Pain

Question 1

Inflammation

Answer 1

The body’s response to damage in order to remove the stimuli (infection/pathogen) and start the healing process
Hypersensitivity is the cause of inflammation and adaptive- helps protect from further pain and damage, healing faster!
Injury  blood vessels dilate  cells are recruited to repair damage
and control pathogens
Stages to inflammation- redness and heat, swelling, throbbing/pain leads to loss of function during healing

Question 2

Inflammatory mediators
“Algogens of the inflammatory soup”

Answer 2

Complicated process
Open wound, germs and bacteria are entering- Following injury, cells are recruited to area- to release chemicals to cause healing
Bradykinin- inc ap firing peripheral activation

Question 3

Inflammatory mediators

Bradykinin

Answer 3

Bradykinin
Released from plasma (mast cells and macrophages) after tissue injury
Produces pain in humans when administered (inc sensitivity to heat activates trpv1)
Activates PKC and possibly TRPV1 channels
Two receptors: B1 and B2
B1 antagonists – no effect
B2 antagonists – reduced C fiber sensitization
B2 qfter injury- rise in mrna, making more, inc receptors, casuing peripheral sensitization
Increased B2 receptor mRNA in the DRG after injury
Negligible effect on B1 receptors

Question 4

Inflammatory mediators

Prostaglandins- nsaids inhibit

Answer 4

Prostaglandins- nsaids inhibit
First isolated from seminal fluid (prostate)
Derived from fatty acids found in the membrane
Locally-active and produced all over
Two cyclooxygenase (COX) enzymes (COX-1 and COX-2) – target of NSAIDS
Both involved in the synthesis of PGE2
COX-1 – baseline prostaglandins
COX-2 – stimulated prostaglandins (inflammation)
Major peripheral effect of PGE2 is to sensitize neurons to noxious stimuli
Modulated through PKA and activity of Nav1.8- sodium channel inc activation

Question 5

Inflammatory mediators Serotonin

Answer 5

Serotonin
Involved in descending pain modulation
Different peripheral vs central receptors have different effects
Released from platelets and mast cells after injury, contributing to pain sensitization — lots of receptors on DRG neurons
5HT receptors activate PKA and PKC to open TRPV1 channels and Nav 1.8, work by controlling and modulating channels important for pain, makes them work better
Many possible actions due to the (approx.) 17 subunits for 5HT receptors

Ondansetron, the 5-HT3 antagonist- blocks it, reduces allodynia in rats, when given into the spine
Neuropathic model- sni, 5ht3 antagonist reduces alloydnia

Question 6

Inflammatory mediators

Histamine- important for allergic reactions

Answer 6

Histamine- important for allergic reactions Histamine- important for allergic reactions
Substance P and PGE2 cause the release of histamine from mast cells
Most often associated with itch, pain and motion sickness
Potentiates nociceptor response to heat and bradykinin- modulating trpv1 receptors

Control animals (open circles) show an increased response to heat following histamine treatment

Question 7

Inflammatory mediators atp Adenosine

Answer 7

ATP rekeased during skin damage , activate p2x or p2y recpetors Adenosine
During inflammation and injury adenosine, AMP, ADP and ATP are released
Adenosine binds to A2 receptors
ATP binds to P2X receptors to initiate cytokine production and release
Agonists increase pain, antagonists block pain

Bbg- works on p2x- gives food blue colour, can block p2x, prevent allodynia in sni mice, and promote recovery when given after injury

Question 8

BBG

Answer 8

BBG is an analogue to the food coloring in blue Gatorade and blue Smarties
– To reverse allodynia, the dose needed turns the blood blue and any tissue that it bathes

Question 9

Inflammatory mediators Cytokines- released by macrophages

Answer 9

Cytokines- released by macrophages Cytokines- released by macrophages
During inflammation macrophages release interleukins to regulate the response
Pro-inflammatory cytokines
Major: IL-1β, IL-6, TNFα
Minor: IFNγ, IL-8, IL-11, IL-12, IL-17, IL-18, IL-33

Anti-inflammatory cytokines
Major: IL-4, IL-10, IL-13
Minor: IL-16, IFNα, TGFβ

Injection of IL-1β into the paw increased pain in a dose-dependent manner

Question 10

Cytokines regulate pain sensitivity

Answer 10

Allodynia after injury
Increased IL-10 gene decreases allodynia
Antibody binds to IL-10 increases allodynia
Addition of IL-10 protein reduces allodynia

IL-10, anti-inflammatory

Question 11

Neurotrophins and Pain

Answer 11

NGF- regulates nerve growth, synaptic plasticity
Mostly fpund in peripheral fibres
Can be released into spinal cord
NGF and BDNF- work with same receptors- the trx a or b family
NGF- have peripherial nerve and apply it, have neuronal sprouting, trying to inc connectivity of neurons, promoting nerve growth

Causes peripheral sensitixation- makes system more responsive to all stimuli and inc inflammatory and pain components in drg
Causes central sensitization- substance p, cgrp in dorsal horn of spinal cord

Question 12

Inflammatory mediators Nerve growth factors

Answer 12

Blockade of NGF reduces
sensitivity to touch
Give antibody against NGF- reduce sensitivity and sensitization

Question 13

Inflammatory mediators Protons

Answer 13

Protons
Tissue damage can cause release of protons
Low pH (acidic) solutions cause pain through nociceptor activation
Receptor in DRG and nocioceptors senses ph changes, acid — ASIC (Acid-Sensing Ion Channel), activate drg
Adenosine binds to A2 receptors
ATP binds to P2X receptors to initiate cytokine production and release
Agonists increase pain, antagonists block pain

Injections of acidic saline (pH = 4.0) into the muscles produces long-lasting sensitivity in both legs, activate asic, causing sensitivity on both sides- mirror pain
This doesn’t happen with pH = 7.2

Question 14

Inflammatory mediators

Substance P

Answer 14

Substance P released from end of nocioceptors, driven by axon reflux,
Released from sensory nerve terminals (c-fibers) upon injury or infection
– causes inflammatory response
Internalization of receptor (NK1) associated with chronic pain
Can be released antidromically- in opposite direction then normal(primary afferent, now released from dendrites)
where it contributes to mast celldegranulation

Plasma extravasation – blood vessels become leaky and dilate refers to the movement of white blood cells from the capillaries to the
tissues surrounding, more opportunity to release inflammation

Substance P- works
peripherally and centrally
When given into the spine, substance P causes allodynia in mice, dose-dependently

Question 15

Pattern Recognition Receptors

Answer 15

Pathogen-Associated Molecular Patterns
Recognition of conserved aspects of bacteria and viruses
Examples include toll-like receptors (TLRs)
TLR2 and TLR4 recognize yeast and bacteria, respectively
Damage-Associated Molecular Patterns
Recognize proteins present in cytosol and nucleus of cells
Examples include P2X4 and P2X7
Signal that cell has died

Question 16

How does the immune system contribute to pain and inflammation?

Answer 16

Innate immune system
Recognition of pathogens based on structural conservation

Question 17

Theories of pain
Specifity theory

Answer 17

These are not very acurate
Specificity theory
Von Frey (1894) - Postulated that there were specific receptors (nociceptors) that recognized pain and sent signals directly to the brain’s pain center
Neurons respond to pain or they don’t respond at all- not the case
Impulses- axons firing, vs intensity
Neurons don’t respond to innocuous, only noxious
Reach certain point- becomes painful, but after injury nonpainful stimuli becomes painful- allodynia

Question 18

Intensity theory

Answer 18

Intensity theory
Erb (1874) – Claimed that pain was produced by stronger activation of nerves by an intense stimulus, while a weak stimulus produced non-painful sensation.
Pain is generated based on intensity of sensory nerve activation
More intense stimuli/more action potentials = more painful

Question 19

Problems with specificity/intensity theory

Answer 19

Problems with specificity/intensity theory
Receptors would only ever signal pain (specificity)- not the case, diffrenet neurons in spinal cord that revieve stimuli of touch too- wide range neurons
Both can’t explain: Phantom limb pain, spontaneous pain, pain denial
(soldiers in battle)
Wide dynamic range- both ad, c and ab vs nociceptive specific- c and ad
Need direvt activation of nocioceptive- not always the cause

Question 20

Pattern theory

Answer 20

Pattern theory
Developed as an alternative to specificity theory
Pain is produced through a pattern of receptor activation
Hebbian summation may play a role in chronic pain
Pain intensity is coded by pattern activation of different fibres- some fibres are less or more activated than innocuous- different cells need different activation to cause pain- cant tell the pattern that codes for pain
Predifined pattern and each cell needs activation state to cause pain

Question 21

Problems with pattern theory

Answer 21

Problems with pattern theory
Ignored physiological specialization of fibers- some fibres code for pain, doent need to be more or less activated
Cell types are unspecified and impossible to study
No experimental verification- cant test it

Question 22

Control gate theory

Answer 22

Physiological and psychological aspects
Most influential theory of pain, ever
Synthesized components of previous theories into an overall theory
Based on physiology and clinical experience
There is a “gate” in the spinal cord that can be opened or closed to pain- neurons within allow or inhibit pain transmission
Brain has master control- descending modulation, brain can trump pain- can dampen pain signals
Most reffered to
Melzack- did this and mcgill pain questionnaire

Question 23

Gate control theory

Answer 23

Substantia gelatinosa (SG)- layer modulates input before it is sent to the T cells- interneuron within SG, inhibitory
Central transmission cells (T) are cells in the SG that project to the brain- second order projection neurons
In the yellow box- dorsal horn of spinal cord- have two types of cell here and spinal types coming in
Have fibres coming in
Small diameter- c fibres or adelta- noxiuous stimuli
Large diameter- a beta
Activate small diameter fibres- activate t neuron and inhibiting SG neuron- presynaptic inhibtion
Anything that activates t neurons- code for pain, allow for pain to transmit
Large diameter- activates SG neuron- inhibiting input at t neuron, pain cant transmit, reducing pain
Start to rub painful area- inhibits pain, because ab fibre activating SG neurons, modulating the pain
Have a beta at top and adelta and c further
Ron welzack- gave idea that brain has control
Helped explain Why rubbing makes pain hurt less
Reduced L fibers in post-herpetic neuralgia- have reduced large diameter
Transcutaneous electrical nerve stimulation- mild current run through ends of patch- activates only ab- making pain better

Question 24

Gate control theory can’t explain

Answer 24

Phantom limb pain
Primary afferent termination patterns- know that primary afferent synapse and connect with more than just SG layer

Question 25

Ion channels and receptors

Answer 25

A lotIon channels and receptors of these repetors are ion channels
Glutaumate receptor- ligand channel
Mechanacilly gated- require mechanical stimuli
Voltage gated- respond to membrane voltage

Question 26

Voltage-gated sodium channels

Answer 26

Sodium channels play a major role in neuronal conduction and communication-
Three are highly expressed in nociceptors- in primary afferent neurons- small fibres

Nav1.7
Tetrodotoxin-sensitive channel (TTX)- sodium channel blocker
Pain syndromes associated with mutations
Paroxysmal extreme pain disorder – increased function- NaV working too well-
painful redness on orfaces –why isn’t it more widespread?
Congenital insensitivity to pain – decrease in function- channel doesn’t work
1.7 Found on most nociceptors
Knock out ion channel- increase threshold for pain
Nav1.7 knockout mice (red) show increased thresholds in thermal tests
Sodium channels play a major role in neuronal conduction and communication
Three are highly expressed in nociceptors

Question 27

Nav1.8

Answer 27

Nav1.8
Tetrodotoxin-resistant channel
Found on most nociceptors and primary sensory neurons
Major sodium channel involved in action potentials
After damage, less channels on injured nerve, more on uninjured nerve- in part explanation for allodynia- uninjured nerves, expressing this channel more, more sensitive to stimuli

Question 28

Nav1.9

Answer 28

Nav1.9
Tetrodotoxin-resistant channel
Found on most nociceptors and primary sensory neurons
Little is known about this channel, but expression is reduced in neuropathic pain- damage to sensory neurons- could ecplain numbness
May play a role in resting membrane potential maintenance-

Question 29

Glutamate

Answer 29

Most abundant excitatory amino acid and neurotransmitter in PNS and CNS
Binds to and activates ligand-gated ionotropic channels and metabotropic (G-protein-coupled) receptor

Question 30

Ionotropic receptors

Answer 30

Ionotropic receptors- allows passage of ions- mostly calcium and sodium
AMPA, NMDA, Kainate receptors- important for synaptic transimmsion
At dorsal horn- transmits info into spinal cord, activating glutamate or substance P
Activation generates EPSP and membrane depolarization
AMPA is involved in baseline transmission; NMDA involved with plasticity (wind- up)
NMDA also linked to central sensitization- sensitize to sensory neurons inc the pain sensitivity (LTP in spinal cord, dorsal horn neurons better at transmitting sensory info)

Question 31

Metabotropic receptors

Answer 31

Metabotropic receptors
Don’t allow passage of ions, activate g protein- ligand binds and causes confirmational change and release g proteins to cause different avtivation in cell
Referred to as mGluRs and involved in slower glutamatergic transmission
Can inhibit or enhance pain depending on location (mGluR1 and mGluR5 enhance pain in the dorsal horn; mGluR2 expressed presynaptically where they regulate neurotransmitter release and are antinociceptive).
Serotonin, dopamine

Axon releases glutamate, have ampa important for baseline transmission, NMDA- enhances sensitivity and communication

Question 32

Ion Transient receptor potential (TRP) channels
and receptors

Answer 32

Unique and specillized channels
cation channels, ligand gated, repond to thermal simulation- noxious heat
TRPV1- 35-44 degress- activated and activated by chili peppers
Capsacin- TRP- sensitive- acts as ligand for it
TRPv1- responds to acid, changes in PH
TRPA1- ion channel, ligand gated, responds to noxious cold stimulates, less than 15 * Celsius and cinnamon and garlic and mustard oil and TRPM8- responds to cool stimuli, mint, upon injury codes for more noxious stimuli

Question 33

Transient Receptor Potential (TRP) Family

Answer 33

TRPV1 (first one cloned, 1997)
Activated by capsaicin, heat (>43°C), low pH
Located on Aδ fibers, but mostly expressed by c- fibers
Mice lacking TRPV1- don’t respond to the stimuli

TRPA1 Noxious cold detection (<15°C)
Activated by menthol, garlic, cinnamon, mustard oil but also responsible for “burning” cold,
Found in many of the same neurons as TRPV1 can partner up to transmit info

TRPM8
Activated by menthol, low temp (<25°C)
Not found in same neurons as TRPV1

Question 34

Pharmacology of spinal pain transmission

Adenosine Triphosphate

Answer 34

Adenosine Triphosphate
ATP plays a role in neurotransmission and neuromodulation in pain pathways
ATP activates ligand-gated purinergic P2X receptors and
metabotropic P2Y receptors
Expressed by primary afferent neurons and second-order neurons
Activates spinal microglia
\atp released- causes pain, esp when already have injury

Question 35

Pharmacology of spinal pain transmission

Inhibitory Amino Acids

Answer 35

Inhibitory Amino Acids
GABA and glycine are inhibitory amino acids- released to modulate pain
Provide inhibitory tone for the spinal cord (and many brain regions)
Reduce excitability limiting transmission of pain signals
Glycine is strychnine-sensitive channel. Binding of strychnine prevents glycine from binding and can cause pain and muscle spasms. Reduces inhibitory pain, can also cause death

Question 36

Pharmacology of spinal pain transmission

Opioids

Answer 36

Opioids
Inhibitory component of pain system, activation will inhibit neuronal activation
Beta-endorphin, enkephalins and dynorphins
Produced by large molecules that are broken down (i.e., POMC)
Why do we have them- to protect us from overactivation, protecting us from pain, are activated by chemicals we have

Opioid receptors
Mu: ligands act at spinal and supraspinal sites- target of angalgesic drugs
Kappa: Binds dynorphins and produces analgesia; activation produces dysphoria- loss of interest/enjoyement
Delta: involved in emotional reactivity and anxiety

Hughes after talking to butcher looked at hypothalamus and extracted chemicals- found Met-enkephalin endogenous opiod peptibe- activates opiate receptors
Beta- endorphin- during exercise and stress

Question 37

Endogenous Opioids

Answer 37

Endogenous opiod peptides
Penk- differ in last AA
Endorphins- highest selectivity- activates most opiod receptors
POMC- pro opiod something
Makes many lignads and chemicals- large gene

Question 38

Opioid Receptors are Everywhere

Answer 38

Darker= higher expression
Expressed differently and bind different receptors

Question 39

Peripheral Sensitization

Answer 39

Overactive peripherial system- linked to nocioception
Reduced threshold and increased excitability of nociceptive neurons in periphery
Occurs following tissue injury (role of inflammatory mediators)- burn, inflammatory injury
Main mechanism for Hyperalgesia vs allodynia-making more likely for those neurons to fire
Many receptors, channels and ligands involved (MAPK, TRPV1, sodium channels).- shift threshold making easier to fire
Experiment- skin nerve preparation- dissect skin- still attached to nerve-can injure skin and record nerve activity. Saphenpus nerve- runs up and down leg, connects with foot
Look at AP firing- how nerve fire before do anything then response to heat
Injure the skin- adding bradikynin- released durring inflammation, known as algegins- causes pain-activates nocioceptors start to get impulses at lower temps and more of them when get to painful stimuli ‘shoifted to the left

Question 40

Skin-Nerve Preparation”-

Answer 40

Skin-Nerve Preparation”- record nerve activity while applying stimulus, can look at ap firing

Algegin- causes pain

Question 41

Primary vs. Secondary Hyperalgesia

Answer 41

2 forms of hyperalgesia
Inject substance that causes sensitivity- capsacian- activates trp-v1- have a pain flare
Measure sensitivity around it and in it- where don’t see physical damage vs where do
Primary hyperalgesia- occurs within the flare
Secpndary- outside site of injury
Primary vs secondary sensitization
Inc sensitivity at primary and secondary sites

Meausre pain inside vs out zone- after- all sensitive
Using thermal stimuli- notice a difference
Site c- shows least change
Secondary- only responsive to mechanical stimuli

Different neurons different responses and riles
Low threshold Mechanical neurons- respond to touch and mechanical stimuli, after pain involved in pain sensitivity and sensitization
receive from a beta fibres, become hypersensitive to mechanical stimuli after
Inc activity of peripheral neurons that lead to sensitization- sensitizing the primary afferents in peripheral system that cause and promote pain

What spinal cord 2° neuron could explain the mechanical specificity of secondary hyperalgesia?- Low threshold Mechano sensitive neurons-

Question 42

Central Sensitization

Answer 42

Central sensitization- changes in cns or spinal cord
Thought to be main mechanism associated with chronic (clinical) pain- no detectable injury, pain persists, sensitize cns- include brain
Pain typically not evoked by a stimulus or normally nonpainful stimuli
Changes in the CNS that lead to enhanced pain
”Pain memory”- neurons can remember the stimuli exposed to, remember what will cause pain- LTP, better at transmitting future stimuli, takes less to send a pain response
Normal- have nocioceptor responding to noxious stimuli, and low mechano responds to mechanical stimuli, little input to pain, under inhibitory control, cant cause pain neurons to fire
After injury- become sensitized, and loose the inhibitory control, - inhibitory control caused by inter-neuron in spinal cord -can now cause pain neurons to fire, eliciting response in pain neurons

What would result if the LTM was stimulated following injury?- now activate pain producing neurons, producing pain

Question 43

Central Sensitization: Woolf, 1983

Answer 43

Put electrons in spinal cord recorded ispalateral and contralateral sides of injury before and after, records neuron firing, spontaneous activity, doing nothing. Induced injury- thermal
Ispalateral- inc activity- where injury is caused
Also changed contralateral side- must be central sensitization- whole area not just site of injury

WDR neuron- wide dynamic range- many fibres- a delta, a beta and c

recording of WDR neurons in spinal cord
after thermal injury to the hind paw…

Question 44

Secondary Hyperalgesia is Due to Central Sensitization

Answer 44

Apply high enough capascin- kills nocioceptors, lets in too much calcium causing death and exocoticity
Still have secondary hyperalgesia bc of mechanical dectectors

capsaicin desensitization
Does capasician cause mirror pain or secondary hyperalgesia- no if you use a high dose and kill off all the nocioceptors, but if don’t then yes

doesn’t work
“mirror pain”- look at other hand, have mirror pain, similar site on opposite side responsive and sensitive to mechanical stimuli, matches site around initial injury- flare

Question 45

Central Sensitization and Temporal Summation (“Wind-up”)

Answer 45

Temporal summation- epsp or ipsp, coming from different times, if happen close enough reach ap threshold- can inc response, longer ap, neurons get better at responding to pain, are sensitized
Needs to be close together, not a potentiation, need to be close
Repetive stimulation
Central sensitization- can stimulate at low frequency and see response

What’s the
stimulation frequency?- volts over time- 1 per every second= 1. hertz

Question 46

Second-Order Projection (STT) Neurons Relevant to Pain

Answer 46

LTP- caused by high frequency- 100hz, contributing to sensitivity
Other neurons- projection neurons- up to brain

What does “STT” stand for?- spinalthalomic tract
What would be the input to the LTM neurons?- a beta
LTMs are relevant for pain after injury.
What concept could explain why?- central sensitization

Major dorsal horn projection neuron types:
wide dynamic range (WDR)
nociceptive-specific (NS)- from a delta and c fibres
low-threshold mechanosensitive (LTM)
(“silent nociceptors”)

Question 47

Ectopic Firing and Spontaneous Pain

Answer 47

Recording electrode in spinal cord
Mainipulate part of foot
What neuron are you measuring- respond to pinch, nociocpeptive- recording from WDR, responds to both noxious and non noxious

Pinch causes reflex- makes us know that it is nocioceptive

Diabetic neuropathy rat- responds to all stimuli, even nothing- spontaneous firing
In diabetic- all foot is sensitive and hyperesponsive

Question 48

Electrophysiological Recording of Anterior Cingulate Cells

Answer 48

CNS0 neurons only activate where receive input from, but If do ACC- any pain manipulation , its all projected to ACC

Question 49

Descending Modulation of Pain: Stimulation-Produced Analgesia

Answer 49

Brain can send signals back down to modulate pain- Reynolds took electrode in Pareaquidetrial grey- inserted current- inc activity and signalling- did surgery without anesthetic by stimulating this area- sufficient to have surgery done without rat seeming to care

Thorn- stimulated PAG- measured tail flix before or after- stimulate it, become less sensitive- takes longer to cause response
Gave naloxone- kicks out opiods to rats, it reversed this effect
The opiod system is responsible for descending modulation- needed to be in PAG- releases endogenous opiods

Question 50

Opiates Activate the Descending Pain Modulatory System

Answer 50

Opiods can act at 3 points along descending pain path- PAG and spinal cord, RVM- less pain sensitivity
Hypothalamus- rememeber pain and causes release of stress hormones
Stress activates this system – stress induced analgesia
Frontal lobe asses the danger- activates this

Question 51

Physiology of Descending Inhibition: ON and OFF Cells in the RVM

Answer 51

RVM- 3 cell types-
Off cell- constantly firing in absence of pain- spontaneously active, become quiet during nocioceptive response,
On cells- quiet until nocioceptive response then fires with pain
and neutral
Put electride in rvm- firing withoit doing anuthing- off cell
Morphine inhibits on cells- and activates off cells, takes on cell longer to fire, have higher threshold

Put heat and get nocioceptive response- recording from off and applu analgesic- activity inc, don’t get pain response
Add opiod to on cell- reduces activity of on cells- dont have pain respose
Naloxone blocks this effect- return to normal
Why?- because of neurons connections and where recpetors are expressed-
On cell- have mu opiod recpeotrs expressed on cell, inc opiods, the opiods work on the on cells, inhibiting them directly
Opiod neuron in rvm- receives input from pag, can release opiods to reduce on cell acticity

Off cell- don’t have opiod recpetors expressed directly on them, gaba neuron has opiod recpeotrs on presynaptic terminal, it usually blocks the off cells a bit, but with opiods, inihibit gaba and gaba cant fire to off cell, causing inc firing, enhancing off cell activity – important to know
Off cell = indirect mu inhibition On cell - direct mu inhibition
Off cells fire when no pain stimulus
On cells fire right before and after pain threshold is exceeded

Question 52

Spinal cord anatomy Rexed Laminae

Answer 52

Posterior grey horn- Dorsal horn
Substantia- layer 1 and 2- conversion of nocioceptive, under microscope- gelatin appearance
What happens in spinal cord
Look at spinal cord- has butterfly esc shape
Within the butterfly- neurons- sensory and motor(ventral)

The spinal cord is divided by cell types and cytoarchitecture
Have 10 layers
Most interested in dorsal part- 1-5
1 and 2- primary afferent coming in- convey nocioceptive infio- a delta and c fibres come here
Some a delta go to 3 and 5

A b- sensory fibres- convey touch, pressure, vibration

Question 53

Spinal Cord Histology: White Matter Staining

Answer 53

Fasciculus gracilis
Fasciculus cuneatus
Tract systems
Sensory info but non painful- a beta fibres

Microscope image of white matter staining
Everything surrounding grey matter= white matter- the neuron tract, relays pain info up into brain

Fasiculus- refers to tract system

Question 54

Spinal Cord Anatomy Relevant to Pain

Answer 54

Another way to see spinal cord

Nocioceptive activation relayed via primary afferent neurons- a delta and c fibres, synapses in dorsal horn layer 1 and 2, can be relayed and crossed over then projected up into brain

Neuroceptive information crosses tp contralateral side first then goes up

Sensory neuron- primary afferent- first neuron in pathway

Neuron in spinal cord- projection neurons, taking the info across the brain(secondary order)

Question 55

Spinal cord anatomy

Answer 55

Pept. C Aδ

Nonpept. C Aβ/Aδ
Ab- 3 and 4 layers, deeper lamina layers
Peptodergic c fibres- lamina 1
A delta mylentated- 1 and outer lamina
Non peptidergic c- lamina 2

Goes into different layers
Primary afferent comes in convey pain- 1 and 2 lamina differences based on peptidergic vs not
Non painful info- deeper lamina

Question 56

Ascending spinal tracts Spinothalamic tract

Answer 56

Spinothalamic tract
Spinothalamic tract
Major ascending spinal
Nociceptive, crude touch and temperature
Project from spinal cord to the thalamus
What is demonstrated
Info comes in synapses with one of two second order neuron- then the info is relayed, crosses over contralalttery then sent to brain

Ascending- bottom up, goes upward

This path demonstrated= most simple- direct projection from second order neuron into thalamus- in thalamus have tertiary neuron

To get pain info into brain- need 3 neurons
\break down name- get tract
Spinothalamic tract codes Nocioceptive, crude touch and temp

LIKES TO ASK TO DRAW PAIN PATHWAY ON EXAM

Question 57

Ascending spinal tracts Lateral Spinothalamic tract

Answer 57

Lateral Spinothalamic tract
Direct projection to VPL thalamus
Codes sensory-discriminative qualities of
pain and temperature
Lots of wide-dynamic range neurons
When goes into thalamus, synapses with VPL- thamalic nuclei and directs into sensory info, somatosensory cortex
Important for sensory qualities of pain

Question 58

Ascending spinal tracts Anterior Spinothalamic tract

Answer 58

Anterior Spinothalamic tract
Project to intralaminar thalamic nuclei
Also sends projections to medulla, pons
and midbrain
Codes crude touch and pressure
Projects to nuclei collection in thalamus- intralaminar thalamic nuclei- affective responses, arousal, autonomic pain
Physiological responses to pain- cortisol, sweating, inc heartbeat

Question 59

Ascending spinal tracts

Answer 59

Spinoreticular tract- more important for arousal
Projects from spinal cord to reticular formation and limbic areas
Axons originate in deeper laminae (VII and VIII)
Important for arousal, autonomic function, emotional aspects of pain
Transmits noxious and innocuous information (mechanical, heat, light touch)
Prokects to reticular formation- in brainstem and important for arousal
Comes in, after seconday neuron goes up- tract is connecting with neurons in reticular formation areas, along ascent activates reticular neurons- ppl with chronic pain could cause constant activation of reticular- cant sleep
Activates cerebellum- coordinates movement

Question 60

Spinomescencephalic tract

Answer 60

Ascending
Spinomescencephalic tract
Projects to the periaqueductal gray (PAG) and parabrachial nucleus
Activation of PAG neurons results in descending pain
inhibition
Parabrachial neurons send projections to amygdala
Starts out same- goes up in bundle of fibres in mindbrain it synapses and activates PAG and periadecurail gray, then sent to the amygdala- not sent to cortex- emotional aspects of pain, like fear
Understand the tracts and how to draw

These tracts synapse along ascent

Structures in midbrain- send prokections back down to spinal cord- periadecurail gray- if synapse here sends projections back dwon to spinal cord to try and modulate incoming pain signals

Question 61

Dorsal column pathway- path for somatasensation

Answer 61

Dorsal column
Comprises direct non-nociceptive pathway
Light touch and tactile discrimination
Decussates at level of the medulla
Fasciculus gracilis – information from lower body- found throughout spinal cord
Fasciculus cuneatus – information from upper body- in upper spinal cord only
collection of Fasciculus- touch, tactile info
Crosses over at medulla
Comes in and goes up right away until reaches medulla and then crosses over- find second order neurons here, synapse with Fasciculus
Crosses over to thalamus to get to sensory neurons

Question 62

Somatotopy

Answer 62

Nonpainful info not just going anywehere in cortex- sent to specific place in homosculous
Look at cortex- specific parts respond to diff sensory info

This process is somatotopy- take sensory info and send it to specific region on somatosensory map
May use a diagram like thois for pain pathway

• Is this just for nonpainful*

brainstem nuclei- spinal pathway

somatosensory cortex (S1)
thalamus (ventrobasal nucleus; VPL, VPM)

Question 63

Brain Areas Involved in Pain: The “Pain Matrix”

Answer 63

ACC and PFC- cog control of pain

Brain tries to modulate incoming pain signal

Escape and planning aspects of pain, pain avoidance
Don’t just code for pain- criticism of pain matrix

Question 64

The Pain Matrix???

Answer 64

Pain matrix received criticms- activate to nonpainful stimuli
This study looked at insula and its activation when in FMRI, used nociocpetive stimulus vs non paindul stimuli
All these sensory stimuli activated insula- important for pain and affective aspects, also codes for nonpainful stimuli
Now call saliency matrix- makes aware that something is happeneing- shift in homeostatic balance, something needs your attention

Question 65

Activation of the “Pain Matrix” in pain free individuals

Answer 65

Goal- to look and insensivity to pain- have no sodium 1,7 channel- don’t respond to pain stimuli- thought wouldn’t have activation
Found that had the same amount of activation, but not experiencing pain
Maybe more of a saliency matrix- stiull feel stimulus, just not perceived as pain- only two patients
Loss-of-function SCN9A mutations
Mechanical pain stimulus
fMRI scanner

Question 66

Shared representations between physical and social pain

Answer 66

Correlation between social pain and acc pain. Both activate similar regions- anterior insula, dorsal ACC, look at fmri- social and physical pain activate same areas. Many things activate these regions, acetaminophen- reduces fmri activation

Question 67

Descending Modulation

Answer 67

Cognitive and motivational modification of sensory input
Many supraspinal sites, cell types and neurotransmitters
Descending control activates PAG- in midbrain- has opiods, projections to regions that control pain, activated bu ascending signals and supraspinal structures- higher cog control structures- like ACC, PFC, hypothalamus project to PAG
This system is activated by stress

Question 68

Supraspinal sites

Answer 68

Descending
Supraspinal sites
PAG and RVM integrate information coming from limbic system
Limbic system (ACC, amygdala, PFC)
Opioid involvement- activated by stress, dec pain and activate dopamine
System is activated by stress- when stressed, activating this system so we don’t perceive pain until later- modulates pain to get finisjed stressful activtivty- ex sports players
Send fibtrs down to lower brain stem structures and spinal cord

Question 69

Monoamine Modulation of Pain-

Answer 69

Descending

Monoamine Modulation of Pain-
Dopamine from VTA and SN (A11) projects to dorsal horn- modulating incoming pain signals
Norepinephrine from LC (A5) projects to dorsal horn- modulate incoming pain signals
Serotonin from dorsal raphe projects to dorsal horn
These transmitters are targets of antidepressants, for chronic pain can give these to target this system, if don’t respond to other treatment these meds can dec pain

Chronic pain- have overactive ascending signals and dysfunctional descending control- taking away systems ability to modulate pain

Question 70

Spinomescencephalic tract

Answer 70

Spinomescencephalic tract-
Blue and red lines say where it is coming from and going from- don’t need to draw both- draw in peripherial nerve with the drg enters spinal cord and synapses with secondary neuron
Primary neuron first neuoron in pathway- the drg
Secon order- projection neuron in dorsal horn and crosses over and ascends to brain- parabrachial nucleaus – ascends and the ascending part from the spinal cord to synapse here, but sends its own projection into the brain in the amygdala and periaquedictal grey
Projection neuron- projects form one to the other over long distance
All the tracts start at the same
On this diagram y= synapse, circle= neuron
Starts in spinal cord ends in mescencaphlon- mid brain, the parabrachial nucleus it whats activates the amygdala- indirect activation of it, does also activate rvm, activates parts of the brainstem

There is simaltaneuous activation of each path, multiple paths activated to give rise to the pain experience
The ascending pain signals also activate the desceninding pathways the PAG to modulate the pain

Question 71

Pathogen-Associated Molecular Patterns

Answer 71

Pathogen-Associated Molecular Patterns
Recognition of conserved aspects of the cell wall and the cell wall doesmt change for lots of bacteria and viruses
Examples include toll-like receptors (TLRs)- bacteria binds and activates it
TLR2 and TLR4 recognize yeast and bacteria, respectively
Specific receptor types
Can divide immune system into two steps- innate- from birth, highly conserved, responds in similar way to all things vs adaptive
Innate immune system- needs to recognize certain bacteria and viruses

Pathogen- PAMP come off pathogen to bind to specific TLR that are found on specific types of immune cells- macrophage, PMN- these immune cells have specific receptors to recognixe pathogen- pathogen producxts bind here and activate cell to have it secrete contents or activate other cells like t cells to fight the pathogen. TLR activate fight against pathogen by detecting pathogen
APC- antigen presenting cell
PMN- polymorphonuclear cell

Question 72

Damage-Associated Molecular Patterns-

Answer 72

Damage-Associated Molecular Patterns- recognize damage, cells secrete contents- need cell lyses
Recognize proteins present in cytosol and nucleus of cells- the proteins normally found in cells, they bind to DAMP
Examples include P2X4 and P2X7
Signal that cell has died

Question 73

How does the immune system contribute to pain and inflammation?

Answer 73

Innate immune system
Recognition of pathogens based on structural conservation- for many types of bacteria, same molecular patterns activating the susyem, the system doesn’t need to learn anything, the pathogens are conserved
Don’t need to build immunity to it
Mast cell- allergic reactions
Macrophage- releases cytokines, pro inflammatory, mast cell neutrophil and macrophage- peripheral and WBC
Microglia and astrocytes- found CNS
Microglia- collect garbage of CNS,activated by bacteria, yeast, chronic pain- expression of PRR for pathogens
A2 astrocyte- activated when there is damage or a pathogen, react to pathogen/damage, secrete own chemicals

Question 74

Adaptive immune system

Answer 74

Adaptive immune system- needs to learn
Recognize, eliminate and control pathogens based on prior exposure
Require exposure to pathogens to be created (cells that give immunity)

Types of T-cells
Helper T cells (CD4+); Th1 is proinflammatory and Th2 is anti- inflammatory

Killer T cells (cytotoxic; CD8+)
Have virus that infects macrophage, it presents itself to other immunce cells like t cells and helper t cells- help t cells become activated so it can fight of infection, cause release of cytokines to recruit more immune cells
Helper t cell present to infected cells to help body fight off the cells
T cell kills off the infected cells

Question 75

Complex and interconnected Immune system

Answer 75

Recognize, eliminate and control pathogens based on prior exposure
Require exposure to pathogens to be created (cells that give immunity)
Following injuiry distinct cgabges happen to heal
Satelitte glial cells- microglial found in drg
Have infection for a few weeks- macrophage go down , t cells inc
Microglial- critical and important for initiation and developpement of central sensitization and chronic pain, but astrocytes sustain this pain

Question 76

Postsurgical Pain Prevention

Answer 76

Around 7% suffer from this, but theres so many surgeries, so a lot of people
Many different things contribute to this- inadequate analgesia/ anesthetic during surgery

Degree of nocioceptive input during and following surgery
During surgery- high nocioceptive input, following surgery still significant activation, theyre continuously being activated

Can block nocioceptive input at different parts through this model
After surgery give analgesia once- nocioceptive comes back
Give it before, blocks it during surgery, but after still have the activation

Wanna provide analgesia during surgery, then continuously treat hypersensitivity, nocioceptive input still there
Postsurgical pain- driven by hypersensitivity, allodynia

Qualioty of life goes down, now in chronic pain

Question 77

Low back pain

Answer 77

Low back pain
For LBP, heavy lifting and lifting weights above the shoulders are risk
factors
Certain professions are also more at-risk (fireman, nurse, miners, construction workers)., laborious and physicaly taxin
Considered musculoskeletal, but can have a neurological component
(disc herniation- neuropathic, radicular pain), slipped disk- causes nerve compression, pressing on nerve
Most prevellant pain condition, and most severe and debilitating- reduced QOL

Question 78

Osteoarthritis

Answer 78

Osteoarthritis
Risk factors for knee pain include:
Age, as get older inc risk
being female- most chronic pain conditions
being ethnic minority
high impact activity
joint trauma
depression
anxiety (stressful job)
Obesity
Bone rubbing on bone, soft tissue on joints wares down
Rheumotoid- inflammation

Question 79

.. Rheumatoid Arthritis

Answer 79

Rheumatoid Arthritis
Chronic inflammatory disorder linked to immune dysfunction, has been considered to be autoimmune disease- lupus, chrones, MS- neuropathic pain
(autoimmune)
Increased amount of pro-inflammatory cytokines in joint
Joint pain, swelling, stiffness, joint degeneration
Treatment included biologic- class of drugs disease modifying anti-rheumatic drugs
Risk factors include:
being female
smoking
certain genetic markers (HLA genes)
fatigue
depression
anxiety
obesity

Question 80

Rheumatoid Arthritis Treatment

Answer 80

Few specific inflamatorry cytokines released at high levels- TNFa and IL6 and IL2
Class of drugs- biologics- target these proinflammatory cytokines
Humira and Simponi- targets tnfa
Andministered via monthly injections – keep activation and release at bay

Question 81

Chronic widespread pain (Fibromyalgia)

Answer 81

Chronic widespread pain (Fibromyalgia)
Fibromyalgia is a chronic condition characterized by widespread pain in the muscles, ligaments and tendons, fatigue, and multiple tender points.
Prevalence of 2-4%, more in women
Not associated with identifiable injury or lesion- idiopathic condition, no identifiabkle cause and don’t understand how it develops
Thought to result from changes in pain processing pathways
All over pain, widespread
Have extreme fatigue
Have altered prain sensing regions of the brain
Considered a rheumatic condition
A condition that affects the joints and/or soft tissues, causing chronic pain
Significant pain and fatigue
But not a form of arthritis
No inflammation or damage to joints, muscles, or tissues- cant measure levels of cytokines
But does produce pain in soft tissues around joints and in skin and organs throughout body
Structurally intact

Light blue- females, higher prevelance in females and higher ages
Rheumatologist- used to be sent if have pain in joints

Question 82

Fibromyalgia Tender Points

Answer 82

Diagnostic Criteria
To diagnose it
Look at tender points- points within body that are more sensitive to pressure, look at pressure semsitivity in these points
Need Widespread pain for at least 3 months

Painful sensitivity to 4 Kg(normally not painful) of digital pressure at 11 (or more) out of 18 anatomically defined tender points- first diagnostic criteria

Question 83

Evidence of Widespread Allodynia
in Fibromyalgia

Answer 83

Look at fibromyalgia patients response to pressure, much more sensitive than controls
Their brain activity is changed too, controls have inc acticity between amygdala, PAG, obfc, while
Fibromyalgias have reduced activity
These regions are important for descending pain modulation - they cant modulate pain as well

Question 84

Headache and migraine

Answer 84

Headache and migraine
Migraine more prevalent in women
Migraine is most prevalent among Native Americans and non-Hispanic Whites, followed by Hispanic and Black individuals
Triggers include bight lights, noise, eye strain, physical and emotional distress, lack of sleep, weather changes (barometric pressure, humidity), foods (cheese, chocolate, wine), strenuous exercise cause onset of migraine
Many different causes to it, genetics, most of the time the vause is unknown
Follows distinct stages
Prodromal- before actual pain- light and sound sensitivity
Aura- hour before headache, only about 20%, changes in visual perception- caused by cortical depression spreading- depolarizing spread across cortical, starts in occipital cortex
Headache- usually associated with other symptoms
Postdromal- everything has happened, residual effects
lack of energy, irritable, fatigue, cant concentrate
Migraine episode can last up to a week
Migraine linked to trigymenial vascular system- blood vessel system
Linked to overdilation and have substance p release

Question 85

Migraine Treatments

Answer 85

Acute phase :Triptans, Analgesics
Taken when a migraine is experienced to reduce pain
Treats pain and other symptoms after the attack has begun
Prophylatic: preventative- Antiepileptics, Beta-Blockers, Antidepressants
Taken on a daily basis
Reduces the frequency and intensity of
Attacks
Prophylatic: Anti-CGRP antibodies
Reduces the frequency and intensity of attacks
Monthly injections injecting antobody to bind to CGRP and neutralize it, cant be released
Cgrp- released in trygmenial ganglion, binds to meneges, can inc pain

Question 86

Neuropathic pain

Answer 86

hic pain
Pain from nerve injury/damage
Described as burning, coldness, “pins and needles,” numbness and itching
Common in cancer, diabetes or herpes infection
Nerves become overly sensitive – allodynia develops
Trigemenial neuralgi- something compressing nerve- jaw pain and head pain
Trigemenial ganglion- sits under brain collection of cell bodies that inervate trigmenial nerve- main cranial nerve- responsible for neck and head sensory input
Dorsal root ganglion- receives from muscle, bones and joints
HIV- dsregulation of peripheral nerves
Reflex sympathetic dystrophy- complex regional pain- localized pain, caused by mild trauma
Tumor can press on nerves, and treatment for cancer can cause neuropathy, kills nerve fibres
Postherpetic neuralgia- after shingles pain- shingles virus lays dormant in DRG until reactivated in the nerve fibres, can cause damage

Diabetic- nerve fibres of legs and feet start to die

Question 87

Syndrome vs. Disease

Answer 87

Disease: a medical condition with a specific cause or causes and recognizable signs and symptoms- parkinsons, huntingtons

Syndrome: a collection of signs, symptoms, and medical problems that tend to occur together, but are not related to a specific, identifiable cause

Question 88

Cancer Pain

Answer 88

Cancer pain- specific type of pain- breakthrough pain – sustained level of background pain but times when it breaksthrough and exceeds normal amount, analgesis is usually enough to keep pain at bay, but pain breakthroughs analgesic

Purdue used breakthrough pain as reason for inc analgesic dose

Q. What causes cancer pain?- many things
The tumor pressing on nerve fibres, lack of oxygenation, chemo,

Question 89

Post-herpetic neuralgia

Answer 89

Consequence of shingles
Varicella virus reactivated later in life, causing a painful rash on an area of the body that is innervated by one sensory ganglion, resulting in herpes zoster or shingles.
Pain persists after rash is gone due to damage of sensory neurons
Pain described as burning, sharp, stabbing
Where u express that rash, where virus was reactivated

Question 90

Phantom limb pain

Answer 90

Phantom limb pain
Phantom limb- still feel body part vs. phantom pain- it hirts
Area of somatosensory cortex from missing limb can be recruited to process other areas of the body
Brushing different areas of the face of an individual following arm amputation produced sensations in different fingers of the phantom hand- reorganization of somatosensory cortex
Caused by amputation or severance of limb
Ultimate neuropathic condition, damaging lots of nerves
All amputess experience phantom limb only 5-10% experience the pain
Still activating somatosensory cortex

Question 91

Symptoms of PLP

Answer 91

phantom vs. phantom pain
variable onset/ persistence
sensation variability- many report low level but go through severe attacks
To reduce it- give feedback to areas, how prosthetic attaches to amputated- adjusts pain, need significant contact – control gate- providing input via a beta and dampening pain
movement, telescoping- once have an amputation and have phantom sensation, feel like arm is there but experience telescoping- shrink and reduce into stump, due to somatosensory cortex reorganization, not receiving own input, sensation shrinks

Question 92

Phantom Limb Pain (PLP) Interventions

Answer 92

Nerve fibres that are severed, clump together form tangled nerve fibres-neuroma that can fire on its own without sensrory input, if provide sensory input, something contacting a beta, can reduce activity of neuroma

PLP eliminated in ≈50% of patients provide peripheral nerve/plexus block

spinal block
(PLP “always”gone)- 100% of the time get rid of it
Involves central sensitization more than peripherial

Question 93

Peripheral and Central Ectopic Firing

Answer 93

Severe limb and have neuroma, have ectopic- sponatanoues firing
In drg- have it firing more
Peripherally- sig componenet driven by changes in DRG

Ectopic firing in neuroma: 25%
Ectopic firing in DRG: 75%

Question 94

Mirror therapy

Answer 94

Mirror therapy
Gives visual illusion and thus visual sensory input that
missing limb is back and moving
Associated with reversing the somatosensory cortical reorganization
Place mirror in position which you can view mirror and makes it appear as though missing limb is there, tricks brain into thinking the limb is still there
Missing limb, have reorganization of somatosensory cortex and mirror therapy over 8 weeks can reverse some of this
Mirror therapy, helps reduce pain drastically
Mental visualization and covered mirror- no changes in pain

Question 95

Complex regional pain syndrome

Answer 95

Complex regional pain syndrome- reflex sympathetic dystrophy
Affects localized area of body (hand, arm, shoulder)
Often due to repetitive strain
1-2 % of population affected
Develops in small proportion of individuals following surgery, sprain,
fracture – but doesn’t need to be trauma
2 – 4 times more common in women
Type I- no identifiable nerve injury and II – have nerve injury, causalgia (no nerve injury vs. causalgia)
May be functional reorganization of somatosensory cortex- affected body part is warm, shiny/glossy, swollen even though usually no active inflamattion Starts w injury, which causes changes in sympathetic nerves, reorganization in brain, neurogenic inflammation- makes it hot to touch
neurogenic inflammation-

AP activated at end of nocioceptor, travels along axon to release NT into spinal cord- primary afferent and nocioceptors
But nocioceptors form a branch, activate one, activate many along dendritic branches, travelling to end of nocioceptors and releases substance P to dilate blood vessels and plasma extraversion- leaky blood vessels, causing inflammation-neurogenic
Neurogenic= originates from nerve

Question 96

What Causes CRPS?

Answer 96

Given the right conditions, hitting knee- can cause CRPS

Peripheral Sensitization- increased excitability of nerves in the peripheral system, causing more sensory info, lowers threshold
Central sensitization is the same but instead happens in the CNS

Question 97

Ketamine-

Answer 97

Ketamine- antagonist of NMDA- which is crucial for LTP and memory formation
Ltp- increased synaptic communication between neurons
If happens in sensory neurons- more able to communicate w each other, inc pain- driven by NMDA receptors
Ketamine- dissocative anesthetic