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Pain Flashcards

1
Q

What is pain?

A

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

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2
Q

Why is pain important:

A
  • it promotes of avoidance of situations which may decrease biological fitness
  • it promotes resting behaviour that either enhances recovery following injury, or modifies behaviour so that further injury or death become less likely.

(protects body from further damage)

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3
Q

Imagine stepping on a piece of lego
What is your response?

A
  • Detect pain
  • Lift your foot off it
  • Feel sharp pain, you recognise as being in your foot
  • Feel a slower throbbing pain
  • Hop up and down
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4
Q

Whats linked to pain detection

A

Activate sensory receptors and nociceptors

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5
Q
  1. Pain detectors:
    Nociceptors
A

Specialised neurons-
- sensory neurons (specific to pain)
- free nerve endings
- synapse in spinal cord to ascending neurons to brain

Nociceptors everywhere in body that will respond to incoming pain stimuli. But in regards to rest of body- when you hurt yourself in an internal organ, you don’t feel it in parts such as your heart, you actually feel the pain in your external body.

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6
Q
  1. Lift your foot off it
A

Spinal reflex, withdrawing from painful stimuli

This withdrawal effect is a spinal reflex- its not being processes up to the brain

Afferent neuron (info going in) → synapses on an interneuron in the spinal cord → onto an efferent neuron (going out) and this is a motor neuron causing a contraction of the muscle that will pull the part of your body exposed to painful stimulus away from it. You’re body is withdrawing from the painful stimulus through this reflex action in the spinal cord before the info has gone to the brain.

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7
Q

Nociceptors - polymodal (respond to multiple stimuli)
Free nerve endings contain receptors sensitive to noxious stimuli. List these recpetors

A

High threshold mechanoreceptors-
intense pressure stretching, striking, pinching

Vanilloid receptor, TRP channels (temperature-gated channels)-
heat, acids (damage) and capsaicin (chilli pepper)

Purinergic receptors-
damage (ATP release)

For all of these receptors:
Channels open, neuron depolarises, fires action potentials

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8
Q

What else is there in addition to lifting your foot

A

Signals to the brain that make you conscious of it

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9
Q

What do nociceptors conduct?

A

Electrical signal to spinal cord

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10
Q

Nociceptors:
Primary afferents - two types, what are these?

A

Ab fibres
- lightly myelinated
- medium diameter
- First pain: fast localisation of painful stimulus
- 6-25m/ sec

C fibres
- unmyelinated
- small diameter
- Second pain: provide the continuing dull ache (slow throbbing pain), poorly localised

compare with
Aa and Ab fibres
(normal propioreceptors)
- myelinated, large diameter

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11
Q

What are the two paths into the brain

A

1) to somatosensory cortex via the thalamus

encode the sensory components
- sensory discrimination
- tell you “where” it hurts

2) to ‘emotional’ cortex (insula and cingulate) via the thalamus

encode the emotional components
- unpleasantness
- negative affect

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12
Q
  • what is a benefit of pain?
  • pain sensitisation process
A

Pain can be protective to allow you to heal

Pain sensitisation processes

Hyperalgesia - noxious stimuli produce exaggerated pain sensation

Allodynia - non-noxious stimuli produce pain sensation (something thats not normally painful is now causing pain sensation)
(e.g. touching sun-burnt skin)

Peripheral sensitisation:
inflammatory response in and around injured tissue

Central sensitisation:
neuroplastic changes at synapses in spinal cord

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13
Q

Peripheral sensitisation:
- what is release + implications
- what happens

A

Chemicals released
- as a result of tissue damage, (e.g. ATP, H+)
- from nociceptors
- as part of the inflammatory response

Directly activate and/or modulate ion channels in nociceptor terminals

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14
Q

Inflammatory response:
- after injury, you get inflammation and what does this release?
- triggers?

A

neuropeptides - substance P and CGRP (calcitonin gene related peptide), released from nociceptor neurons

trigger:
- vasodilation,
- plasma extravasation (leakage of proteins and fluid from capillaries- not enough damage for red blood cells)
- activation of Mast cells and neutrophils

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15
Q

The “inflammatory soup”:

A

Histamine (mast cells)

Nerve Growth Factor (mast cells)

Serotonin (platelets)

Proteases
cleave extracellular
peptide to bradykinin

COX enzymes (cyclo-oxygenase) convert arachidonic acid (lipid) to prostagland

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16
Q

What do components of the inflammatory soup do?

A

Components of the inflammatory soup, Bradykinin, NGF and Prostaglandin feedback back to their own metabotropic receptors on the nociceptor neurons

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17
Q

Modulation of the nociceptor activation:
- what receptor?
- channel?

A

(VR1- temperature gated receptors which is activated if you put your hand on a burning stove/ touch something hot)

VR1 receptor is phosphorylated and threshold changes so opens at lower temperatures (when burn yourself then pick up a cup of tea, this will feel hotter than normal)

A sensory nerve specific (SNS) Na+ channel is phosphorylated so threshold voltage for firing is decreased, making the nociceptor more excitable

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18
Q

What is peripheral sensitisation

A

Nociceptors become hypersensitive to stimulation

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19
Q

Peripheral sensitisation

A

Bradykinin and prostaglandin are acting at metabotrophic receptors and their downstream pathways- the signal transduction cascades downstream of them are phosphorylating VR receptors so that they’re opening at lower temperatures. And they’re phosphorylating these sodium channels so these are becoming more excitable.

So when there is depolarisation here, you will get an increase of sodium coming into the cell and the cells going to start firing APs much earlier than it otherwise would have done.

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20
Q

Why increase pain sensitivity?
- “Good pain”
- how do we know this good pain is important?

A

“Good pain”
- Reminds you that you have hurt yourself
- Protecting injured area for recovery without further damage

How we know this good pain is important:

Congenital disorders where people have no pain perception
- if theres no signals to indicate to avoid painful stimulus, you don’t avoid it and may cause yourself more pain
- low life expectancy

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21
Q

Example reading showing congenital disorders

A

Families which have an SCN9A channelopathy that causes this congenital inability to experience pain. This is hereditary, they realise there was a mutation in this sodium channel so this is one of those sodium channels that gets activated in the nociceptors. When nociceptors depolarise a little bit that channel activates and lets a bit of sodium in which causes APs and the nociceptors fire and you feel pain. In these families there are people who feel no pain. They worked out in these families, there are individuals carrying this mutation in the sodium channel which is stopping the sodium channel from functioning.

22
Q

Central sensitisation (“wind up pain”)
- What is it?
- How is it done?

A

This is a way of sensitising our responses to pain by strengthening those synapses in the spinal cord, done by…
1) Nociceptor afferents release glutamate and substance P in spinal cord
- activate the spinothalamic neurons

2) Repetitive firing results in neuroplastic changes in the spinal cord strengthening the synapse
- so less stimulation will create a larger signal

3) NMDA receptor activation leads to influx of Ca2+

4) Substance P activates NK1 receptor (metabotropic)
– phosphorylation of NMDA and AMPA receptors
– receptors become more responsive to glutamate
– neurons more excitable (LTP)

5) Substance P diffuses to other synapses - so “wind up” can spread causing a generalised sensitisation to painful stimuli

23
Q

Explain gate control theory

A

Hopping up and down rubbing, blowing!

stimulation of Aa or Ab fibres in vicinity of injury activates interneuron in dorsal horn which inhibits spinothalamic neuron from firing

competition between excitation (from nociceptor) and inhibition (from propioreceptor)

Prevents pain signals getting to brain

In spinal cord, you can cut off C fibre (which causes longer pain) activity coming in by this pathway where you activate an interneuron and have competition between interneuron inhibiting this neuron and c fibres trying to activate it. This competition can switch off the spinothalamic neuron from being activated as well as the c fibre.

24
Q

What are mechanisms to decrease pain?

A
  • distraction
  • stress induced analgesia
25
Q

Mechanisms to decrease pain:
Distraction

A
  • Gate control theory in the mind….
  • Blowing or rubbing site of injury
    (can be explained at level of nociceptor and spinothalamic neuron)
  • But must also be central correlate….
  • Biting finger to block pain from stubbed toe? (happening in different part of spinal cord- these are confusing pain signals)
  • Example of this- Virtual reality treatments in burns units
26
Q

Treatment of burns patients

A
  • Changing dressings, physiotherapy etc. very painful
  • Opioid treatments but issues with dosing/tolerance etc.
  • Virtual reality environment (snow world)
    – patient’s pain ratings reduced by 30-50%
    – reduction in time spent thinking about pain, pain intensity and in how unpleasant they found the pain
27
Q

Central processes:
What is found with activity in pain processing areas of the brain linked to virtual reality?

A

Reduced activity in pain processing areas of brain when treatment in presence of virtual reality (VR).

Brain areas where alterations were found: Somatosensory cortex, anterior cingulate and insula + thalamus.

28
Q

Other internal mechanisms to decrease pain:
Stress induced analgesia

A

Adaptive response to down-regulate pain

Central mechanism triggers descending regulation of pain circuitry to inhibit pain signals arriving in the brain

One mechanism involves the release of endogenous opioids
- naloxone challenge (opioid antagonist) blocks the analgesic effect.

(Example –soldiers escaping from danger with bd wounds – don’t feel pain till in safety)

29
Q

Descending modulation of spinal neurotransmission

A

Shows how these analgesic pathways occur- how you can have activity from brain talking to spinal cord pathways into where nociceptors are synapsing to send info up to the brain and how that descending modulation can be switching off activity of the ascending pathways and causing that stress induced analgesia through opioid receptors across this descending pathway

  • outputs from somatosensory cortex via thalamus to midbrain
  • hypothalamus to midbrain
  • midbrain to medulla
  • medulla into spinal cord
  • variety of onward projections
    (opioid peptide, serotonin, noradrenaline) to dorsal horn of spinal cord
  • modulation (“gating”) of transmission by dorsal horn nociceptive neurons
30
Q

Descending Inhibitory Control:
The endogenous opiate system
- what does the brain do?
- opioids acting at?

A
  • brain overrides pain signals switches them off in spinal cord
  • Opioids acting at inhibitory metabotropic receptors
31
Q

The endogenous opiate system
What are the multiple sites of action?

A

1) opioids can inhibit inhibitory neuron in the PAG (e.g. allow excitation)
PAG neurons disinhibited (fire) and activate serotonergic neuron from raphe which act to excite enkephalinergic neurons in spinal cord.

2) release of enkephalin acts at opioid receptors on the nociceptor terminal in dorsal horn inhibits firing of
spinothalamic neuron (pre and postsynaptic effect)

32
Q

Descending Modulatory Pain Pathway
INACTIVE

A
  • haven’t got activation of neurons in PAG
  • don’t have opioidergic interneurons releasing opioids onto GABA interneurons
  • GABAergic projection from PAG to raphe fire normally
  • They are inhibiting this serotonin neuron from firing
  • not getting activation of opioidergic interneurons in Dorsal horn
  • so- this pathway is switched off because this GABA neuron is firing
  • as this downstream pathway is switched off, the nociceptor neuron is activating the spinothalamic neuron and pain signal is transmitted to the brain
33
Q

Descending Modulatory Pain Pathway
ACTIVE

A
  • brain sends glutamatergic protection from the cortex to PAG
  • projecting onto opioidergic interneuron- this is releasing opioids onto GABAergic interneuron which are hitting inhibitory metabotropic receptors and switching this GABA interneuron off.
  • if this interneuron is switched off, it can’t stop the serotonin neuron from firing, so this neuron becomes disinhibited - serotonin is released to dorsal horn
  • activates another opioid interneuron which inhibits the upstream spinothalamic neuron and stops this pain signal
34
Q

Descending Modulatory Pain Pathway- inactive and active sum

A

Inactive:
- GABA neuron is firing so the pathway is switched off
- Nociceptor neuron is activating the spinothalamic neuron and pain signal is transmitted to the brain

Active:
- GABA interneuron turned off
- Interneurons inhibit neurons that transmit pain messages to brain

35
Q

Reducing Pain

A
  • Acute pain treatments and underlying mechanisms
  • Drugs and techniques producing analgesia
  • Chronic pain (neurogenic - nocigenic)
  • Chronic pain treatments and underlying mechanisms
36
Q

How can pain be reduced?

A

Acute pain – we know the biology so can target directly

Potential sites of action for local anaestetics, NSAIDS, opiates, and cannabinoids to mediate analgesia

Sodium channel blocker stops generation of action potentials

NSAID blocks synthesis of prostaglandin

Opiate and/or cannabinoid receptors (Gi coupled) activated leading to inhibition of adenylyl cyclase

37
Q

What is capsaicin and possible mechanism of actions?

A

Capsaicin
– active ingredient in chilli
– agonist of TRP channels

Possible mechanism of actions:
- desensitises receptors (stop fluxing ions)
- massive release of Substance P in Spinal cord, depletion of substance P blocks central sensitisation

38
Q

Opates:
- example
- mechanism of action
- multiple sites of action

A

e.g. morphine, codeine, fentanyl

Mechanism of Action
- agonists of the endogenous opioid system
- tap into bodies own system of pain regulation

Multiple sites of action
- peripherally
- spinal cord
- centrally

39
Q

Other methods of tapping into the endogenous opioid system?

A

Electrical stimulation of PAG - clinically significant pain relief
(stimulates release of opioids?)

Acupuncture
- (a bit like gate control theory)
- some evidence can be blocked by naloxone implicating opioid system

Placebo - effects can be blocked with naloxone
(the power of suggestion)

Non - opioid mechanisms
multiple ways the brain can modulate pain signals and information
e.g. some stress induced analgesia is not blocked by naloxone endocannabinoids?

40
Q

Cannabinoid system and stress-induced analgesia
(Opioid independent mechanism)

A
  • Endocannbinoids, 2 arachidonoylglycerol (2-AG) and anandamide, act at CB1 receptor
  • Levels of 2-AG and anandamide in PAG increase with stress
  • Injection of CB1 agonist into PAG is analgesic
  • Injection of CB1 antagonist into PAG blocks stress induced analgesia
    (Hohmann et al (2005) Nature 435, 1108-1112)
  • Multiple target mechanisms for treating pain.
  • More research - individual treatments etc.
41
Q

What is the difference between Nocigenic pain and Neurogenic (or neuropathic) pain?

A

Nocigenic pain
Pain caused by the actions of painful stimuli on triggering the firing of nociceptors

But also:

Neurogenic (or neuropathic) pain
Pain caused by damage to the nerves themselves

  • spontaneously discharging nociceptors
  • or lack of inhibitory mechanisms

eg.
- shingles (caused by herpes zoster virus)
- phantom limb pain or amputated stump pain
- fibromyalgia
- trigeminal neuralgia

42
Q

Possible mechanisms leading to chronic pain?

A

Peripherally
- sensitisation of peripheral neurons
- increased activity of damaged axons and sprouting

Centrally
- hyperexcitability of central neurons
- reorganization of synaptic connectivity in spinal cord
- disinhibition - removal of tonic descending inhibitory control

43
Q

What is found under normal conditions and chronic pain syndromes?

A

Under normal conditions:
- normal pain transmission
- inhibitory interneuron
- control of pain signal to switch off

Chronic pain syndromes:
Peripheral sensitisation/ long term sensitisation where things are being abnormally activated to cause pain or you’ve lost that top down inhibitory control so things are causing pain that otherwise would have been inhibited

44
Q

Management of chronic pain:
- is it simple?
- example
- list drugs for chronic pain

A

Complicated as many other associated problems that need to be treated in conjunction

eg.
primary disease
depression
sleep disturbance
fatigue

80% depressed people present at clinic with physical symptoms

Drugs for chronic pain include, tricyclic antidepressants, anticonvulsants, NMDA antagonsists, cannabinoids etc.

45
Q

Psychology of Pain:
- what is pain perception in terms of differences?
- identical injury?

A

Pain perception is very individual

Identical injury - chronic pain does not manifest in every patient

  • what kind of factors may influence this
  • how brain processes may affect pain perception etc.
46
Q

What are the levels at which you can explain individual differences in pain sensitivity and response?

A

–Biological factors
–Gender
–Psychopathology
–Social factors
–Personality
–Cultural factors
–Situation and circumstance
–Beliefs about pain

47
Q

Biological Factors

A

Genetics
Disorders with genetic component
e.g.
- congenital pain disorders
- migraine
- temporomandibular joint disorder

Genetic variability in components of system
e.g.
- failure to increase levels of analgesic peptides (NPY)
- marked decline in GABAergic function
- accentuated sympathetic responses

Interactions with other systems
e.g. Irritable bowel syndrome - brain-gut dysfunction

48
Q

Sex differences in pain perception
- what is associated with a particular sex
- example?
- what differs between sex
- what has been reported?

A

Some disorders associated with a particular sex

e.g.
- cluster headaches → more common in males
- migraine, TMJ, Rheumatoid Arthritis, Fibromyalgia → more common in females

Pain perception (thresholds) differ with sex
Females report:
- more intensive acute pain
- more chronic pain
- greater intensity
- pain in more bodily areas
- longer duration

49
Q

Sex differences: Why ?

A

Biological factors
- Genetic differences
- Sex hormones
- Brain imaging

Psychosocial factors
- Negative emotion
- Coping strategies
- Social influences

50
Q

Sex differences in opiodergic mechanisms:
- differential sensitivity to ______ in males and females
– who tend to be more sensitive?
- Mu opioid receptor activity
- what have stronger effects in females
- what do women with the Mc1r 2 allele show?
- need for?

A

Differential sensitivity to morphine in males and females (to get same pain relief) - females tend to be more sensitive (need less morphine)

Mu opioid receptor activity
- females may show less endogenous analgesic effects
- differential distribution and activation of receptors in male/females

Kappa opioid receptor agonists have stronger analgesic effects in females
- mediated by melanocortin-1 receptor (Mc1r)
(also involved in regulating skin and hair colour)

Women with the Mc1r 2 allele (associated with red hair and fair skin) display greater analgesic response than men with same allele or females with other variants

Need for:
- Sex specific treatments
- Pharmacogenetics
- Other descending control mechanisms

51
Q

What does research need to take account of?

A

Diversity in responses

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