Lecture 3A and 3B Flashcards
To be able to describe and differentiate between cold and warm temperature sensitive neurons.
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To understand and describe static and dynamic responses of cold and warm temperature sensitive neurons.
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To explain how afferent inputs represented by skin and core temperature participate in the control of human thermoregulatory responses.
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To name and describe 9 membrane channels of interest from the family of Transient Receptor Potential (TRP) membrane channels and how each channel’s conductance changes as a function of it’s temperature.
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To name the chemical agonists for each of these 9 channels interest in the family of Transient Receptor Potential (TRP) membrane channels.
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To understand & describe the mechanisms of how these TRP channels are thought to participate in thermosensation and thermoregulation as well as which TRP channels are active over which range of temperatures.
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What is static response of a temperature sensitive neuron
for a given level of temp there is a given level of firing of the temp sensitive neuron
What is dynamic response of a temperature sensitive neuron
for changing levels of temp, there is an increased level of firing relative to the static firing rate at the temp same level
What is the overshoot seen in temperature sensitive neurons
A dynamic response
The hypothalamus is “integrative center” that gives ____ control of body temp
proportional
Describe the preoptic anterior hypothalamus
- has neurons that INC firing with INC temp
- Stimulates HEAT LOSS responses -> This output is INHIBITED by COLD input from the skin
Describe the dorsomedial posterior hypothalamus
has neurons that INC firing with DEC temp. This output is INHIBITED by WARM input from the skin
As the skin gets cooler the point of onset of sweating is ____
delayed
As core temp increases the onset of shivering is _____
delayed
Certain ion channels of the transient receptor potential (TRP) family can be activated by increases or decreases in _____
temperature
What kind of receptor is TRPM8
cold receptor
What kind of receptor is TRPA1
noxious cold
What kind of receptor is TRPV3 and TRPV4
warm receptor channels triggered by innocuous warm temps
What kind of receptor is TRPV1
sensitive for noxious heat but less support that is involved in thermoregulation
TRPV1, TRPV3, TRPV4, and TRPM8 are ion channels each involved in _____ and possibly
______
- thermosensation
2. thermoregulation
Describe TRPM8 channel (cold or warm receptor, how activated, what range activated, what plant derivative is it activated by)
- potential cold receptor
- activated by either MENTHOL or cool temps
- apparent threshold for TRPM8 activation by cold is 25 °C
- TRM8 expression is confined largely to a subpopulation of small-diameter peripheral sensory neurons that under normal conditions are distinct from those that express TRPV1
Describe how TRPM8 involves a negative feedback Loop for Behavioural Temp Regulation
- If Tskin is < 28.4°C, delta T is neg, then thermoregulatory responses to warm the skin e.g. Brown Adipose Tissue (BAT) - Movement of rodents along floor, heated with a gradient from cool to warm, is the behavioral response
- Cooling-sensitive TRPM8 is directional comparator of skin temps inducing output (y) when DeltaT is neg. If neg DeltaT-dependent output (y) induces thermaregulatory responses to warm skin recursively, neg feedback loops having 28.4°C as set-point temp are formed and TRPM8 fxns as thermostat for minimizing DeltaT against cooling. In behavioural regulation, when room is cooled, TRPM8 induces behaviour to move heated floor to warm the sole skin, which effectively maintains temp of sole skin against cooling. In autonomic regulation, when room is cooled, TRPM8 induces small rise in core temp, but skin temp is severely dec, as if regulation of skin temp not fxning.
Describe TRPV3 (cold or warm receptor, how activated, what range activated, what plant derivative is it activated by)
TRPV3:
- warm receptor
- activated by warm temps btwn 34 and 39°C.
- repetitive stimulation of TRPV3 with heat results in a current response of gradually increasing amplitude
- activated by CAMPHOR, irritant extracts from OREGANO and CLOVES
- expressed within keratinocytes, the stratified epithelial cells that are the major constituents of skin epidermis -> suggests some aspects of heat transduction may not be confined to cutaneous sensory neurons
Describe TRPV4 (cold or warm receptor, how activated, what range activated, what plant derivative is it activated by)
TRPV4:
- warm receptor
- activated by warm temperatures btwn ~25°C to 34°C
- PLANT DERIVATIVE UNKNOWN
- expressed within keratinocytes, the stratified epithelial cells that are the major constituents of skin epidermis -> suggests some aspects of heat transduction may not be confined to cutaneous sensory neurons
Describe TRPV1 (temp range, plant derivative activated by, what blocks it)
- might act physiologically as a transducer of noxious heat, highest conductance at ~ 40-42°C; suggests not involved in temp reg.
- a detector of CAPSAICIN and ARACHIDONIC ACID metabolites
- Ruthenium red (RR) inhibits heat-evoked responses in expressing cells (blocks channel)
4 mechanisms how TRPV1 can be activated
Mechanism 1: TRPV1 activation at the peripheral terminals of cutaneous or visceral warm fibers, whose cell bodies are in DRG, leads to stimulation of neurons w/in the most superficial layer of the SC dorsal horn. These neurons decussate, then ascend w/in spinothalamic tract, and send collateral branches to parabrachial nucleus in pons. Pontine projections to the PO/AH then activate WARM SENSITIVE neurons and/or INHIBIT COLD SENSITIVE neurons
Mechanism 2 and 3: activation of TRPV1 on presynaptic terminals (from the pons or elsewhere) impinging on the PO/AH results in increased excitatory NT release onto warm sensitive neurons (2) or increased inhibitory NT release onto cold sensitive neurons (3)
Mechanism 4: Activation of TRPV1 intrinsic to warm sensitive neurons results in their direct activation
Describe TRPA1 (cold or warm receptor, temp range, plant derivative its activated by). How did mice lacking TRPA1 differ?
- TRPA1 appears to be highly CO-EXPRESSED with TRPV1 in a subset of small- to medium-diameter peripheral sensory neurons
- TRPA1 may act as a SENSOR of PAINFULLY COLD TEMPS… activated by temperatures <18°C.
- ISOTHIOCYANATES (e.g. mustard oil, wasabi, and garlic), as well as other irritant chemicals such as ACROLEIN, can activate this channel
- mice LACKING TRPA1 shown to exhibit BLUNTED behavioral responses to a cold metal surface or to acetone-mediated cooling of the hind paw skin
How is TRPM subfamily TRPM4, TRPM5, TRPM2 activated? What range of degrees?
- by warming
- > 15°C for TRPM4 and TRPM5
- > 35°C for TRPM2.
Where are TRPM channels expressed? Importance?
- none of these channels are expressed in peripheral somatosensory neurons or in skin keratinoctyes,
- suggests they are not involved in temp sensation in skin.
- TRPM5 is expressed in epithelial taste cells in the tongue
- TRPM5 is required for the ability of warm temps to enhance sweet-tastant evoked firing of gustatory neurons in mice
Discuss roles of TRPV1, TRPV3/V4, TRPM8 n thermosensation
Top: sensation of burning pain can b evoked by activation TRPV1 in nociceptive neurons in skin. Many TRPV1-expressing neurons also express TRPA1 which has been proposed to participate in the transduction of painfully cold temps.
Middle: warm temps apparently activate TRPV3, TRPV4, expressed prominently in epidermal keratinocytes.
Bottom: modest skin cooling most likely activates TRPM8, expressed in distinct subset of sensory neurons
To describe the neural pathways of eccrine sweating and cutaneous blood flow responses.
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To understand and describe how plethysmography, iontophoresis and changes in skin resistance are employed to study human heat loss responses.
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To describe the different stages of cutaneous vasodilatation and the underlying physiological control mechanisms of this heat loss response.
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To understand and describe the types of sweating and the physiological control of eccrine sweating response.
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To describe how eccrine sweat glands function.
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To describe different types of sweating disorders and heat injuries plus treatment of heat disorders.
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How does phethysmograph measure cutaneous BF
A plethysmograph is an instrument for measuring changes in volume within an organ or whole body (usually resulting from fluctuations in the amount of blood or air it contains). Measuring conductance gives you indec of change in CIRCUMFERENCE.
What is a meta arteriole and its fxn
- a short, small vessel, that connects the arteriole and venule.
- They have a pre-capillary sphincter that when constricted can limit flow to that section of capillary bed to permit shunt flow…bypassing the capillary bed
what is an AVA
Arteriovenous anastomosis (AVA)= a vascular shunt under sympathetic control, allows us to vent heat
What is an anastomosis
A precapillary or postcapillary communication btwn neighboring vessels
Circulation of blood through the anastomosis is called
collateral circulation
What is acral
- aka GLABROUS or NONHAIRY
Example of acral areas
regions of skin including palms, plantar aspect of feet, lips
In acral regions of the skin, the cutaneous arterioles are innervated by?
solely by noradrenergic sympathetic vasoconstrictor nerves
In acral/nonhairy regions of the skin, the blood flow to capillaries is referred to as? Blood flow bypassing capillaries via AVAs is referred to as?
- nutrient blood flow
- ‘non-nutrient blood flow
Cutaneous arteriovenous anastomoses (AVA) in acral/non hairy regions receive what input
tonic SNS input
In acral/nonhairy regions of skin, AVAs are thermoregulatory organs with _____ innervation pathways
alpha adrenergic
How does the response to inc heating vary in acral and non hairy regions
- acral/nonhairy = 1 phase response (big vasodilation)
- nonacral/hairy = 2 phase response: 1st = (release of) sympathetic tone… leads to small inc in BF, 2nd = Ach giving vasodilation to vessel and some unknown co transmitter (big inc in BF)
Examples of non-acral, non-glabrous or hairy areas
limbs, head, and trunk
Reflex changes in skin BF of non-acral/hairy areas of skin are mediated by?
- 2 branches of the SNS: NORADRENERGIC VASOCONSTRICTOR NERVES and CHOLINERGIC ACTIVE VASODILATOR NERVES (unique to humans)
- as well as local effects of temp
What did the study involving body heating and atrophine demonstrate
- During body heating, there
is marked neurally mediated cutaneous vasodilation in skin and Ach is not responsible for this. When atropine blocked both sweating and dilator responses to ACh, forearm (cutaneous) vasodilation associated w/general body heating delayed blunted but most of dilator response still present. NO may play role in dilator response, but likely some unknown factor that is cotransmitted w/ACh from sympathetic cholinergic nerves that govern sweating contributes to cutaneous vasodilation during body heating.
What did research involving the effect of surgical sympathectomy on cutaneous BF response to whole body cooling and heat stress in humans tell us
- With cooling, there’s cutaneous vasoconstriction and reduction in forearm BF mediated by inc in NE release from sympathetic vasoconstrictor fibres. W/whole body heating, this vasoconstriction eliminated, and after some time there’s marked cutaneous vasodilation and progressive rise in forearm BF. This cutaneous vasodilation occurs ~same time/slightly after onset of sweating.
- In surgically sympathectomised arm, vasoconstrictor response to whole body cooling, vasodilator response to whole body heating, and sweating are absent. Interpreted to suggest there’s an ACTIVE VASODILATOR SYSTEM in human SKIN
What is iontophoresis? Purpose?
A transdermal delivery system in which a substance bearing a charge is propelled through the skin by a low electrical current. This method can be used to drive a drug across the skin barrier
What are eccrine sweat glands
produce sweat that is employed in body cooling after increases in body temp
- > millions of glands, shallow in dermis of skin
- > open to surface via single pores
- > secretes dilute, watery copious fluid
- > SG density: forehead>upper limbs> trunk> lower limbs
What are apocrine sweat glands
- produce sweat often after an emotional event
- > deep in dermis of skin
- > usually associated w hair follicle
- > oily secretions (what leads to the smell)
Describe the afferent pathway for eccrine sweating
-thermoreceptors in skin, viscera, spinal cord (SC) and in medial POAH
-pathways ascend in multisynaptic fibres in the lateral SC and spinothalamic
tract to reticular formation of brainstem
- then to thalamus and hypothalamus
Describe the efferent pathway for eccrine sweating
sympathetic outflow to skin sweat glands (SG)
- pathway is incompletely defined
- ipsilateral, polysynaptic through lateral tegmentum of pons
- then to lateral reticular substance of medulla to intermediate columns of SC
- preganglionic cholinergic neurons synapse w paravertebral sympathetic ganglia
- postganglionic sympathetic cholinergic fib synapse to eccrine (& apocrine) SG
Describe integration and sudomotor control for eccrine sweating
-in medial preoptic-anterior hypothalamus
How is sweat gland stimulated
- by cholinergic (mainly) & adrenergic fibers innervation
- stimulated by alpha & beta adrenergic as well as cholinergic agonists (by far the largest response)
- stimulating mainly M3 muscarinic receptors
- elevating extracellular calcium with iontophoresis stimulates sweating
- beta adrenergic stimulation depends on accumulation of intracellular cAMP
How is sweat gland secretion occuring
- biochemistry of secretion not well understood
- most likely involves active transport of electrolytes
- a fxn of Na/K-ATPase in basal-lateral membranes of secretory c.
- ouabain blocks the Na/K-ATPase enzyme & sweat secretion
What is sweat composition
- varies greatly as fxn of secretory rate
- generally as secretory rate increases there is an increased rate of reabsorption & a decrease in the rate of secretion
- Na+ < 50 mM
- HCO3-, isotonic to 1.0 mM
- urea, at ECF [ ]
- K+ > ECF [ ], but at low sweat rates may exceed 50 mM
- at low sweat rate pH can be 5.0
- cystic fibrosis increases [Na+] & [Cl-].> 60 mM
- 2 x [K+] in CF patients
What solutes is reabsorbed in sweat
- Na, Cl, & probably glucose & other small molecules
- conserves solutes & is unique in primates, most highly evolved in humans
- also conservation of ECF & blood vol; makes us better able to cope in heat stress
- mobilize ICF fluid to replace that lost by sweat with this conservation of electrolytes.
How does sweating differ in cystic fibrosis individuals differ
patients w/cystic fibrosis can’t reabsorb sweat solutes and are prone to heat stress.
Define coagulopathy
a condition in which the blood’s ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spontaneously or following an injury or medical and dental procedures
A disorder that results in impaired blood coagulation.
Usually causes prolonged or excessive bleeding.
Define encephalopathy
a general term that means brain disease, damage, or malfunction. The major symptom of encephalopathy is an altered mental state. The causes of encephalopathy are numerous and varied; they include infections, anoxia, metabolic problems, toxins, drugs, physiologic changes, trauma, and other causes.
Damage to brain normally due to disease and results in altered mental state
Define Endotexemia/endotoxin
The presence of endotoxins in the blood, which, if derived from gram-negative rod-shaped bacteria, may cause hemorrhages, necrosis of the kidneys, and shock.
Endotoxin = lipid that’s within a gram neg bacteria cell. When it dies it releases endotoxins.
Define shock and its 3 stages
When there’s a dec amt of blood so O2 not getting to tissues and build up of waste
Stage 1 aka non progresive: Dec in perfusion of blood to organs n tissue and compensated by more reabsorption, HR inc, vasoconstriction
Stage 2 Progressive: when mechanisms of compensation fails. Insufficient BF to brain so person becomes confused n disoriented. Missing O2 and nutrients.
Stage 3 Irreversible: With enough length of time there’s not enough perfusion to organs that cells start dying. Can lead to patient death.
Define shock types: Cardiogenic
Cardiogenic shock is a condition in which your heart suddenly can’t pump enough blood to meet your body’s needs, caused by dysfunction of the ventricles of the heart. The condition is most often caused by a severe heart attack, but not everyone who has a heart attack has cardiogenic shock.
Define shock types: hypovelemic
Hypovolemic shock is a life-threatening condition that results when you lose more than 20 percent (one-fifth) of your body’s blood or fluid supply. This severe fluid loss makes it impossible for the heart to pump a sufficient amount of blood to your body. Can be caused by serious cuts or internal bleeding from abdominal organs.
Define shock types: septic
Sepsis occurs when chemicals released into the bloodstream to fight the infection trigger inflammatory responses throughout the body. Septic shock is a serious medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism
Define heat stroke
Heatstroke is a condition caused by your body overheating, usually as a result of prolonged exposure to or physical exertion in high temperatures. This most serious form of heat injury, heatstroke, can occur if your body temperature rises to 104 F (40 C) or higher.
Define Stroke
A medical condition in which poor blood flow to the brain (so no O2 supply) results in cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. They result in part of the brain not functioning properly.
What is hyperhidrosis
- large sweat production, variety of disorders that are localized or systemic
What causes localized hyperhidrosis
emotional, gustatory or neurological lesions
What causes systemic hyperhidrosis
usually ANS disturbance & is episodic
What is anhidrosis
- lack of sweat production with heat or with pharmacological stimulants
- systemic (worst possibly fatal), segmental or localized
What is congenital sweating disorder
- anhidrotic ectodermal displasia = few sweat glands
- simultaneous inability to regulate cutaneous vasodilatation
What is heat syncope
- temporary circulatory failure due to blood pooling in peripheral veins
- venous return, decreased skin turgor
- probably DEC baroreflex in heat
- standing still in the heat/unacclimated (e.g. Guards at Buckingham Palace)
- less often seen in heat acclimated individuals
What is heat exhuastion
- DEC VR
baroreflex is likely OK, Tcore <40˚C cf Heat Stroke
hydration important, heat acclimation (?), little known
What is stroke
classically - environmental heat stress/overwhelmed thermoreg. syst.
exertional heat stroke - elevated metabolic rate (athletes/military)
often unacclimated, unfit, obese individuals with history of heat illness
Tcore >40˚C, CNS disturbances, multiple organ sys. failures, sweat fails
less often in heat acclimated individuals
compensable and non compensable (next slide)
Describe the sequence of events that lead to heat stroke
a
What are possible treatments for heat injuries
- patient: supine, elevated legs, rehydration, cooling, decrease core temperature, MD & paramedic
Whole Body Cooling in Ice Baths (D. Casa)
Hand and Foot Cooling (C. Heller, cf Lec 2)
Describe the research on the effect of botulinum toxin on the cutaneous vasodilation during whole body heat stress in humans
- Whole body heat stress caused marked sweating and concurrent vasodilation. Atropine iontophoresis ABOLISHED SWEATING but only delayed and slightly ATTENUATED VASODILATION. But local administration of botulinum toxin (blocks presynaptic release of NT) ABOLISHED SWEATING and cutaneous VASODILATION. Cutaneous vasodilation in response to local warming maintained after all 3 treatments, indicating cutaneous blood vessel responsiveness unaltered. Data suggest some unknown co-transmitter released from cholinergic nerves evokes cutaneous vasodilation during whole body heat stress in humans
Describe the research on the effect of surgical sympathectomy or atropine on forearm BF response to severe mental stress in humans
- Severe mental stress resulted in big inc in forearm BF
- Atropine given selectively to one forearm blunted did not eliminate vasodilator response to severe mental stress
It has been found that cutaneous active vasodilation is mediated by _____ nerve cotransmission
Cholinergic
ACh and other cotransmitters released from ______ symapthetic nerves dilate cutaneous vessels and activate _____ during heat stress. Evidence suggests _______ may be a cotransmitter in this system
- ACh and other cotransmitters released from CHOLINERGIC sympathetic nerves dilate cutaneous vessels and activate SWEATING during heat stress
- Evidence suggests VASOACTIVE INTESTINAL PEPTIDE may be a cotransmitter in this system
Local warming responses and vasodilator mechanisms in human skin. Increases in the ______ of cutaneous blood vessels increase SkBF in a ______ response: an initial _____ increase to a peak followed by prolonged ______ phase. Initial phase mediated by ________ NT release from sensory afferents mediated by ________ receptors. Sympathetic active vasodilator nerves aren’t involved. Plateau phase observed w/prolonged local warming of skin mediated by _______ generation. Source of NO partially thru _______ activation of endothelial NO synthase. None of the responses to inc local skin temp depend on presence of ______
Local warming responses and vasodilator mechanisms in human skin.
- Increases in the LOCAL TEMP of cutaneous blood vessels increase SkBF in a BIPHASIC response: an initial RAPID increase to a peak followed by prolonged PLATEAU phase.
NEURAL MXN (INITIAL VASODILATION): 2. Initial phase mediated by ANTIDROMIC NT release from sensory afferents mediated by TEMPERATURE-SENSITIVE VANILLOID TYPE 1 (VR-1) receptors (AP in a normal afferent would go from periphery to CNS. But in antidromic its opposite. So when VR-1 releases antidromic NT, its causing vasodilation there).
NON-NEURAL MXN (PROLONGED VASODILATION):
3. Sympathetic active vasodilator nerves aren’t involved. Plateau phase observed w/prolonged local warming of skin mediated by NO generation. Source of NO partially thru HEAT SHOCK PROTEIN 90 (HSP90) activation of endothelial NO synthase. None of the responses to inc local skin temp depend on presence of INTACT CUTANEOUS ACTIVE VASODILATOR NERVES
