23-10-23 – Pain Flashcards
Learning outcomes
- Describe the physiological processes behind the perception of pain
- Define pain
- Explain that the dual quality of pain (sharp/pricking/stabbing versus slow/burning/aching) results from activation of either A delta or C nerve fibres.
- Explain the term ‘referred pain’ and explain its probable neural basis.
- Define the different types of pain and explain terms such as nociceptive and neuropathic pain, allodynia, hyperalgesia, and dorsal horn wind-up.
- Recall the chemicals that sensitize or activate nociceptive nerve endings
- Explain the gate control theory and the mode of operation of transcutaneous electrical nerve stimulation (TENS).
- Be able to describe the pathophysiological changes that may lead to chronic pain
What is the definition of pain according to the International Association for the Study of Pain?
- International Association for the Study of Pain:
- Pain is an unpleasant sensory and emotional experience associated with either actual or potential tissue damage.
- It is actually subjective and not a substantive construct of the real world
What is the function of pain?
Where does the sense of pain occur?
What does this mean for pain?
What do nociceptors detect?
How do they do this?
What is a noxious stimuli?
What are 4 factors that alter our perception of pain through modulation?
- The function of pain is to protect the body
- The sense of Pain only occurs in your brain, prior to that its just a code
- Pain is therefore highly subjective and very contextual
- Nociceptors detect noxious stimuli in the world around us (using free nerve endings) and relay these signals to the brain
- A noxious stimulus is a stimulus strong enough to threaten the body’s integrity.
- 4 factors that alter our perception of pain through modulation:
1) Situation
2) Emotion
3) Genetic susceptibility
4) previous experience
What is responsible for the peripheral perception of pain?
What are 4 parts of nociception?
- Nociception is responsible for the peripheral perception of pain
- 4 parts of nociception:
1) Nociceptive receptors
2) Nociceptive activation
3) Sensitization of receptors
4) Nociceptive fibres (send signals to the brain)
Are there receptors for pain?
What do nociceptive nerves have on their membrane?
What is the most common pain channel?
What are 5 variables Transient Receptor Potential family of channels (TRP) are sensitive to?
What 9 factors can sensitise TRP? What are TRPs composed of?
How does this sensitisation occur?
What do they allow to move into the cell?
- There are no receptors for pain in the way they exist for other modalities (no easily identifiable feature)
- Nociceptive nerves have free unspecialised nerve endings with ‘pain’ channels inserted in the membrane
- The most common is the Transient Receptor Potential family of channels (TRP)
- 5 variables Transient Receptor Potential family of channels (TRP) are sensitive to (among others):
1) O2
2) pH
3) Osmolarity
4) Vanilloid (capsicum – red peppers)
5) Heat - 9 factors can sensitise TRP:
1) Substance P
2) Bradykinins
3) Prostaglandins (produced from bradykinins)
4) Serotonin (5-HT receptors)
5) pH (H+)
6) ATP
7) NO
8) K+
9) Histamine - Tissue damage can lead to this sensitisation due to a soup of these chemicals around the receptors
- TRPs are composed of a 6 unit trans-membrane portion and a ‘basket’ of regulatory complex in the cytoplasm.
- Allows Ca2+ & Na+ into the cell.
- B is a potassium channel for comparison (in picture)
What 3 factors can activate nociceptor receptors?
- 3 factors that can activate nociceptor receptors:
1) Temperature:
* Extreme heat and extreme cold open ‘Transient receptor potential vanilloid’ (TRPV) channels inserted in the membrane.
* Allows Na2+ and Ca2+entry and so depolarises the cell to give an action potential.
2) Mechanical:
* Actual mechanism still unknown.
* Presumed to be a form of insensitive mechanoreceptor which allows Na entry when activated
* The thinking is part of the receptor is connected to the cytoskeleton so excessive deformation of the cell can mechanically open up the receptor
3) Chemical:
* Apart from TRPV receptors, it’s largely unknown but chemical transmission can cause sensitisation of pain receptors
What 9 factors can sensitise TRP?
What do these factors increase sensitivity to?
How does this sensitisation occur?
How does sensitisation affect the receptor?
What is the role of Calcitonin gene related peptide (CGRP ) and Substance P (SP)?
What does histamine do?
What is hyperalgesia? What is the role of bradykinin?
When can tissue damage produce H+ ions?
What is prostaglandin E2 made by?
What medications inhibit this enzyme?
- 9 factors can sensitise TRP:
1) Substance P
2) Bradykinins
3) Prostaglandins (produced from bradykinins)
4) Serotonin (5-HT receptors)
5) pH (H+)
6) ATP
7) NO
8) K+
9) Histamine - All these processes increase the sensitivity to pain and non-pain stimuli.
- Tissue damage can lead to this sensitisation of the nerve ending due to a soup of these chemicals being released around the receptors
- This sensitisation makes the receptor activate more easily
- Calcitonin gene related peptide (CGRP) and Substance P (SP) both recruit silent receptors which increase summation in the dorsal horn
- Silent receptors don’t respond to anything until they are sensitised
- There are also receptor branches that feed back onto the skin and release CGRP and SP in order to sensitise the area
- They stimulate mast cells to produce histamine, which causes hyperalgesia through its effects on blood vessels
- Hyperalgesia is a symptom that causes unusually severe pain in situations where feeling pain is normal, but the pain is much more severe than it should be (increased sensitivity to pain)
- Bradykinin activates pain fibres directly and causes increase in prostaglandins
- Tissue damage produces H ions which give muscle ache (e.g. weight lifting)
- Prostaglandin E2 is made by cyclooxygenase.
- Aspirin and other NSAIDs act to inhibit this enzyme
What are the 2 types of fibres involved in Nociceptive signal transmission?
Are they myelinated or unmyelinated?
What type of pain are they each responsible for?
What modalities do they detect?
Where do they each project to in the brain?
What do both of these axons/fibres send signals from?
- 2 types of fibres involved in Nociceptive signal transmission:
1) Aδ fibres
* Lightly myelinated
* Sharp primary pain
* Mechanical pinching
* Extreme hot or cold
* Goes to somatosensory cortex
2) C fibres
* Unmyelinated
* Secondary slow pain (diffuse)
* Mechanical pinching, Thermal and Chemical stimuli (polymodal)
* Largely responsible for emotional component of pain and autonomic responses to pain e.g sweating
* Projects to the limbic association cortices
- Both of these types of axons/fibres send signals from polymodal receptors, so we get all sorts of signals for all sorts of reasons going up the same fibres
What are the 3 neurotransmitters released on stimulation of nociceptive fibres?
Where are these neurotransmitters released?
Where is there synapsing onto the secondary part of the pain pathway?
Where does peripheral release of of neurotransmitters cause?
- 3 neurotransmitters released on stimulation of nociceptive fibres:
1) Glutamate
2) Substance P
3) Calcitonin gene-related peptide (CGRP) - These neurotransmitters are released at both central synapses and peripheral synapses
- There is synapsing at the dorsal horny onto the secondary part of the pathway
- Peripheral release of neurotransmitters gives the red flare and tenderness associated with pain
What 3 local physiological signs of pain are SP and CGRP responsible for?
What are they each caused by?
- 3 local physiological signs of pain are SP and CGRP responsible for:
1) Calor (heat)
2) Rubor (redness)
3) Tumor (swelling) - 1 & 2 caused by local hyperaemia (increased blood flow) and the third by plasma extravasation
Ascending pain system - How the peripheral pain signal is transmitted to the CNS (in picture).
What is the ascending pain system called?
- Ascending pain system How the peripheral pain signal is transmitted to the CNS (in picture)
- The ascending pain system is called the anterolateral spinothalamic system
What are the spinothalamic pathways composed of?
What 3 modalities do Aδ fibres detect?
What 4 modalities do C fibres detect?
Describe the route of the spinothalamic pathways
- The spinothalamic pathways are composed of smaller diameter (slow either Aδ or C fibres) fibres with no specialized sensory endings
- They are lightly or unmyelinated fibers which are ‘Quick to cross’
- 3 Modalities Aδ fibres detect:
1) Discriminative sensation (strong stimuli that does not damage the skin)
2) Heat or cold
3) Sharp pain - 4 modalities do C fibres (arrive later at the cortex) detect:
1) Dull aching pain
2) Itch (histamine sensitive)
3) Thermal
4) Mechanical - Route of the spinothalamic pathways:
- 1st order neurons synapse with 2nd order neurons in the dorsal horn, which then decussate (cross-over) and ascend in either the lateral or anterior spinothalamic tract depending on the sensory modality
- At the thalamus, the 2nd order neurons synapse with 3rd order neurons, which then projects to the sensory cortex in the same way as the DCML
What are all spinothalamic pathways together referred to as?
How many spinothalamic pathways are there?
What are the 2 different types of spinothalamic pathways?
What fibres do they consist of?
What are their sensory modalities?
- All the spinothalamic pathway routes together are referred to as the anterolateral (pain) pathway
- There are four main spinothalamic pathways, each having a specific function
- There are 2 lateral spinothalamic and 2 anterior spinothalamic pathways, all routes however follow the same basic pattern of connectivity:
1) Spinothalamic lateral route
* Mixture of 2 pathways, one for mainly Aδ fibres (destination is somatosensory cortex) and the other for C fibres which feeds into the emotional and memory processes.
* They carry information about pain and temperature via Aδ heat or cold activated fibres and C fibres (dull pain and itch)
* This route links an emotional aspect to pain and memory
2) Spinothalamic anterior or ventral route
* Only C fibres carrying information about coarse, non-discriminating touch via mechanosensitive receptors, destination brainstem areas
What can Lesions in the lateral spinothalamic tract alter the perception of?
What condition can this lead to?
What can lesions be caused by?
How can patients become aware of their sensory deficits?
- Lesions in the lateral spinothalamic tract cause decreased perception of pain and temperature on the contralateral side of the body, always one or two dermatomes below the level of the lesion
- Lateral spinothalamic tract lesions can cause paraesthesia which is experienced as shooting pain or ‘electrical’ pain, usually caused by the broken end of an axon
- Lesions can be caused by an injury to the spinal cord, from loss of blood supply or genetic problems
- Patients can also become aware of their pain and temperature deficit when they experience painless cuts or burns.
What will lesions in the lateral spinothalamic tract block?
- Lesion in the lateral spinothalamic tract blocks ascending pain and temp originating contralaterally from below the lesion (couple of dermatomes below lesion)
Anterolateral spinothalamic system.
Where does this pathway go through?
Where does the Neospinothalamic tract (lateral pathway) terminate?
What is it composed of?
Where does the Palaeospinothalamic tract (anterior pathway) terminate?
What is it composed of?
How do these pathways differ in terms of generalised and localised sensation?
What is the limbic system association cortices associated with?
Describe a diagram of the anterolateral system (in picture).
- Anterolateral spinothalamic system (anterior and lateral spinothalamic tracts together) aka anterolateral pain pathway
- Both pathways go through the thalamus
- The Neospinothalamic tract (lateral pathway) terminates in the ventral posterior lateral nucleus (VPL) is mainly composed of Aᵟ fibres.
- The Palaeospinothalamic tract (anterior pathway) which terminates in the dorsomedial (DM) and intra laminar areas is composed of C fibres.
- As the VPL is somatotopic, there is locational discrimination along this pathway whereas the dorsomedial (DM) nucleus and intralaminar areas only provide a generalised location for pain.
- Limbic system association cortices are associated with emotion, pain and other association cortices, which allows us to develop a fear of pain etc
- Diagram of the anterolateral system (in picture)
Where does the spinomesencephalic and spinoreticular tracts branch off from the from the anterolateral pathway?
What are they each for?
What are the PAG and reticular formation largely composed of?
- The Spinomesencephalic (Periaqueductal (PAG) and superior colliculus) and Spinoreticular tracts (reticular formation) branch off from the ascending anterolateral pain pathway prior to the neo and paleo divisions
- The Spinomesencephalic is for descending pain regulation
- The Spinoreticular tract is for motor response and ascending arousal
- The PAG and reticular formation are largely composed of C-fibres
How do anterolateral tract lesions affect sensation?
How can this be used as a treatment for terminal pain?
- Lesions in the neo part of the anterolateral tract cause decreased perception of pain and temperature on the contralateral side of the body, always one or two dermatomes below the level of the lesion (Lissauers tract).
- This neo pathway is lesioned using electrical current in a surgical procedure (cordotomy) for terminal disease pain, but pain returns after about 1 year.
Where does pain signal processing begin?
Where do nociceptive fibres synapse?
How quick are they to cross?
What are the 2 types of ascending axons?
What is another process NS and WDR neurons are involved in?
- Pain signal processing begins in the dorsal horn
- Nociceptive fibres synapse in the dorsal (posterior) horn and are quick to cross
- 2 types of ascending axons:
1) Nociceptive specific (NS)
* Input from C and Aδ only
* Only nociception, but takes any modality involving nociception
2) Wide dynamic range neurons (WDR)
* Any sensory input including pain, can fire in a graded fashion based on C fibre frequency of input (higher the pain higher the input)
* WDR neurons can measure how much traffic is coming into the spinal cord and send ascending messages to tell the brain what the current state is, particularly with pain
- The NS and WDR neurons are points of descending pain modulation from PAG in the brainstem
Central sensitisation – Wind up.
What is windup?
What type of system is it?
How does it affect firing in the dorsal horn?
What are 4 steps in the mechanism of windup?
- Central sensitisation – Wind up
- Wind up is a long-term sensitisation of post synaptic neurons in the dorsal horn
- It is a system by which the intensity of signal from the C fibres is translated through the WDR neurons into variation in sensitivity.
- The stronger the C fibre (pain) signal the more the dorsal horn post synaptic fibres become sensitive to input
- 4 steps in the mechanism of windup:
1) When WDR neurons are firing at high frequency, it opens NMDA channels.
2) The inrush of Calcium causes nuclear expression resulting in increased Na channels and a blockade of K channels.
3) The net result is a resting potential closer to threshold and a more sensitive cell.
4) This effectively amplifies the pain signal like turning up the amp on a microphone
What does gate theory provide?
What is it the balance between?
Describe the 2 steps in the mechanism behind gate theory?
How can this inhibition from C-fibres be overcome?
What is this a similar theory for?
- Gate theory provides pain modulation at the dorsal horn
- It is the balance between two systems which determines the pain that gets through to the brain
- 2 steps in the Mechanism behind gate theory:
1) C fibres carry a painful (positive) stimulus to the WDR neuron, with there being a potential need for dorsal horn wind up
2) In order to get the WDR neuron to focus on this stimulus, the C fibre can silence any inhibition by inhibiting an interneuron that may try to inhibit the WDR neuron
- The inhibition of the WDR neuron from these C-fibers can be overcome by rubbing the area around a source of pain, as it activates inhibitory input to the anterolateral system.
- Similar theory behind transcutaneous electrical nerve stimulation (TENS) and capsaicin treatment
What are 2 parts of the Descending analgesia system in the spinal cord?
What are 2 reasons this system is exploited by a number of CNS centres?
- 2 parts of the Descending analgesia system in the spinal cord:
1) Inhibition of incoming pain signals at the cord level
2) Presence of encephalin - secreting neurons that suppress pain signals in the cord.
* Inhibitory interneuron becomes excited by descending pathways that come from the PAG
- 2 reasons this system is exploited by a number of CNS centres:
1) Increase salience (noticeability) of selected signals
2) Decrease some prolonged unimportant signals
Where can brainstem structures in the pan matrix travel?
What is this action based on?
What happens when the PAG is stimulated?
How can it be blocked?
What is a placebo example of this pathway being used?
Describe the pain matrix in picture). What can damage to structurs in the pain matrix cause?
- Brainstem structures can travel up or down in order to modulate nociception and provide a saliency (gate system).
- This action is based on information from other brain centres
- Electrical stimulation of the PAG induces strong analgesia
- This pathway can be blocked by Nalaxone
- The Placebo effect of parental kiss utilises the PAG pathway to reduce pain
- Pain matrix in picture
- Damage to one or more of these centres can give a different effect on the detection and perception of pain as well as its modulation
What are 7 potential signs of Complex Regional Pain Syndromes?
- 7 potential signs of Complex Regional Pain Syndromes:
1) Severe continuous neuropathic pain
2) Abnormal sensation
3) Vasomotor change (capillary constriction/dilation)
4) Sudomotor change (eg sweat glands – can cause a lot of seating)
5) Motor / trophic change
6) Regionally restricted e.g. hand
7) Disproportionate to the trauma that causes the injury
What causes referred pain?
Describe the 3 steps in the mechanism behind referred pain?
- Referred pain is due to the visceral pain not mapping well to the somatosensory cortex
- This results in it being localised to the skin
- 3 Steps in the mechanism behind referred pain:
1) Signals of noxious stimuli and normal cutaneous (skin) stimuli enter the spinal cord and project to the dorsal horn at the same point
2) There aren’t direct sensory routes from the viscera up to the somatosensory cortex, so these signals piggy back on the ascending nerves fibres that are mapped cortically to dermis
3) This results in visceral pain being localised to the skin
Describe the referred pain mapping diagrams for:
1) Oesophagus
2) Heart
3) Bladder
4) Left ureter
5) Prostate (right)
