STRESS and the STRESS RESPONSE
JF Morris
Definitions
Stress:
Any change/event that either disrupts, or threatens to disrupt homeostasis to an unusual degree.
Any change that threatens a “negative reward”
Stressor: Can be almost any severe disturbance:
• Acute stressors: Physical - extreme heat/cold; blood volume depletion by bleeding, dehydration; hypoglycaemia; pain;
surgery; toxins from infection; severe exercise; sleep deprivation; Psychic – anything causing fear reaction.
• Chronic stressors may be obvious or more subtle - 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 (eg phobias).
If any stress is sufficient it can trigger a general adaptation stress response. This involves many body systems and is
largely independent of the stressful stimulus.
Normal homeostatic mechanisms function gently to restore and ‘fine-tune’ the milieu interne in terms of its chemistry,
temperature, etc.
The stress response is, at least in the short term, counter-homeostatic (counter-regulatory). It raises blood pressure,
blood sugar, ventilation, cardiac output etc. The purpose of these changes is to enable the body to meet an emergency
situation. It has evolved in order to allow the individual to survive the emergency, and return to normal homeostasis
when the stress is no longer present.
It involves: a short-term alarm reaction; and
a more long-lasting resistance reaction.
If the stress cannot be overcome, a stage of exhaustion ensues, which can be terminal.
The hypothalamus controls and coordinates the stress response via its actions on the autonomic nervous system and the
endocrine systems.
Its inputs from
• brain stem (specific – e.g. from nucleus tractus solitarius; non-specific from raphé (5-HT), locus coeruleus (NA))
• higher centres (fornix from hippocampus; amygdala; orbito-frontal and septal cortex; dorsomedial and midline
thalamic nuclei) convey potentially stressful information from the external world, the internal organs, and the ‘psyche’.
Alarm Reaction
The acute ‘alarm reaction’ (fight-or-flight) involves hypothalamic control by
activation of:
• CNS outputs - neurohormones controlling pituitary; actions on respiratory
centre; arousal reaction
• sympathetic nervous system - effects specific to terminals of nerves
• adrenal medulla - effects widespread via adrenaline (some noradrenaline)
The responses are immediate but can be relatively short-lived.
They mobilise the body’s resources for immediate physical activity, and cause
arousal of the cerebral cortex.
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CNS outputs:
increased respiratory rate/depth (via somatic NS); increased cardiac output
via cardiovascular centre and ANS
secretion of CRH to activate the pituitary adrenal axis (but NB most
corticosteroid actions are slow, by transcription)
secretion of ADH to conserve body water (also increases liver
glycogenolysis)
arouses the cerebral cortex by stimulation of the locus coeruleus and
widespread central release of noradrenaline
blunts pain by release of endorphins and enkephalins; stimulation of
descending pain-control circuits
Sympathetic nerve increased activity causes rapid changes which
(a) increase circulation, respiration;
(b) promote catabolism for energy production;
(c) decrease non-essential body functions.
They include:
• increased heart rate & force of contraction - speeds up supply of blood-born substances to where they are most needed.
• vasodilatation of muscle vascular beds - preparation for intense physical exertion
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vasodilation of the adrenal vasculature
vasoconstriction of visceral and skin arteries and veins - redistributes blood away from organs that do not have an
immediate role (kidneys are relatively spared); contraction of veins and spleen reduces venous pooling of blood.
N.B. there is no constriction of heart, lung, or cerebral blood flow
increased erythrocyte production; ability of the blood to clot - preparation for possible bleeding
dilation of the respiratory tract by relaxing smooth muscle - permits greater O2, & CO2 exchange
increased sweat production - improves heat loss; eliminates some wastes
decreased secretion from the GI tract; decreased GI motility, closes sphincters
increased glycogenolysis - from adrenaline (ß); reduction of insulin and increase of glucagon secretion
the decreased insulin causes reduced use of glucose by muscle and fat - conserves glucose for CNS etc (muscle runs
on stored glycogen, free fatty acids)
increased activity of preganglionic sympathetic nerves stimulates the adrenal medulla to release catecholamines,
largely adrenaline (NB the Adrenaline:Noradrenaline ratio is increased by cortisol)
Adrenaline supplements and prolongs all the above reactions; it also causes
• increased liver glycogenolysis - mobilises glucose to avoid risk of brain hypoglycaemia
• stimulates hormone-sensitive lipase - mobilises free fatty acids for use as energy substrates by many organs
Resistance reaction
If the stress is more long-lasting, more prolonged effects of the acute response, and more chronic responses occur to
produce the resistance reaction (NB the initial components of this are switched on immediately).
These involve the more long-lasting results of the sympathetic nerve stimulation, and actions of various hormones that
are more prolonged than those of the catecholamines.
Sympathetic nerves stimulate juxtaglomerular cells of the kidney. This causes the production of angiotensin II
which both causes vascular constriction, and also stimulates mineralocorticoid (aldosterone) release which
• increases renal Na reabsorption which in turn retains water, maintains a high BP, counteracts fluid loss
• increases elimination (exchange) of H+ ions (which accumulate as a result of the increased catabolism)
Hypothalamic CRH stimulates the release of pituitary ACTH and adrenal glucocorticoids (cortisol) which:
• accelerates lipid and protein catabolism in liver and peripheral tissues; gluconeogenesis in liver
• increases the sensitivity of blood vessels to vasoconstrictors, prevent increased capillary permeability
• maintains the contractility of cardiac muscle
Glucocorticoids also
• 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 (see Pathology course)
Glucocorticoids also affect other hormonal systems
In many physical stresses, hypothalamic TRH stimulates the release of TSH
and therefore thyroid hormones. Thyroid hormones increase the metabolic
rate and the catabolism of glucose, fats and proteins
NB In starvation stress – glucocorticoids reduce T4 conversion to T3,
blunting catabolic response and preserving nutrients
In starvation, hypothalamic GHRH stimulates the prolonged release of GH (normally it is secreted in short pulses every
4-6h); sustained increase of plasma GH has an ‘anti-insulin’ effect which causes:
• increased liver breakdown of fats to fatty acids and glycerol
• increased liver conversion of glycogen to glucose.
By these effects the resistance reaction allows the body to continue fighting a stressor long after the effects of the acute
alarm reaction. It produces the energy and circulatory changes required for the performance of strenuous tasks, fighting
infection, avoiding fatal haemorrhage. If there is greatly increased metabolism, blood glucose returns nearly to normal
during the resistance reaction as input = output; blood pH is controlled by the kidney. However blood pressure remains
raised because of retention of water.
When the stress is 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 glucocorticoid receptors to
modify emotional reactions - induce mild euphoria, diminishing the
psychic effects of the stress. Prolonged stress kills hippocampal neurons.
The stress response is variable in extent and effect:
• stress response varies with diurnal rhythm: in human, greater in morning
than evening or at night
• effectiveness is reduced if there is a pre-existing metabolic problem
(such as hypothyroid; starvation)
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
mineralocorticoid receptors (MR) and swamp the protective 11ßOHSD enzyme) causing continuing loss of K (in
exchange for Na); cells become progressively depleted and may die;
• adrenal medullary exhaustion occurs (run out of adrenal catecholamines) - this causes a profound fall in blood
glucose; loss of vascular tone; hypotension, and death
Treatment of ‘exhaustion’: catecholamines
Stress-related illness
The changes produced by the stress response have been honed by evolution to counter physical stressors.
However, humans are often stressed by circumstances in which major physical activity is either inappropriate or
counterproductive. Therefore the rise in BP, plasma glucose and FFA etc are not used by any physical exertion and
remain as counter-homeostatic.
People who have continuing psychological stress levels appear to be in a continuous state of mild resistance response.
This could be a major factor in the many “stress-induced illnesses” e.g. heart disease, peripheral vascular disease. Hence
the use of anxiolytics, β-adrenergic blockers; ACE inhibitors.
Note: bus drivers and bus conductors (when the latter used to exist) had similar levels of stress, but the drivers had far
more resultant illness because they were not making a physical response to it.
“Treatment” for people in highly stressed jobs: substantial exercise; relaxation techniques
Animals in the wild do not obviously suffer such chronic stress-related illnesses. Their stress response either saves them
or they are killed.
By contrast, animals in zoos which cannot mount a physical response to the stress of inappropriate conditions, can lead
to similar problems to those found in man.
Low ranking in a dominance hierarchy (evidence from monkey groups) is clearly a form of stress that leads to reduced
reproductive capacity. Evidence from groups such as military training academies suggests similar effects in humans.
Chronic stress at different ages
Old Age: The morning peak of cortisol occurs earlier in aged; the cortisol
response to the stress of an operation is prolonged.
Childhood: Chronic stress in childhood is associated with retarded growth
In utero:
the stress of undernourishment/poor oxygen leading to low birth weight
is associated with a significant increase in hypertension, diabetes
mellitus, in adult life, and lower life expectancy
maternal stress during pregnancy is said to be associated with a greater
incidence of homosexuality in male offspring
Stress and other diseases
Diabetes: because many of the effects of acute and chronic stress responses involve changes in glucose handling, control
of plasma glucose in diabetics is more difficult. In stress conditions – e.g. infection, operation, increased amounts of
insulin are likely to be necessary to achieve reasonable control.
Autonomic failure: An inactive/hypoactive sympathetic system means that an acute stress response cannot be mounted
Adrenal failure: Addison’s disease - adrenal cortical failure is associated with very poor responses to stress
Cushing’s disease: mild Cushing’s disease (increased cortisol secretion) can be mimicked by chronic stress, and can be
overlooked.
Syllabus:
17.1 Body temperature regulation; 8.8 Regulation of cardiovascular system .... etc
45.8 Social/health psychology
51.1 Hypothalamus
51.2 Physiological responses to stress
52 Responses to environmental stress
Core learning objectives – by the end of this lecture and associated reading you should be able to:
Define and give examples of stress, acute and chronic stressors
Describe the role of central nervous system in analysing stressful stimuli and initiating the stress response
Distinguish between and describe major features of the acute alarm reaction and chronic resistance reaction.
Outline how exhaustion of the stress response can occur.
Additional reading:
Fechir M et al (2008) Open Neurology 2:25-31. Patterns of sympathetic responses induced by different stress tasks
Buckingham JC (2006) Brit J Pharmacol 147:S258-268. Review of stress and glucocorticoids
De Kloet et al (2005) Nature Reviews Neuroscience 6:463-75. Stress and the brain: from adaptation to disease