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PHYSIOLOGY OF PAIN - 40

Terms

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Define pain and distinguish it from nociception?
Pain is an unpleasant sensation which may be associated with actual or potential tissue damage and which may have physical and emotional components.

The term "pain" is a subjective experience that typically accompanies nociception, but can also arise without any stimulus. It includes the emotional response. Nociception, on the other hand, is a neurophysiological term and denotes specific activity in nerve pathways. It is the transmission mechanism for physiological pain, and does not describe psychological pain. These pathways transmit the nominally "painful" signals, though they are not always perceived as painful.
Describe tissue injury and inflammation
“Inflame” – to set fire.
Inflammation is “dynamic response of vascularized tissue to injury.”
Is a protective response.
Serves to bring defense & healing mechanisms to the site of injury.

NOTE:

Inflammation is a response to injury and is also a protective response. Protective mechanism with survival value. Tissue injury hurts because it triggers the animal to guard or protect the injured areas.
Describe how inflammation starts and the triple response of Lewis?
Inflammation starts with a flush – due to capillar dilatation and then a flare – occuring due to arteriolar dilatation, and finally the weal or welt – due to edema. This all occurs because more blood flows into the area. Hyperalgesia occurs in areas surrounding the injury, producing the guarding effect.

Inflammation controls how a human responds to an injury. The mechanism that explains how the triple response of Lewis works and gives insight into pain

MORE NOTES - MO

The red line is called a flare and then you get a welt which is after the flare where it has swollen up and became a wheel
The triple responsive lewis = what happens when you get a tissue injury
Tissue injury is accompanied by inflammation
The area around the triple response of lewis has a greater sensitivity to pain after the injury instead of before so what we learn about the skin and about many injuries asoc with inflammation is that
there is a ring around the injury where there is high awareness about the pain so that it can guard it more carefully and keep it from getting worse, it is a stop signal! So a protective mechanism!
Illustrate the triple response of lewis?

Flush: capillary dilatation.
Flare: arteriolar dilatation.
Weal: exudation, edema.

NOTES:

Infammation plays a big role in controlling how an animal responds to injury
Sometimes called the line, flare, and weal
Hyperalgesia is a guarding effect
What are the 2 reasons for pain?
1. Tissue injury or in the absence of tissue injury.

2. Neurotransmitters are released to trigger pain.
What are Noiceptors?

They play a role in indicating tissue injury. Axons are stimulated by prostaglandins, potassium leaking out, and bradykinins as a response to tissue damage. Potassium ions are high in the intracellular fluid so when damage occurs to cells the potassium leaks out and interacts with potassium leaking channels.
Discuss 4 transmitters released by tissue damage?

1. Lactic acid

2. Histamine

3. Substance P

4. ATP
Describe the role of lactic acid in pain?

Lactic acid is released when there is an increase in anaerobic metabolism and the tissue has been deprived of oxygen and you switch to anaerobic metabolism so there is a build up of lactic acid, which acts as a mediator.
What is the role of ATP in pain response?

Most importantly, ATP also has a role in mediating pain, able to stimulate noiceptors at a threshold lower than anything else. There must be a membrane receptor on the noiceptor, that modulate and control the firing of that noiceptor. ATP is going to work on the membrane receptor of the noiceptor – Purinergic receptor.

NOTES

But most important is ATP because during tissue injury, it seems like ATP stimulates nociceptors at a threshold that is much lower than anything else so the adequate stimulus for nociceptors is ATP working on the nociceptors
Remember that there has to be a membrane receptor for nociceptors but 2 kinds of receptors
There are bare naked nerve endings which are neuron receptors that depolarize when there is an adequate stimulus. But nociceptors are membrane proteins assoc. with ion channels for example modulating control how much fiber that nociceptor is going to be
ATP will work on nociceptors= puranegic or P receptors
Describe the association between heat and pain?
There is a close association between heat and pain – hot chili peppers which contain capsocum – capsaicin – a drug that interacts with heat receptors and also desensitizes the pain receptors.

NOTES:

Hot chilli pepper receptor is for sensation of heat and pain = hot C P have a chemical capsicun that has been turned to a drug called capsiasin that keeps the knees warm and desensitize the pain receptors
There is no assoc btw cold and pain but there is for heat and pain
Describe the effect of an agonist on the firing rate of a receptor?

The higher the concentration of an agonist, something that stimulates the receptor the lower the firing rate of the receptor. It desensitizes receptors at high concentration, at low concentration the receptor is up-regulated.

NOTES:

The higher the conc of the agonist that stimulates the receptor, the lower the firing of the receptor so it desensitizes receptors that have a high conc. But at low conc, there is hypersensitivity of the resceptor so the receptor becomes upregulated with a low conc of agonist and desensitize with a high conc of agonist
Describe antidromic stimulation?

Antidromic stimulation – opposite direction of normal neuron response; axon terminal à axon à cell body à dendrite à to site of injury; Orthodromic stimulation – in the normal direction of stimulation – dentrite à cell body à axon à axon terminal.

NOTES
Antidromic stimulation – opposite direction of normal neuron response; axon terminal à axon à cell body à dendrite à to site of injury; Orthodromic stimulation – in the normal direction of stimulation – dentrite à cell body à axon à axon terminal
What is the role of seratonin and histamine in pain and discuss the angry axon reflex?

Seratonin and histamine together help to make the capillary leaky – plasma fluid leaks into the tissues producing the weal response;

The angry axon reflex – turns back on itself, keeps going and amplifies the stimulus.

NOTE:

e.G serotonin, 5 HT are the anti group
Serotonin and histamine togther make the capillary leaky and this is what produces the weal because plasma fluid leaking into tissue and irritates the skin and you get the wheel response (line, flare, ….weal) all due to the angry axon reflex turning back on itself and this amplifies the stimulus
What is STT?

The spinothalamic system provides for temperature and pain sensibility. This small fiber, evolutionarily old system provides for perceptual capabilities that have a larger component of emotional tone, the affective component, than do perceptions provided for by the DC-ML system. Because its fibers ascend in the anterolateral portion of the spinal cord, the spinothalamic system is also called the anterolateral system.



NOTES:

Spinothalamic tract brings pain stimuli into the CNS for processing which is what you do with neurosignals, you process them in the spinal cord and brain and then you perceive the pain and you are aware of the pain, then you get a general feeling if you are made aware of it generally but if you are made aware of it in a specific way, you get a localized and precise feeling
Highest level of perception is localization in the primary somatosensory cortex or S1 cortex
Compare the 2 portions of STT?

There are two portions of the spinothalamic or anterolateral (anatomical name) system
Antero portion: crude touch and it does not dessicate
Lateral portion: pain and temperature sensibility or perception and it dessicates across the midline
So we will concentrate on just the lateral portion today
It is an old system from our ancestors due to its need for survival
Compare STT and DCMLS and what is the need for this comparison?

STT is older. In the DCMLS there is localization of tactile sensation. In the STT there is only localization of pain and the temperature response – much more emotional component.

Why compare the two systems? Because they use the same somatosensory homunculus (topographical map of the body projected onto the somatosensory cortex). They both use the same thalamic nuclei and cortex for localization. The thalamic nuclei relays information and preprocesses the information for the somatosensory cortex.

NOTES:

Compared to dorsal columns, in STT, there is also localization of pain and temp. response, but we also have an emotional component here too along with it
The two use the same somatosensory homocunlus system: Homonculus system : a topographical map of the body projected onto the somatosensory cortex , S1 cortex, so they both use the same cortex for localization and same thalamic nuclei for relay of info and pre - processing of the info for the somatosensory cortex
Describe nociceptors of STT?
Receptor = Nociceptor (responds to noxious stimuli such as pain and temperature)
Nociceptors are naked nerve endings of primary (first order) afferent neurons
Nociceptor signaling regulated by ion channels and membrane receptor proteins
What happens to pain and temperature signals transmitted from nociceptors?
They go to first order primary afferents without synapse btw the receptor and first order neurons
First order neurons release SP and glutamate and synapse in SG
. SG is an area in the spinal cord called substantia gelasinosa and SP stands for substance P.
Describe how pain signals are transmitted to second order neurons and the effect of this?
Pain signals transmitted to second order neurons contralaterally at spinal level of stimulated receptor or at a spinal segment above or below the stimulated receptor (tract of Lissauer) making pain and temperature difficult to localize to a single dermatome precisely.

NOTES:

What is the diff btw STT and dorsal columns?
Dorsal coulmn = once the receptor is stimulated the tactile sensation goes up and does not dessicate in the medulla into the medial leminiscus. After the medial lemin,
The spino crosses the medial leminiscus where the receptor is attached at the same spinal level but the problem is that the signal might go up a bit up a segment or down a segment sometimes up 2 segments or down 2 segments b4 it crosses over so it intermingles with fibers that are coming from lower and upper segments sometimes because it goes up and down in the tract of Lissauer and this is a problem which is another diff btw DC and STT, which is :
They have poorer localization because they can up and down a few segments so it is difficult to localize it to a single dermatome
Describe Brown-Sequard syndrome ?
It is a spinal cord hemisection and the lesions produce ipsilateral and contralateral loss of pain and temperature sensation in the dermatomes at the spinal level of the lesion but only contralateral loss in the dermatomes below the spinal level of the lesion
What can happen if we shoot a professor and the bullet lands on the spinal cord?
There is a hemisection of the spinal cord because only one side is affected and because of how the tracts run, the dessication might be down here, but at the level where you have the lesion, you loose pain and temp sensitivity on both sides because the fibers coming from the inside are knocked out because fibers coming from one side can cross over to another side associated with the bare naked nerve endings so the hemisection affects both sides at the same level of the lesion. Below the level of the lesion, it will only affect the neurons contralaterally because the bare naked nerve endings will miss it. So this is the significance of the Brown-Sequard syndrome .
How do the second order neurons of STT transmit pain and temperature signals?
Second order neurons transmit pain and temperature signals to thalamus contralateral to stimulated receptor.
Describe the 2 thalamic nuclei involved in transmission?
1. VPM processes pain and temperature signals from trigeminal (CN V) analog of spinothalamic system for head and neck

2. VPL processes pain and temperature signals from peripheral regions of the body such as viscera, trunk and limbs (most of the body at each spinal segment)

NOTES:

Becos of this, 2 dff regions of the S1 cortex are involved in head and neck versus rest of the body, so if you look at your homonculus, and see the pic, of the SI cortex, you see that
So head and neck in the S1 cortex is served by a diff niclei , the VPM, which is more in one that is more medial than the one in the rest of the body in the arms and the leg, so 2 diff regions of the s1 cortex are involved in the localization
VPL = Arm and leg,
What is the role of Medial (intralaminar) thalamic nuclei
They process pain and temperature signals from reticular formation (spinoreticular fibers) such as raphe nuclei and locus coruleus


NOTES

There are a group of medial intralaminar nuclei called nonspecific bcos it sends info to the whole cortex (S1 or S2 (somatosensory associaton cortex)cortex) , remember that the cortex is like a computer, and when you set up a program, the program on it, you need to make the proper association btw the program and the stimuli so the S2 association cortex will associate pain and temperature responses with responses from othert parts of the cortex = cognotive they stimulate the whole cortex so you are more aware and wakefullnes and there is inhibition of sleep bcos of the pain, a lot of repair when you are sleeping
S2 is somatosensory assoc. cortex = pain amd temp responses with responses from other parts of the cortex e.g other cognitive maybe memory associated with burning yourself from a hot stuff
Where does the emotional component of pain stem from?
Emotional component comes from stimulation of spinal reticular fibers that are ascending the spinal cord with same info as from the pain receptor and they go to the medial intralaminar non-specific thalamic nuclei so tjey go raphe nuclei and locus coruleus in the reticular formation and those spinal reticular fibers will project to the intralaminar ..nuclei and the purpose of this is that first of all, the intralaminar alert the whole cortex instead of just S1 and S2. AND stimulate the whole cortex so you are more aware and wakefullnes and there is inhibition of sleep bcos of the pain, a lot of repair when you are sleeping like your immune system.
What happens when pain is received in the thalamus?
When pain is received in thalamus, it is localized so it goes to the S1 and S2 cortex so tger is activation of the executive decision making other area of the pre frontal cortex e.g write or wrong, should I stop exercising due to pain? They are from the prefrontal cortex = intralaminar nuclei
Discuss central (thalamic) pain signals?
It means pain signals cannot be localized (e.g., metastatic cancer) and central (thalamic) pain syndrome is relieved by producing electrical lesions in a thalamotomy procedure

NOTES:
Central thalamic signals means generalized sensatin all over your body e.g like what you get in metastatic cancer, so stimulating tissues all over the body = intractable pain!!! (same thing as central or thalamic pain) = only relieved by electrical lesions to the thalamus and burn small portions of the thalamus to destroy it and relive the pain (thalamotomy)
Describe the role of the cerebral cortex in pain?
Pain and temperature signals transmitted from VPL and VPM (specific thalamic nuclei) to somatosensory cortices SI and SII for localization
Pain and temperature signals transmitted from medial intralaminar (nonspecific) nuclei to all regions of cerebral cortex for “alerting” response, which induce wakefulness and inhibit sleep
What happens to pain and temperature signals from intralaminar nonspecific nuclei?

They go to the limbic system, hypothalamus and associated structures for emotional, endocrine, stress and autonomic responses which produce fear, suffering, cardiovascular, respiratory, gastrointestinal, urogenital and stress-related hormonal responses
What is a good model for looking at nociceptors and what are the afferent fiber types?

Skin is a good model for us to look at nociceptors and we have group.., A,B,C, is cutaneous nerves and they are all based on conduction velocity
Delta are the slowest of the A fibers
C are the unmyeleinated fibers so they are slow.

NOTES

designations of muscle nerves as III and IV.
A-delta are the slowest of the A fibers; (III)
C(IV) represent the unmyelinated fibers which are slower than the A-delta fibers;
Discuss receptor potentials and what must be done in order for them to be propagated?
Receptor potential are transient and local. In order to be propagated they must be summated either temporally or spatially. Read this when you have time, it provides some insight.
How is ATP related to nociceptors?
At the lowest concentration, ATP released by tissue injury is the adequate stimulus for noiceptors.
How is ATP related to purinergic receptors?
How is ATP related to purinergic receptors?

NOTE:
In the lowest cinc. It is ATP released by tissue injury that is the adequate stimulus for nociceptors and it is called a Purinergic Receptors and ATP is a ligand for the P2X and P2Y receptor
Also acid sensing channel
All these channels play a role in nociceptors
Reviewing the circuit diagram of the spinothalamic tract, discuss what activates noiceptors?
Nociceptors are activated by Vanilloid-1 (TRPV1) Channels that has been associated with the (vanilloid receptor subtype 1, VR1) so it produces a very transient receptor potential, in order to be propagated, it needs to be summatted either by temporal or spatial summation so not local so the role of the Vanilloid-1 (TRPV1) Channels activating the nociceptors.
Reviewing the circuit diagram of the spinothalamic tract, explain how noiceptors are activated by vanilloid or purinergic receptors?

Reviewing the circuit diagram of the spinothalamic tract we realize that the noiceptors activated by vanilloid or purinergic receptors (P2x and P2Y) where capsaicin is a ligand or ATP respectively, when they fire they transmit signals across the midline either up or down a segment which makes it more difficult to localize, they decussate in the spinal connesseur, but before decussating they synapse in the substantia gelatinosa. The SG then transmits a second order neuron across the midline to the contralateral thalamus (VPL or VPM) and to the spinal reticular fibers which go to the locus coruleus or the raphe nuclei which then go to non-specific intralaminar nuclei and alert the cortex that there is pain which makes you aware of the pain. The NC receptors for which capsaicin is a ligand. –
Ligand for purinergic receptor = ATP;
When they travel across the midline may travel up or down making them harder to localize.

The spinal reticular fibers go to the reticular formation.


NOTES:
Vanilloid
Puranegic…for which capsaicin is a ligand
ATP
When they transmit signals across the midline, they dessicate in the spinal connesur? But b4 they dessicate, they synapse in the Substantia gela..and the SG transmits a signal to the midline to the thalamus, the contralateral thalamus (VPL, VPM) and to the spinal reticular fibers b4 they go to the locus.. Or the raphe and then they go to nonspecific intralamina nuclei to alert the whole cortex that there is pain and so this makes it difficult to sleep and makes you more aware of the pain so you are more effective in guarding the area that is affected by the pain, where there is tissue injury presumably taking place.
How does the the spinothalamic system receive its input?

The spinothalamic system receives its input from free (naked, bare) nerve endings that are the peripheral terminals of small- diameter myelinated (A) and unmyelinated (C) primary afferent fibers.
What are multimodal receptors?

They are bare naked nerve endings that respond to more than one mode of stimulation; A-delta and C for cold, just C for warmth.

NOTES:

Temp and pain sensation are served by the same bare naked nerve endings, these are multimodal receptors so bare naked nerves are this because they respond to more than one sensation
Thermal is C, group 1 fibers and they are the slowest and are called the Ad
diff cold and hot regions on the skin = receptor fields are overlapping and you need experiments to diff
What do thermoreceptors respond to?

Thermoreceptors do not respond to absolute temperature but the change in temperature. Delta T is the difference in temperature from a set point; when the temperature changes by ten degrees, as temperature change increases, response increases; The set point at 34 degrees, it fires when it goes from 34-44 degrees not just at 34 degrees.

NOTES:

Thermoreceptors are responding to delta T
Diff between the actual temp and the set temp for the receptor is delta T e.g 34 degreees around the surface of your skin might be the temp of blood but if it gies up to 44 it is not responding to actual temp but to delta T
What is firing frequency and what happens to it as you decrease the temperature?

Firing frequency is the frequency of action potentials and it increases as you decrease the temp at a higher firing freq you get the sensation of cool, cold, and very cold you can get paradoxical cold.

NOTES
The firing frequency increases as the temperature decreases or increases beyond the normal threshold between 32-40 degrees, at higher and lower temperatures the firing frequency for cold increases
Discuss paradoxical cold?

Paradoxical cold response (not for heat) – can detect going from cold stimulus by addition of cold sensation when introduced to heat;

Paradoxical cold sensation – occurs when you warm a cold spot with warm water for example, you feel the warmth and then the cold returns;

NOTE:
paradoxical cold: as you are going from left to right on the graph, you are warming the cold spot
Since thermoreceptors are multimodal, discuss what happens when there is an increase in temperature?

Many of the thermal receptors, if not all of them are multimodal for warmth and pain so at very high firing freq you get pain like capsaicin in the beginning to get warmth so the firing rate of the receptor is increasing but when he starts sweating, running up and down the court or if he takes a hot shower and no capsaicin off, you get very painful!
So warmth and pain bcos added stimulation of sweating or hot water increases firing freq

NOTES:

Hot fibers – high rates of firing due to increases in temperature at a warm spot; most receptors are multimodal for heat and pain – think back to hot chili receptor reaction -
Compare the mechanisms of the 2 types of pain?

1. The C fibers – slow pain; ex. burning; more visceral pain – internal structures, organs;

2. A-delta – fast pain – shooting pain; ex. sharp; more somatic pain – from the body wall; superficial – muscle; the more superficial the pain the sharper it is;

The deeper structure of the body wall – somatic pain;

NOTES:

Heat is followed by pain
C fibers are the slowest pain

Fast pain is called shooting and sharp pain = more somatic= body wall, skin, muscle, and fat tissues

Slow pain is burning = more visceral pain (internal structures are affected)
Slow pain receptors can slowly or rapidly adapting
Adaptation = How fast it comes back to baseline after being stimulated
Fast pain is only the slowly adapting receptor!!
Affective to slow pain or burning so it means that a deep structure is involved like internal organs
Could still get some slow burning pain in the body wall too
Regarding the body wall, what happens when you have a more superficial pain?

In the body wall itself, the more superficial a pain is, the sharper it is so shooting pain that are more quickly are the superficial layer and the slower sharp pain is from the less superficial layer
Body wall and affective structure is more of the slow burning pain with emotional component e-.g fearful and naseous

NOTES:

Vanilla is similar in structure capsaicin.
Cold receptors – not readily associated with pain;
Warm receptors – related to pain receptors;
Slow pain is more emotional pain.
Suppose there is an old lady that gets fearful before she eats, why is this occurring and what is it called?
This happens because the old lady has pain everytime she eats so she is fearful b4 she eats so she stops and she looses weight, all due to gall bladder pain attack everytime she eats so they take out the gall bladder and what she is experiencing is called avoidance reaction
Differentiate between A delta and C fibers in terms of their location in the skin?

A delta is the superficial skin in muscle and C is the less superficial skin but it is not precise because you can still get a slow burning pain even if it is not a visceral structure
What does a large receptive field mean and how does this relate to STT and DCLMS?
Large receptor fields means more difficulty in localizing. STT has large receptor fields and the dorsal column has smaller receptor fields – more precise localization. Therefore:
The central processing of large receptive fields means more difuculty to localize so STT is large receptive field
Small receptive fields in transduction so more localized and in the dorsal columns so more precise localization

NOTES:

Large Multimodal RFs:

Receptive fields of central neurons within the spinothalamic system are often large. Individual neurons may respond to several different stimuli (multimodal responses). RFs may be bilateral. Some neurons are specifically sensitive to noxious stimulation; others are sensitive to temperature changes.

This shows what?

This explains the flow of neural information involved in sensory transduction.
The frequency of the action potential is proportional to ?

The intensity of the stimulus.
In the receptor potential, the amplitude of the receptor potential is propotional to what? why is this?

It is propotional to the intensity because more sodium channels are opening or more calcium channels are opening.
What is the role of the trigeminal analog of the spinothalamic system ?

It transmits pain and temperature signals from head and neck to VPM of thalamus of the brain.

NOTES:
Here is the trigeminal analog of the STT so there is something called the spinal tract or fiber where from the trigeminal nerve, as the trigeminal nerve enters the brain, from nociceptors in the region of the of the face or head , and neck, subserving pain and temperature in this region, b4 it dessicates and joins the VPM, it goes down because the trigemina nerve enters around the pontomedularry junction and then it goes down to the medulla and it crosses over but it may go down as far as the cervical spinal cord.
What is the role of second order neurons in the spinal tract of CN V?

It transmits pain and temperature contralaterally via decussations in pons, medulla or cervical spinal cord.
Cervical spinal lesions can produce what?
Abnormal pain and temperature sensations in head and neck (e.g., cervical arthritis, whiplash injury producing temporomandibular disease)

NOTES
Sometimes, it could be loss of pain!
Compare:
1. partial crush
2. hyperalgesia
3. hypoalgesia
1. A partial crush can cause a heightened response

2. hyperalgesia means increased sensitivity to pain due damage that irritates the tract

3. Complete damage would trigger hypoalgesia, which is decreased sensitivity to pain

NOTES:

When you crush you loose tactile sensation first. You would feel numb followed by a high sensation of pain. The faster conducting fibers inhibit the lower conducting slow fibers.
Describe a compound nerve?
Compound nerve has the A B and C fibers in them. Within the bundles of the spinal cord – lie the A, B and C fibers - when the spine is crushed those fibers with myelin are affected first (some A fibers and B – sympathetic fibers); those affected last are the A-delta and C fibers. Therefore, When you crush you loose tactile sensation first. You would feel numb followed by a high sensation of pain. The faster conducting fibers inhibit the lower conducting slow fibers.

NOTES:

A partial crush can cause a heightened response, because a peripheral nerve including a cranial nerve like the trigeminal nerve is a compound nerve = A, B, and C bundles in it, these are nerve fasicles , bundles sorrunded by endoneurium and epineurium in the same one. “A” fiber is the biggest one so the neurons with the lots of mylein so when you crush a nerve, neurons with a lot of mylein like A fibers will be affected first so, you loose touch and motor because the fastest fibers are touching fibers and remember that a peripheral nerve is a compound nerve means that they have motor neurons as wells as A,B, C, fibers, which are sensory neurons, so motor neuron, and sensory in one compound. B could be sympathetics. C and A delta are affected last! So when youcrush, you loose tactile sensation first from A and feel numb first.
Describe classic crush injury using IAN?
So in the case of IAN, he felt numb first followed by a heightened sensation of pain, hyperalgesia, because the faster A and B inhibit the slower responding C fibers, C fibers is heightened response, this is classic crush injury!!!
Screamed when someone came in the room bcos, when ppl open the door, the air con brings in currents of air and the pain is so severe so cold in the skin so the cold currents moving into the skin were producing pain= CRUSH injury.

NOTES:

When there is spontaneous pain caused by something pain = neuralgia, but something not normally painful like cold = causalgia! So ian has causalgia
Most severe form of causalgia is allodynia
Describe neuralgia?
"Spontaneous" pains arising in a root or nerve distribution due to relatively long-term damage (tension, pressure, crushing). An innocuous stimulus in the nerve distribution can elicit the pain, which is often severe. Examples: herpes zoster (shingles) infection, trigeminal neuralgia.
Describe causalgia?
"Spontaneous" pains arising in a nerve or root distribution following rapid, violent injury to a nerve, such as due to a bullet wound. Probably due to a disorder of sensory processing. Example: anesthesia dolorosa (tactile anesthesia with intense pain in the affected area).
What is phantom limb pain?
Burning, shooting, or crushing pains may be experienced in the missing part following amputation. When triggered from the stump, they may be a type of neuroma pain. In other cases, a disorder of central processing is implicated.
Differentiate btw neuralgia and causalgia, and mention Ian and allodynia?
1. Neuralgia is spontaneous pain caused by something that is usually painful;

2. Causalgia is pain produced by something that is not normally painful;

Causalgia vs. Neuralgia – Ian has a causalgia and allodymia is the most severe form of causalgia
Discuss Coarse Somatotopic Organization?
Somatotopic organization in the spinothalamic system is not as distinct as in the DC-ML system, except in the spinal cord.
Discuss the spinal organization of spinothalamic somatosensory system fibers?

In the spinal cord, there is lamination from the sacral, lumbar, and spinal thoracic regions. This is the anterolateral system and in this system, the fibers are arranged sacral to cervical, lateral to medial, so within the spinal cord, you can have an injury that is not a hemisection but only affects one portion so what is the significance of this?
What could happen if the cervical region of the spinal cord is affected by a bullet or some injury?

It will only be represented in the upper portions of the spinal cord; If it wasn’t organized in this way an injury in the sacral region would be reflected as an injury in the cervical. regions.

NOTES:

If the cervical region is affected by a bullet or some injury, this region will be represented at the highest levels of the spinal cord, not represented in the lower levels
If there is a Sacral or lumber region lamination, there will be cervical region too and so there is abnormal pain and temp responses in the dermatome that is served by the lumbar and sacrum so it could be your toes having abnormal pain and temp responses and you’ll first expect sacrum or in your legs, it might be lumbar, but it could be cervical based on this!
Cervical region lamina could carry the spinothalamic from sacral, lumbar, thoracic, and cervical too so could be on your toes
Cervical injury producing abnormal pain and temp sensation if the lamina is from lumbar and sacral dermatomes
Discuss the emotional aspect of pain?
The emotional and motor component because sometimes the people have heightened pain and temp sensation or a very severe shock to their pain and temp systems and they actually freeze and it may decrease their motor output
For pain from superficial tissues:

1. Fast (pricking) pain is due to activation of what?

2. Slow (burning) pain is due to activation of what?
1. Fast (pricking) pain is due to activation of A (GIII) fibers.

2. Slow (burning) pain is due to activation of C (GIV) fibers.
Compare the pain experience of fast pain and slow pain?
1. Fast pain does not last much longer than the stimulus, is easy to endure, and is not accompanied by much of an affective, or emotional, component. It is like the pain from a hypodermic needle during an injection.

2. Slow pain persists, is hard to endure, and has a large affective component; autonomic responses may occur. Slow pain is associated with suffering and is most often the kind of pain that brings the patient to the doctor's office.
How does the brain modulate pain responses?
The brain is able to modulate all the varieties of sensation via efferent connections to receptors or neurons in sensory pathways. This is also true for nociception and there are three (non-mutually exclusive) mechanisms by which nociceptive inputs are modulated.

NOTES:

We have many mechanisms for decreasing pain = opiates
What is the Gate Control Theory of Pain?
The gate control theory of pain is the idea that physical pain is not a direct result of activation of pain receptor neurons, but rather its perception is modulated by interaction between different neurons.

The theory, which arises from evolutionary psychology, holds that evolution of intelligence in any natural environment, historically, begins with proprioception, the recognition of the entity's own body. Pain, in this view, is then a part of this very sense, a way in which parts of the body learn where they should and should not be.
Describe the gate control theory of pain?
Large-diameter primary afferent fibers (Aα and Aβ fibers) can inhibit, via inhibitory interneurons, dorsal horn neurons (projection neurons) that give rise to spinothalamic tract fibers. This form of control of nociceptive input is known as the gate control theory of pain.

NOTES:

Afferent pain-receptive nerves, those that bring signals to the brain, comprise at least two kinds of fibers - a fast, relatively thick, myelinated "Aδ" fiber that carries messages quickly with intense pain, and a small, unmyelinated, slow "C" fiber that carries the longer-term throbbing and chronic pain. Large-diameter Aβ fibers are nonnociceptive (do not transmit pain stimuli) and inhibit the effects of firing by Aδ and C fibers.

The central nervous system has centers at which pain stimuli can be regulated. Some areas in the dorsal horn of the spinal cord that are involved in receiving pain stimuli from Aδ and C fibers, called laminae, also receive input from Aβ fibers (Kandel et al., 2000). The nonnociceptive fibers indirectly inhibit the effects of the pain fibers, 'closing a gate' to the transmission of their stimuli (Kandel et al., 2000). In other parts of the laminae, pain fibers also inhibit the effects of nonnociceptive fibers, 'opening the gate'.
How can pain be relieved by the gate control theory of pain?
Electrical stimulation of the dorsal columns or of large, myelinated peripheral nerve fibers by transcutaneous electrical nerve stimulation (TENS) may relieve pain by this mechanism
Why is acupuncture anesthesia considered an example of dorsal column-anterolateral system ?
It is because it is reported to be effective only when needles are inserted near bundles of Group II fibers. Dorsal column-anterolateral system interactions may occur at several levels, including spinal cord dorsal horn, spinal V nucleus, and thalamus.
Discuss the role of C fibers in the gate control theory?

Here we have the C fibers exciting a second order neuron, this is what we expect but at the same time, it is inhibiting an inhibitory interneuron by releasing an inhibitory neurotransmitter (e.g., GABA, enkephalin) that is serving as a gate, where if the inhibitory interneuron is not inhibited then the pain signals or response will be transmitted up the second order neurons of the thalamus .

NOTES:

An inhibitory connection may exist with Aβ and C fibers, which may form a synapse on the same projection neuron. The same neurons may also form synapses with an inhibitory interneuron that also synapses on the projection neuron, reducing the chance that the latter will fire and transmit pain stimuli to the brain. The C fiber's synapse would inhibit the inhibitory interneuron, indirectly increasing the projection neuron's chance of firing.
What happens if A beta fibers excite the inhibitory interneuron of the gate control theory?

Then the pain and temp signals will be inhibited and we call the A alpha and the A beta fibers are a system that can close the gate and the C system opens the gate! Transmitting the signals is opening the gate, inhibiting the signals is closing the gate. So if we open the gate, we get more pain perception, if we close the gate, we get less pain perception.

NOTES:

The Aβ fiber, on the otherhand, forms an excitatory connection with the inhibitory interneuron, thus decreasing the projection neuron's chance of firing (like the C fiber, the Aβ fiber also has an excitatory connection on the projection neuron itself). Thus, depending on the relative rates of firing of C and Aβ fibers, the firing of the nonnociceptive fiber may inhibit the firing of the projection neuron and the transmission of pain stimuli.
How do we close the gate of the gate response theory?

Massage, touch, stroke the area of the pain and the pain is lessened because A alpha and A beta fibers are the tactile sensations that are faster conducting fibers from receptors serving tactile sensation and they close the gate and stimulate the inhibitory interneuron

NOTES:

Gate control theory thus explains how stimulus that activates only nonnociceptive nerves (such as rubbing a bumped knee) can inhibit pain. The pain seems to be lessened when the area is rubbed because activation of nonnociceptive fibers inhibits the firing of nociceptive ones in the laminae (Kandel et al., 2000). In transcutaneous electrical stimulation (TENS), nonnociceptive fibers are selectively stimulated with electrodes in order to produce this effect and thereby lessen pain.
Where is this theory proposed to be located at?

This is a theory because we never found a place where all these components come together the way that they need to but it is proposed to be in the Substantia gelainosa but it is a theory that has not been found but it explains the pain experience and it is a good model for us.

NOTES:

Experiments were performed on dogs who were raised confined in cages. When released, the dogs were excited, constantly ran around, and required several attempts to learn to avoid pain. When pain such as a pinch or contact with a burning match was encountered, the animals could not take action to avoid the stimulus immediately. This finding seemed to demonstrate that pain is understood and avoided only by experience- aversion to it is not inbuilt or automatic, and the organism has no way to know what will cause repeated pain without a repeated experience.
What is the function of raphe nuclei?

The raphe nuclei (Latin for 'the bit in a fold or seam') is a moderately sized cluster of nuclei found in the brain stem, and releases serotonin to the rest of the brain. Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to act at these nuclei.

Raphe nuclei are the major seratonin regions of the brain stem that modulate the release of enkephalin which is a neural peptide which acts like endorphins and produces IPSPs.
Describe the mechanism of the raphe nuclei?

The spinal reticular fibers that end in the raphe nuclei, stimulate fibers that send signals back to the dorsal horn of the spinal cord and this is where the raphe nuclei are projecting down to the dorsal horn and releasing serotonin. Raphe nuclei are the major serotonin or 5 hydroxy tryptomine regions of the brain stem and there they modulate the release of enkephalin , a neuropeptide that has in common with endorphins the property to produce an IPSP , which then inhibits the transmission of pain signals.
What is the role of enkephalin and in what 2 regions is it located?

Enkephalin is found:

1. The dorsal horn of the spinal cord.

2. It is rich in the hypothalamus.

It modulates pain responses throughout the spinal cord at every spinal level.
If there is low serotonin or norepinephrine in raphe nuclei e.g bipolar disease and depression, what will happen to the threshold of pain in depressed or highly aggressive people due to low levels of serotonin?
It will decrease their pain threshold , so they have heightened response to pain so antidepreessants that raise the serotonin and norepinephrine levels will act as analgesics
Why is pain treated with antidepressants?
Pain is treated with antidpressants because by producing more serotonin, we are producing more enkephakin, which will produce more IPSPs and inhibit the pain response.
How are enkephalins and endorphins similar?
They are both considered endogeneous oppiates because they are made by the body as opposed to the exogeneous opiates from the poppy flower that are the bases of morphine, methadone, heroin. So, endorphins and enkephalins have a similar pentapeptide sequence consisting of glutatmate, 2 glycines, a phenylalanine, and a methionine, and we call this metenkephalin and another pentapeptide with the same sequence of glutamate, glycine, phenylalanine and leucine and this is callled leuenkephalin. Both of these enkephalins are represented in endorphins too and it is the active ingredient at the active site.
What is the difference between enkephalin and endorphins?
Enkephalin is released locally and its effect only last for a few seconds but endorphins are secreted into the general circulation and they last for hours and more pain relief.

What does this figure illustrate?

This is showing the IPSP, which makes it more difficult to transmit the pain impulses and the chloride ion channels open to produce the IPSP
IPSP, chloride channels are open to produce it
What is the role of Reticulospinal fibers from locus coruleus ?
Locus coruleus is in the brainstem and its fibers project to the dorsal horn of the spinal cord and release norepinephrine which inhbits pain and temperature signals by an unknown mechanism.
Describe mental illnesses and the effects of antidepressant drugs?
Mental illnesses such as depression decrease serotonin and norepinephrine and lower pain thresholds while antidepressant drugs and therapies (e.g., exercise) which increase serotonin and norepinephrine levels raise pain thresholds
Describe how enkephalin functions with respect to glutamate?
. Certain inhibitory interneurons in the dorsal horn use enkephalin as a neurotransmitter. The interneurons are activated by serotonergic fibers that descend from the reticular formation. Enkephalin causes a decrease in the EPSP produced by the 1o nociceptor via a presynaptic inhibitory action. In part, the effect is due to a decrease in the duration of the action potential in the C fiber terminal. When that occurs, less glutamate (GLU) and substance P are released from the terminal. Enkephalin also may cause a postsynaptic hyperpolarization due to a conductance-increase IPSP.

Enkephalins are released and their affects only last for a few seconds, endorphin affect lasts longer. Chloride ion channels can be open to trigger IPSP.
Disscuss the idea of plasticity of pain perception?
The pain experience is complex and remarkably plastic. Drugs, fear, stress, joy, hypnosis, ritualistic participation, psychosurgery, etc., may profoundly influence it. Both the perception of pain (knowledge that tissue has been damaged) and the emotional reaction to it (the degree of suffering) can be altered. Pain is not necessarily commensurate with the extent of tissue damage.


NOTES:

pain responses can take diff pathways
Surgery on the brain can affect the limbic system
Emotional component of pain is suffering and fear so avoidance
e.G broken leg will be less pain than sprained angle because more chemicals or neurotransmitters are released from person with ankle injury so there are individual differences in pain response
So, to relieve pain, you do not prescribe pain medication based on tissue injury, you base it on the amount of suffering!
Can’t give standard dose of pain medication based on how much tissue injury you see, based on amount suffering!
What are the 3 major clinical features in spinothalamic lesions?
1. Decrease in pain sensibility (hypalgesia or analgesia).

2. Decrease in temperature sensibility.

3. Increase in pain sensibility (hyperpathia or hyperalgesia).
Describe projected pain?
Activation of nociceptive fibers anywhere along their course is felt (projected) as a pain in the peripheral distribution of the fibers. Examples: "to hit one's funny bone" or pain in the leg due to pressure on a spinal nerve at its entrance to the spinal cord.
Describe referred pain?
Pain arising from disease of the viscera, but felt at a relatively distant superficial site. Referred pain appears in parts of the periphery supplied by the same segment of the spinal cord as the affected organ; referred pain occurs in the associated dermatome. It probably arises due to convergence of visceral nociceptive afferents (sympathetic afferents) and skin afferents onto the same dorsal horn neurons. Hyperpathia and reflex muscle spasms may also be present
Describe how C or A fibers from the dermatome intermingle with A alpha and A beta fibers of tactile sensation?
C fibers or A delta fibers from the dermatome intermingle with A alpha and A beta fibers which are tactile sensation fibers and other and also intermingles with fibers from the somatic regions so a visceral structure like the heart in the thoracic region served by A delta and C fibers that are intermingled as the fibers pass into the spinal cord central processing with fibers from the outer chest wall of the region and the left arm not the right arm
What is the effect of how C or A fibers from the dermatome intermingle with A alpha and A beta fibers of tactile sensation?
as a result, you get a heart attack, where there is decreased blood flow through the coronary artery through the myocardium which produces anaerobic metabolism in the heart muscle myocardium and releases lactic acid which stimulates nociceptors and there are acid sensing or hydrogen ion sensing channels on the nociceptors and so they get spontaneous pain responses. And this will be referred not to the visceral structures but to the left arm because the fibers of the visceral structures are intermingled with A delta and C fibers from the somatic regions since they are from the same embryonic dermatome
What is unque about the development of lung buds and the diaphragm?
Lung buds and diaphragm first developed very high in the cervical region and then descend as the embryo grows it takes it to a new position so an injury to the diaphragm or certain structures in the lungs, the pain will be in the shoulder since it is in the cervical region.
Describe the reward pathway?
The reward pathway is a neural network in the middle of the brain that prompts good feelings in response to certain behaviors, such as relieving hunger, quenching thirst or having sex, and it thereby reinforces these evolutionarily important drives. However, the circuit also responds to drugs of abuse, such as heroin, cocaine, amphetamine and nicotine, which seem to hijack the circuitry, altering the behavior of its neurons.
What is the pleasure molecule and what is its mechanism?
Dopamine is referred to as the pleasure molecule;The nucleus occumens secretes dopamine – pain threshold goes up; Everything that has been studied; Dopamine is an anti-stress molecule because it modulates how much ACH is released by the hypothalamus.

There is a connnection between award, stop and continue; there is a dopamine 2 receptor – self-medicated to compensate for deficiency syndrome; Extremely depressed, anti-social, etc.


NOTES:

Association btw the reward system and pain
Locus seraleus and the raphe are abe to modulate pain responses through norepinephrine.
Dopamine, serotionin, and norephinephrine are all part of the mesolimbic system meaning it affects the limbic system
It is the molecule in the nucleus sucumbus that secretes dopamine, the pleasure molecule, everytime thete is secretion, your pain threshold goes up because dopamine cause release of serotonin and serotonin causes release of enkephalin in the brain as well as in the dorsal horn of the spinal cord so there is a higher pain threshold. So since dopamine is the reward and pleasure molecule, then all the addicted behaviors produce reward from dopamine e.g excessive gampling and sex, and food intake raise the dopamine, so serotonin and enkephalin, so raising the pain threshold and you get euphoria which increases self esteem
Dopamne is the antistress molecule because dopa also modulates how much CRH and ACTH are released by the hpothalamus of the pituotary and this stimulates the adrenal cortex to release cortisone, which is your blood index of stress so, if we take a scapel and make an incision of the skin is a surgical stress and dopa decreases the amount of cortisol released
Reward is a paradign for continue, so rewards you for behaviors in the interest of your heath and survival, produce pleasure, and raise your pain threshold, so there is the reward deficiencysyndromer, the dopamine 2 receptor A1 allele that produces an abnormal dopamine 2 receptor that makes ppl with this allele susceptible to addictive behaviors, bipolar, autism, schrirophenia, so genetic abnormailty and there is a reward deficiency syndrome, person susceptible to addiction self medicate to reward themselves. There is a genetic condition so as they take the opiates and stimulate theur endoenous response stimulates their stress response so they are unable to respond to stress physiologically because the dopamine(anti stress) is so high that they cannot be achieved physiologically so when they go through withdrawal and come down from it, they are extremely unhappy, depressed, antisocial!

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