Pain Flashcards
What is the definition of pain?
Pain is an unpleasant sensory and emotional experience associated with either actual or potential tissue damage
Pain is actually subjective and very contextual and is not a substantive contract of the real world
Just a stream of 1’s and 0’s until reaches brain- Pain is constructed in mind and can adjust in mind
Why do we have pain?
To protect the body from harm
How does pain work?
Nociceptors detect noxious stimuli in the world around us (using free nerve endings) and relay these signals to the brain
Works like a TV set where the signal is given out, TV decodes it and you either ignore it or take it in (you can modulate how much gets through receptor stage - depends on situation you are in (i.e solider leg blown off running back to trench, then starts feeling pain)
Also a genetic susceptibility to pain and some feel more and some feel less
What influences how we perceive pain?
How we perceive these signals is highly modulated and depends on situation, emotion, genetic susceptibility and previous experience (i.e fear of pain from torture makes pain worse)
What are the different peripheral aspects of pain?
- Nociceptive receptors
- Nociceptors activation
- Sensitisatiion of receptors
- Nociceptive fibres sends signals back to the brain
How do Nociceptive fibres respond to stimuli ?
There are no pain receptors for pain in the way they exist for other modalities
Nociceptive nerves have free unspecialised nerve endings with ‘pain’ channels inserted in the membrane
Most common being the Transient Receptor Potential family of channels (TRP) which are specialised polymodal receptors and will respond to many stimuli (e.g extreme high or low temp, pressure - anything that should give you pain)
They are sensitive to (amongst others) to O2, pH osmolarity and heat - valinoids (capsicum) most common receptor type in this family
Can be sensitised by substance P, bradykinin, serotonin, pH, ATP, NO etc….
But if have tissue damage then these receptors become more sensitive to pain modality detecting at that time (issue in chronic pain)
Composted of a 6 unit trans-membrane portion and a ‘basket’ of regulatory complex in the cytoplasm
Allows Ca2+ & Na+ into the cell
What are the 3 ways that Nociceptive receptors are activated and how?
Temperature;
- Extreme heat and cold open ‘Transient receptor potential vallinoid (TRPV) channels inserted in the membrane
- This allows for Na2+ and Ca2+ entry which depolarises the cells to give an action potential (High influx positive charge causing neuron to depolarise very quickly)
Mechanical;
- Actual mechanism is still unknown
- Presumed to be a form of insensitive mechanoreceptor which allows Na entry when activated
- We think when a cell is being pulled it opens up receptors ?
Chemical;
- Apart from TRPV receptors, its largely unknown but chemical transmission can cause sensitisation of pain receptors (1 receptor can respond to many chemicals)
How does sensitisation of receptors occur?
All of the processes in image attached increase sensitivity to paint and non pain stimuli such as;
- Calcetonin gene related peptide (CGRP) and Substance P both recruit silent receptors which increase summation in the dorsal horn.
- Histamine secreted by mast cells causes hyperalgesia through its affects on nerve endings (An increased sensitivity to feeling pain and an extreme response to pain).
- Bradykinin activates pain fibres directly and causes an increase in prostaglandins. Prostaglandin E2 is made by cyclooxygenase. Aspirin and other NSAIDs act to inhabit this enzyme
- Tissue damage produces H ions which give muscle ache (e.g weight lifting)
When get pain from mechanical injury get a ‘soup’ of chemicals causing pain and sensitive nerve ending and make those receptors activate much more easily
What fibres carry nociceptive signals?
Aδ fibres;
- Lightly myelinated
- Sharp 1st pain
- Mechanical pinching
- Extreme hot or cold
C fibres;
- Unmyelinated
- Secondary slow pain (diffuse)
- Mechanical pinching, thermal and chemical stimuli (polymodal)
- Responsible for emotional components of pain, sweating etc
Image attached just shows how was discovered
What neurotransmitters are involved in nociceptive transmission ?
Neurotransmitters of nociceptive fibres
On stimulation they release’
- Glutamate
- Substance P
- Calcitonin gene-related peptide (CGRP)
At both central synapses and peripheral synapses
Peripheral release (recall histamine practical) give the red flare and tenderness associated with pain
What neurotransmitters are responsible for the 3 physiological signs of pain and what are those signs?
Substance P and CGRP release is responsible for the 3 local physiological signs of pain;
1). Calor (heat - On cut or bruised area due to blood flow increase / hyperaemia)
2). Rubor (redness - increase blood flow / hyperaemia)
3). Tumour (swelling - due to plasma extravasation)
What is the ascending pain pathway ?
The ascending pain system is the anterolateral system
Neospinothalamic (Fast sharp pain);
- Splits off from anterolateral system
- Goes through thalamus into VPL (ventral posterolateral nucelus)
- Forms discriminatory system to go into the Primary somatosensory cortex
- Pin points pain
Paleospinothalamic (Slow burning pain);
- Splits off from anterolateral system
- Goes through thalamus into DM intralaminar (Dorsal medial intralaminar)
- Forms undiscriminating system to go into the Limbic system associated cortices
Reticular formation;
- Splits off from anterolateral system and becomes Spinoreticular tract
- Responsible for motor response and ascending arousal
Periaqueductal grey and superior colliculus;
- Splits off from anterolateral system and becomes Spinomesencephalic tract
- Responsible for descending pain regulation
Where does signal processing begin ?
Signal processing behind in the dorsal horn includes;
- Synaptic targets
- Wind up
What are the synaptic targets for nociceptive fibres/descending pain?
Nociceptive fibres synapse in the dorsal (posterior) horn (quick to cross) with 2 types of ascending axons
There are different types of cells in different portions of the dorsal horn involved in descending pain and are modulated from PAG in the brainstem;
1). Nociceptive specific (NS) - any pain that come along from C and Aδ only - only nociception but any modality
2). Wide dynamic range neurons (WDR) (“gatekeeper cells”) - take any sensory input including pain, can fire in a graded fashion based on C fibre frequency of input (higher the pain the higher the input to brain). Tells brain if a lot of pain, and prewarns brain a lot is coming its way
A closer look at the excitatory synapse in the dorsal horn its a very complicated system of neurotransmitters and receptors which is important to know cause its this synapse and the balance of transmission within it which causes dorsal horn windup - the sensitisation of WDR cells which tells the brain there’s a lot of pain coming up its way / they overtire for a signal.
What happens in Central sensitisation / dorsal horn wind up ?
Central sensitisation - wind up;
1). Incoming pain signal into Nociceptive afferent, central terminal
2). CGRP, Glutamate and SP are neurotranmtteres which travel over the synapse and into the post synaptic membrane where they act upon receptors
3). Glutamate and some of the CGRP receptor (which has already ben activated by CGRP) releases the Mg2+ block on the NMDA receptor which activates it.
4). Increase intracellular Ca2+ causes a change in cation channel kinetics, and causes the insertion of more Na+ channels and the blocked of K+ channels (makes depolarisation easier)
5). Wind-up causes an amplification of the pain signal
Wind up is a long term sensitisation of post synaptic neurons in the dorsal horn
It is mediated by WDR neurons which when firing at high frequency, opens NMDA channels
The inrush of calcium cause nuclear expression resulting in increased Na channels and a blockage of K channels. The net result is a resting potential is close to threshold and a more sensitive cell. This effectively amplifies the pain signals like turning up the amp on a microphone.
Explain the gate theory ?
Gate theory;
It is the balance between these 2 systems which determines the pain that gets through to the brain
Rubbing the area around a source of pain activates inhibitory input to the anterolateral system. Similar theory behind transcutaneous nerve stimuation TENS and capsaicin treatment
E.g - Rubbing area of skin around a source of pain activates the AB fibres (non-panful) inhibitory input to the anterolateral system which sends strong fast signals and overcomes the C fibre stimuli and brings excitable level down, mechanosensory decreases WDR neuron.
What happens in descending analgesia ?
Another way to modulate pain other than dorsal horn wind up;
Another inhibitory interneuron becomes excited by descending pathways that come from the Periaqueductal grey (PAG - side branch of Anterolateral system)
PAG can pass excitatory messages onto another part of brainstem where eventually goes to inhibitory enkephalin neuron which acts to quiet down all of the synapses where the pain receptor neuron synapses with the secondary neuron in the pan pathway
2 points in dorsal horn where can shut down pain - by adding a competing mechanosensitive signal int thee dorsal horn or send down a descending analgesia into periaqueductal grey (PAG is sensitive to different things like emotional state)
Periaqueductal grey allows to save puppy, something normally wouldn’t do, helps to ignore pain
Descending analgesia system in the spinal cord showing;
- Inhibition of incoming pain signals at the cord level
- Presence of encephalin secreting neurons that suppress pain signals in the cord
Note that this system is exploited by a number of CNS centres to;
- Increase salience of selected signals as well as
- Decrease some prolonged unimportant signals
(Chronic pain, get into mindset to ignore some pain)
How does the pain matrix work?
Brainstem structures can up or down-modulate Nociception to provide slinky (gate system). This action is based on information from other brain centres. This action is based on information from other brain centres.
Electrical stimulation of the PAG induces strong analgesia (blocked by Nalaxone)
Placebo effect of paternal kiss (limbic system emotional talking to PAG)
Note: Damage to one or more of thee centres can give a different effect on the detection and perception of pain as well as it’s modulation (e.g Accounts of children with no pain receptors who broke legs didn’t realise, sat on hot stone burning themselves didn’t realise etc)
What is involved in Complex Regional Pain Syndromes ?
Complex Regional Pain Syndromes;
- Severe continuous neuropathic pian
- Abnormal sensation
- Vasomotor change (capillary constriction / dilation)
- Sudomotor change (e.g - sweat glands)
- Motor / trophic change
- Regionally restricted (e.g hand)
- Response is disproportionate to the trauma
What is the mechanism of referred pain ?
Referred Pain - Mechanism;
Signals of noxious stimuli and normal cutaneous stimuli enter the spinal cord at the same point
Cross talk in the dorsal horn between modalities is common
Signals from viscera get picked up by ascending never fibres that are mapped cortically to dermis
Piggy back on other ascending nerves as enter dorsal horn at same place
Visceral ones and skin sensory project same area and send fibre from where it thinks pain came from
Where does referred pain from the Oesophagus map to?
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Where does referred pain from the Heart map to?
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Where does referred pain from the Bladder map to?
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Where does referred pain from the Left Ureter map to?
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Where does referred pain from the Prostate (on right) map to?
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