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Brain and Behaviour > Pain > Flashcards

Pain Flashcards

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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.
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3
Q

Detect pain:

A
  • Activate sensory receptors and nociceptors
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4
Q

Pain detectors:

A
  • Specialised neurons - nociceptors:
    • Sensory neurons (specific to pain)
    • Free nerve endings
    • Synapse in spinal cord to ascending neurons to brain
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5
Q

Spinal reflex:

A

Withdrawing from painful stimuli

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6
Q

Nociceptors:

A

· Polymodal - respond to multiple stimuli
· Free nerve endings contain receptors sensitive to noxious stimuli:
· Intense pressure stretching, striking, pinching
- High threshold mechanoreceptors
· Heat, acids (damage) and capsaicin (chilli pepper)
- Vanilloid receptor, TRP channels (temperature-gated channels)
· Damage (ATP release)
- Purinergic receptors
- Channels open, neuron depolarises, fires action potentials

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7
Q

Nociceptors conduct electrical signal to spinal cord:

A

· Primary afferents - two types
· A fibres:
- Lightly myelinated
- Medium diameter
- First pain - fast localisation of painful stimulus
· C fibres:
- Unmyelinated
- Small diameter
- Second pain - provide the continuing dull ache, poorly localised
· Compare with A(alpha) and A(beta) fibres (normal propioreceptors)
- Myelinated, large diameter

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8
Q

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 effect
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9
Q

Thank about how you respond to an acute injury?:

A

Pain is an alerting signal that something is wrong

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10
Q

What happens if you have caused real damage?:

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 (e.g., touching sun-burnt skin)
· Peripheral sensitisation - inflammatory response in and around injured tissue
· Central sensitisation - neuroplastic changes at synapse in spinal cord

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11
Q

Peripheral sensitisation:

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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12
Q

Inflammatory response:

A

· Neuropeptides - substance P and CGRP (calcitonin gene related peptide), released from nociceptor neurons
· Trigger:
- Vasodilation,
- Plasma extraversion - leakage of proteins an fluid from capillaries
- Activation of Mast cells and neutrophils

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13
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 prostaglandin

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14
Q

Modulation of the nociceptor activation:

A

· Components of the inflammatory soup, Bradykinin, NGF and Prostaglandin feedback back to their own metabotropic receptors on the nociceptor neurons
· VR1 receptor is phosphorylated and threshold changes so opens at lower temperatures
· A sensory nerve specific (SNS) Na+ channel is phosphorylated so threshold voltage for firing is decreased, making the nociceptor more excitable
· Nociceptors become hypersensitive to stimulation - peripheral sensitisation

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15
Q

Peripheral sensitisation 2:

A
  • lower thresholds of thermoreceptors
  • Na+ channels more excitable
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16
Q

Why increase pain sensitivity?:

A

· “good pain”
· Reminds you that you have hurt yourself
· Protecting injured area for recovery without further damage
· Congenital disorders where people have no pain perception
- No signals to indicate to avoid painful stimulus
- Low life expectancy

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17
Q

An SCN9A channelopathy causes congenital inability to experience pain:

A
  • no Na+ channel on nociceptors
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18
Q

Central sensitisation “wind up pain”:

A

· Nociceptor afferents release glutamate and substance P in spinal cord
- activate the spinothalamic neurons
· Repetitive firing results in neuroplastic changes in the spinal cord strengthening the synapse
- so less stimulation will create a larger signal
· NMDA receptor activation leads to influx of Ca2+
· Substance P activates NK1 receptor (metabotropic)
- phosphorylation of NMDA and AMPA receptors
- receptors become more responsive to glutamate
- neurons more excitable (long term potentiation)
· Substance P diffuses to other synapses - so “wind up” can spread causing a generalized sensitization to painful stimuli

19
Q

Gate control theory:

A

· Hopping up and down rubbing, blowing!
- stimulation of A(alpha) or A(beta) 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

20
Q

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?
· Virtual reality treatments in burns units

21
Q

Treatments 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.

22
Q

Central processes

A

· Reduced activity in pain processing areas of brain when treatment in presence of virtual reality (VR)
· Somatosensory cortex, anterior cingulate and insula + thalamus

23
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)

24
Q

Descending modulation of spinal neurotransmission:

A

· 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

25
Q

Descending inhibitory control:

A

· The endogenous opiate system
· Brain overrides pain signals switches them off in spinal cord
· Opioids acting at inhibitory metabotropic receptors
· Multiple sites of action:
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)

26
Q

Reducing pain:

A
  • How we can treat pain “bad pain”
    • Acute pain treatments and underlying mechanisms
    • Drugs and techniques producing analgesia
    • Chronic pain (neurogenic - nocigenic)
    • Chronic pain treatments and underlying mechanisms
27
Q

Acute pain:

A
  • Potential sites of action for local anaestetics, NSAIDS, opiates, and cannabinoids to mediate analgesia
    • Sodium channel blocked stops generation of action potentials
    • Opiate and/or cannabinoid receptors (Gi coupled) activated leading to inhibition of adenylyl cyclase
    • NSAID blocks synthesis of prostaglandin
28
Q

Capsaicin:

A
  • Active ingredient in chilli
    • Agonist of TRP channels
29
Q

Possible mechanism of actions:

A

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

30
Q

Opiates:

A

· E.g., morphine, codeine, fentanyl

31
Q

Mechanism of action:

A

· agonists of the endogenous opioid system
· tap into bodies own system of pain regulation

32
Q

Multiple sites of action

A

· peripherally
· spinal cord
· centrally

33
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?

34
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.

35
Q

So far we’ve been focusing on:

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

36
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

37
Q

Chronic pain:

A

· Nerve damage causes resprouting and new synapse formation in dorsal horn
· Ab fibres synapse onto nociceptive neurons
· Excess glutamate release during painful stimulus results in excitotoxicity, loss of inhibitory interneurons, no brake on excitiation

38
Q

Management of chronic pain:

A

· Complicated as many other associated problems that need to be treated in conjunction
- e.g. 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.

39
Q

Psychology of pain:

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.

40
Q

Many levels at which you can explain individual differences in pain and sensitivity and response:

A

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

41
Q

Biological factors:

A

· 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

42
Q

Sex differences in pain perception:

A

· Some disorders associated with a particular sex
- e.g. - cluster headaches - male
- migraine, TMJ, Rheumatoid Arthritis, Fibromyalgia
- female
· Pain perception (thresholds) differ with sex
· Females report:
- more intensive acute pain
- more chronic pain
- greater intensity
- pain in more bodily areas
- longer duration

43
Q

Sex differences - why?:

A

· Biological factors
- Genetic differences
- Sex hormones
- Brain imaging
· Psychosocial factors
- Negative emotion
- Coping strategies
- Social influences

44
Q

Sex differences in opiodergic mechanisms:

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

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