Pain Flashcards
What is pain
An unpleasant sensory or emotional experience associated with actual or perceived tissue damage- a product of higher brain processing
What is congenital insensitivity to pain
Don’t feel pain, can easily injure yourself
What can cause congenital insensitivity to pain
Na+ channel mutation, nerve growth factor mutations, overexpression of opiods
Congenital insensitivity to pain- Na+ channel mutation
Mutations in the voltage-gated Na+ channel in pain afferent neurons, means info about noxious stimuli is not transmitted
Congenital insensitivity to pain- nerve growth factor mutations
Mutations in NRTK1, the nerve growth factor necessary for the growth and survival of nociceptive neurons
Congenital insensitivity to pain- opiods
Overexpression of opioids, the brain’s natural pain relief
How does congenital insensitivity to pain suggest pain and touch pathway are separate
Sensation of touch is normal in these disorders
What are the 3 main types of nociceptors
Adelta mechanosensitive, Adelta mechanothermal, and C fibre polymodal receptors
What sort of structure do Adelta and C fibres have
Free nerve endings, thin, Adelta is slightly wider and myelinated
What types of temp do Adelta and C fibres detect
Adelta- cold thermoreceptors
C fibres- warmth receptors
What sort of touch and pressure do Adelta’s free nerve endings detect
Crude touch- we’d only be aware of it if our dorsal columns were damaged
What are nociceptors
Sensory receptors that respond to dangerously intense stimuli to signal that tissue is at risk of being damaged
What is the threshold of nociceptors
High thresholds of stimulation
What is the receptive field size of nociceptors
Large receptive fields
A delta < C fibres
What neurotranmitters do Adelta and C fibres release at the first synapse
Adelta- glutamate
G fibres- glutamate and substance P
What is the consequence of the large receptive field sizr of nociceptors
Make fine localisation difficult, but this isn’t really necessary, more important you feel the pain
What stimulation do Adelta mechanothermal nociceptors respond to
Dangerously intense thermal stimulation
What stimulation do Adelta mechanosensitive nociceptors respond to
Dangerously intense mechanical stimulation
What do C fibre polymodal receptors respond to
Have lots of receptors that bind to different ligands produced in tissue injury, and report back using EPSPs from all the different ligands present
Where do the nociceptors first synapse
Substantia gelatinosa in spinal cord
What is substance P
Neuropeptide, no obvious clearance mechanism so hangs around a lot longer, can cause prolonged depolarisation when they bind to the NK1 receptor AKA hyperalgesia
What is the result of the different fibres having different conductino speeds
First pain- sharp, brief better-localised pain (Adelta)
Second pain- duller, poorly -localised long-lasting pain with a burning quality (C fibre)
How can we isolate the effect of Adelta vs C fibres
Can selectively block either pharmacologically, can separately stimulate each fibre to elicit 1st vs 2nd pain
Experimental demonstration that nociception involves specialised neurons NOT greater discharge of neurons that respond to normal stimulus intensity
Applying increasing heat to a hand gradually increases firing rate of thermoreceptors, but thermosensitive nociceptors only become active when the heat becomes noxious (45degC), at which point the normal thermoreceptors are at max rate
How do we know where pain comes from
By the location the fibres enter the spinal cord, the nerves the info is sent in, the separate pathways for different fibres despite them mixing together in the same nerve
How does pain in the face and neck differ from in the rest of the body
The face and neck take a different path to the thalamus
What do second-order neurons go from the substantia gelatinso
Decussate and enter the anterolateral quadrant, then travel up the spinothalamic tract contralaterally
What happens to the 3rd neuron in the pain pathway
Neuron sends info from the thalamus to the somatosensory cortex
How are the pain and touch relays similar despite being completely separate pathways
Pain and touch are both 3 neuron relays with 2 synapses
What is referred pain
Pain detected by nociceptors in internal organs is often sensed on the surface of the body
What is a possible explanation of referred pain
Nociceptors from several locations converge on a single ascending tract- since pain signals are more common than pain from internal organs, the brain associates activation of the pathway with pain in the skin (McGraw Hill 1987)
What is Brown-sequard hemiplegia
Lateral hemisection of the spinal cord- loss of motor function and touch on the same side as the injury, loss of pain sensation on the opposite side to injury
What does Brown-sequard hemiplegia demonstrate
Touch is carried on the same side as it is detected, whereas pain info crosses over and is carried on the opposite side of the body
What are the main ascending pathways for pain
Spinothalamic tract (MAIN), spinoreticular tract, spinotectal tract
What is the main descending pathway for pain
Spinomesencephalic
What does the spinothalamic tract do
Important in localisation of painful or thermal stimuli- principal ascending pathway
What does the spinoreticular tract do
Causes alertness in response to painful stimuli
What does the spinotectal tract do
Orients eyes/head towards stimuli
What does the spinomesencephalic tract do
Important in descending modulation- main descending pathway
How have we identified the pain matrix
Scientists give people painful stimuli and see which parts of the brain light up- very many areas!
Why does the pain matrix involve so many brain areas
Due to evolutionary importance of pain
What do polymodal C pain fibres do instead of adapting to stimuli
They become sensitised to subsequent pain- for a lower stimulus intensity we get a greater pain intensity pain perception
What is allodynia
When we experience pain from normal touch, well before normal pain response would be generated eg putting on clothes
What can cause hyperalgesia in C fibres
Sensitisation of the peripheral nerve endings or at the first/second synapse as info travels to the brain
What is hyperalgesia
increased amount of pain associated with a mildly noxious stimulus
What 2 differently located effects does hyperalgesia involve
Sensitisation of peripheral nociceptive nerve terminals
Central faciliation of transmission aka ‘wind up’
What do C fibres have receptors for
eg bradykinin, serotonin, ATP, H+ released in response to tissue injury
Peripheral hyperalgesia- what transmission occurs as a result of mediators released by injured tisse binding to C fibres
Generated EPSPs on each C fibre summate to form APs that go up into the spinal cord and down the many branches of C fibres
Peripheral hyperalgesia- what is the result of APs being sent down lots of C fibre branches
Neurotransmitters stored in these branches eg substance P and CGRP are released at the nerve ending
Peripheral hyperalgesia-What is the effect of neurotransmitters eg substance P and CGRP released by the nerve endings
They act on mast cells and cause them to release histamines, and act on blood vessels to make more blood come to the damaged tissue area and make them leaky
Peripheral hyperalgesia- what is the result of mast cells releasing histamines and increased leaky blood flow
NEUROGENIC INFLAMAMTION
Histamines sensitize polymodal C fibres
Swelling and reddening, allowing the area to fight damage and infection
Peripheral hyperalgesia- why can pain be felt over large distances of the body
Mediators released by the injured tissue can diffuse to non-injured areas, and CGRP and substance P can be released at sites distance from the injury since the C fibres are so branches
What is the protective function of pain being felt over long distances away from the injury
Forces you to protect the tissue and prevent further damage
What is central hyperalgesia
Central sensitisation to pain by facilitation of pain transmission particularly in extended pain states eg chronic pain, aka ‘wind up’
Why is central hyperalgesia/chronic pain bad
Untreated pain becomes worse, no longer helpful as an illness signal
Where does central hyperalgesia occur
In the dorsal horn of the spinal cord (1st synapse), in the thalamus (2nd synapse)
What is central hyperalgesia a form of
Neuronal plasticity
Central hyperalgesia- what happens in terms of receptors under low levels of stimulation
Glutamate binds to AMPA receptors and signals pain to the brain
NMDA receptors bind glutamate but remain inactive due to the Mg2+ block
Central hyperalgesia- what happens under repetitive stimulation
C fibres fire repeatedly, causing the release of glutamate AND substance P (which binds to NK1 receptors) causing slow prolonged depolarisation
Central hyperalgesia- what is activated as a result of prolonged depolariation due to substance P
NMDA receptors (coincidence receptors) are activated as glutamate is bound AND depolarisation has removed the Mg+ block
Central hyperalgesia- what is the result of NMDA receptors opening
Influx of Na+ down its conc gradient, but more importantly Ca2+ which activates calmodulin kinase and protein kinase C
Central hyperalgesia- what is the result of activation of calmodulin kinase and protein kinase C
Phosphorylation/transcription/insertion of AMPA receptors, increasing sensitivity to glutamate
The whole process is a loop, causing hyperexcitability of nociceptive receptors after severe or persistent injury
Central hyperalgesia- what is the effect of NK1 antagonists in animals
Have tried to reduce wind up in animals, reducing the chance NMDA will open to allow Ca2+ in, but these haven’t translated well to humans
Central hyperalgesia- how can chronic pain be treated?
By giving NK1, NMDA or AMPA antagonists- however, these can cause side effects eg blockage of NMDA receptors can cause memory loss as the receptor is involved in memory
Pain medications for inflammatory pain- what are NSAIDS
Non-steroidal anti-inflammatory drugs
eg can reduce prostoglandin (receptor) synthesis to reduce pain
Pain medications for inflammatory pain- how do local anaesthetics work
Block VGNa+ channels in primary afferent fibres, preventing APs travelling up the spinal cord to create the perception of pain
Pain medications for inflammatory pain- how do opiates work
Can can hyperpolarisation/IPSP by binding to u receptors to open K+ channels and close Ca2+ channels, reducing the amount of neurotransmitter released
What are alternative pain medication examples
Acupuncture, TENS machines, deep brain stimulation, antidepressants, hypnosis
What is acupuncture
Invasive procedure where small needles are inserted below the skin to relieve pain
Study into how acupuncture works as pain relief
Goldman (2010)- acupuncture causes the release of adenosine that binds to A1R causing analgesia (pain relief)
What is TENS
Transcutaneous electrical nerve stimulation- delivery of mild electric current through patches attached to the skin
How is TENS believed to reduce pain
By creating electrical impulses in Abeta fibres, we can affect pain fibres via interneurons that connect the two
What are 2 theories of the physiology behind TENS
Gating of pain transduction, production of natural endorphins
What is the gate theory of pain
Melzack and Wall 1960s- Abeta fibre releases glutamate to stimulate an inhibitory neuron in the dorsal horn that releases GABA to cause an IPSP onto the C fibres, reducing their firing
Major criticism of the gate theory of pain
No concrete evidence that this circuit exists
Alternatve theory for gate theory of pain- cortical mechanism
Inui et al (2006)- suggests TENS relieves pain by cortical mechanisms with minimal spinal involvement
Study supporting alternative theory for gate theory involving cortical mechanisms
Inui et al (2006)- using the different speeds of conductinon of Abeta and Adelta fibres, they stimulated them to ensure their signals never passed through the dorsal horn at the same time so the inhibitory circuit could not work- YET Abeta fibres still relieved pain despite only crossing the Adelta fibres in the cortex
Examples when our perception of pain is altered
Beecher- WW2 soldiers with severe battle wounds experienced no pain
May not notice an injury while playing sports
What are opioids
Natural pain relievers produced by our body, mimiced by manmade opiate drugs
What placebo effect can occur if we think we’ve taken pain relief
We produce natural opioids, producing a real effect that can be blocked by opiate receptor antagonists
What structures can enable descending modulation of pain
Collaterals from the relay neuron go to individual sites in the brain that determine how much pain is perceived
Can affect PAG, NRM, LC, NRPG
Descending pain modulation- what is the PAG
Periaqueductal grey
Descending pain modulation- what is the LC
Locus coeruleus
Descending pain modulation- what is the NRM
Nucleus raphe magnus
Descending pain modulation- what is the NRPG
Nucleus reticularis paragigantocellularis
How does the PAG modulate pain
PAG can be stimulated or inhibited by the cortex depending on emotional state, can stimulate the NRM
How does the NRM modulate pain
NRM can be stimulated by the NRPG or PAG, releases 5HT and enkephalin through dorsal lateral verniculus that comes into the dorsal horn to reduce pain transmission up the relay neuron
How does the LC modulate pain
LC produces noradrenaline, which can inhibit pain transmission in the dorsal horn
Evidence of the PAG being able to reduce pain
In animal models, stimulation of the PAG allows painless surgery on animals
Where can opioids act in the body to modulate pain
Can reducing firing of nociceptive afferent neurons in the periphery, can cause IPSP in dorsal horn, can stimulate NRPG, can stimulate PAG by inhibiting an interneuron that usually inhibits PAG
How do opioids have an effect on target areas
When opiates bind to a u receptor, they can open K+ channels to cause hyperpolarisation or close VGCa2+ channels to reduce the amount of neurotransmitter produced
What is deep brain stimulation used to treat
Chronic neuropathetic (nerve) pain Successful in 60% of patients halving pain
What is deep brain stimulation
Electrodes implanted into the brain which send electrical current to stimulate brain areas to relieve pain (eg PAG, thalamus)
How is is thought that deep brain stimulation reduces nerve pain
Increases levels of opioids, cause release of adeosine, or modify brain circuits to reduce transmission of pain
What is the nocebo effect
When you feel a stimulus as painful because you expected it to be painful
Study showing effect of nocebo effect on pain perception
Yoshida et al (2013)- a group who saw ‘participants’ screaming out in pain when touching a hot stimulus reported very high levels of pain when touching the stimulus themselves, compared to a group who just watched a nice film beforehand
How can the nocebo effect be caused in pain perception
PAG can cause descending FACILIATION of pain rather than inhibition
Where is the pain gate that determines how mcuh pain we feel
In the substantia gelatinosa of the dorsal horn, at the first synapse between the Ad or C fibres and the relay neuron
Examples of factors that close the pain gate
Mechanosensitive stimulation, placebo, distraction, opiates, environmental danger etc
Examples of factors that open the pain gate
Infection, depression, anxiety, nocebo effect, inflammation
How is the intensity of pain encoded by the relay neuron
Frequency of AP firing
What has to happen in the relay neuron for pain to be perceived
The relay neuron must reach threshold for an AP to fire to allow perception of pain
What may cause phantom limb pain
When the severed ends of nerves that believe they are still connected to the limb are abnormally stimulated, causing the sensation of pain in the missing limb- missing limb may feel twisted, contracted etc
Cortical reorganisation
What is mirror box therapy for phantom limb pain
Individual sees both of their hands as if they’re intact, move the intact hand but look in the mirror so it appears as the severed hand, tricks the brain into thinking the severed arm is no longer bent into the abnormal shape (Ramachandran et al, 2000)
What is nociception
Refers to the peripheral and CNS processing of info about the internal or external environment, as generated by the activation of nociceptors
How are nociception and pain different
Pain is the feeling, while nociception is the sensory process that provides signals that trigger pain
What does congenital insensitity to pain suggest about the importance of pain
Low levels of nociceptive activity are important to tell us when a particular movement/posture is putting too much strain on our body- patients often injure themselves a lot, bite their tongue/lip
How are Adelta mechanosensitive receptors activated
Mechanically gated ion channels in their membrane are bent by eg stepping on a thumbtack, depolarising the channel and generating APs
What effect can proteases released at the site of injury have
Proteases can break down extracellular peptide kininogen to form bradykinin, that binds C fibre receptors
How does ATP affect the C fibres
ATP depolarises receptors by binding directly to ATP-gated channels
How are Adelta mechanothermal receptors activated
Heat above 43C burns tissues, causing heat-sensitive ion channels to open, leading to depolarisatino and APs
Evidence for H+ acting on C fibres
Anaerobic metabolism causes a build up of lactic acid leading to an excess of H+ in the extracellular fluid, activating H+ gated ion channels on C fibres, causnig the dull ache associated with exercise
Evidence for the role of histamines
Creams that contain antihistamines block histamine receptors, reducing pain and swelling
What is primary vs secondary hyperalgesia
Primary- within area of damaged tissue
Secondary- tissues surrounding the damaged area
Peripheral hyperalgesia- how can bradykinin have long-lasting effects
Bradykinin makes heat-activated ion channels more sensitive
Peripheral hyperalgesia- what are prostaglandins
Chemicals generated by the enzymatic breakdown of lipid membrane, that greatly increase the sensitivity of nociceptors to other stimuli
How can secondary hyperalgesia interact with CNS mechanisms
Following injury, activation of mechanoreceptor Abeta axons by light touch can evoke pain, allowing cross-talk between the touch and pain pathways in the spinal cord
What do the pain fibres do before synapsing on cells in the substantia gelatinosa
Branch and travel a short distance up and down the zone of Lissauer
What add neurotransmitter of the pain afferents appears necessary to experience moderate to intense pain
Substance P- stored in storage granules in the axon temrinals, released by high frequency trains of action potentials
Example of referred pain
Pain in the heart from angina is often reported in the upper chest wall and left arm
Which pathway conveys info about pain and temp from the spinal cord to the brain
The spinothalamic pathway
Where does the second-order neuron synapse
The spinal thalamic fibres project through the spinal cord, medulla, pons and midbrain without synapsing until they reach the thalamus
Where do the pain and touch pathways get close to each other
The pain pathway eventually comes to lie alongside the medial lemniscus, and some spinothalamic axons terminate in the VP nucleus but the two pathways remain distinct (different region of the nucleus)
How great a region of the thalamus do the spinothalamic tract/trigeminal lemniscal axons synapse on compared to those of the medial lemniscus (touch pathway)
A much wider region- also project over a wider area of the cerebral cortex
Which regions of the thalamus do the spinothalamic axons terminate in
Ventral posterior nucleus, small intralaminar nuclei of thalamus
What is the trigeminal pain pathway
Fibres in the trigeminal nerve synapse on second-order sensory neurons in the spinal trigeminal nucleus of the brain, that then cross and ascend in the trigeminal lemniscus to the thalamus
What is the role of pain pathways other than the spinothalamic and trigeminothalamic
Send axons to a variety of structures at all levels of the brain stem before they reach the thalamus- some important in generating sensatinos of slow, burning pain, while some trigger behavoural arousal and alertness
Examples of opioids
Morphine, codeine, heroin
Evidence of role of endorphins in pain relief
Small injections of endorphins into the PAG can produce analgesia by binding to opioid receptors
Evidence of role of endorphins in pain relief from a blocker
Administering the blocker of opioid receptors, naxolone, blocks the effects of endorphins
