metabolic problem (e.g. hypothyroid; starvation) adrenal medullary exhaustion occurs - plasma adrenaline falls - profound fall in blood glucose - loss of vascular tone and profound fall in BP - renal failure - death

6 Stress-related illness Chronic stress at different ages - 1 Stress response evolved to counter physical stressors. Humans are often stressed by circumstances in which major physical activity is either inappropriate or counterproductive. The rise in BP, plasma glucose, FFA are not used, remain counterhomeostatic. Continuing psychological stress > continuous state of mild resistance response. Major factor in stress-induced illnesses e.g. heart, peripheral vascular disease. Treat: anxiolytics, β-adrenergic blockers; ACE inhibitors. Bus drivers and bus conductors - similar stress - drivers had far more resultant illness because they were not making a physical response to it. Aged: Morning peak of cortisol occurs earlier Cortisol response to the stress of an operation is greater Treatment for people in highly stressed jobs exercise relaxation techniques Childhood: Chronic stress causes retarded growth Chronic stress at different ages - 2 In utero: Stress of undernourishment/poor oxygen > low birth weight associated with significantly more hypertension, diabetes mellitus, lower life expectancy; resetting of HPA axis in utero Coronary heart disease and stroke Age-adjusted relative risk Systolic blood pressure Barker DJP Mothers, Babies and Health in Later Life; (Ed 2) Churchill Livingstone Birthweight Birthweight

7 The poor die young Excess cortisol (chronic) Cushing s disease hypertension polycythaemia, bruising osteoporosis muscle weakness poor collagen production impaired glucose tolerance abnormal fat distribution increased response to sympathetic stimulation Inadequate cortisol Addison s disease hypotension anaemia poor bone growth muscle weakness hypoglycaemia decreased adiposity decreased response to sympathetic stimulation Stress-related illness Animals in the wild do not obviously suffer stress-related illnesses. Their stress response either saves them or they are killed. Animals in zoos which cannot mount a physical response to stress; often leads to similar problems to those found in man (gastric ulcers etc) Low ranking in a dominance hierarchy (evidence from monkey groups) is clearly a form of stress that leads to reduced reproductive capacity. isolated male only Plasma testosterone Dominant male Subordinate male male and female Sex behaviour Subordinates in military academies - similar effects in humans Post-traumatic stress disorder: anxiety, memory disturbance; hippocampal loss on MRI

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