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BIOM30001 - Frontiers in Biomedicine > Lecture 29 - Neuropathic Pain I > Flashcards

Lecture 29 - Neuropathic Pain I Flashcards

1
Q

What is the active component of cannabis?

How does it act?

A

**THC: **tetrahydrocannabinol

  • Acts on:
    • CB1 R
      • ​Expressed in:
        • Brain & peripheral nerves
        • Muscle, liver, adipose
    • CB2 R
      • ​Expressed in:
        • Nonneuronal tissue
          • Immune cells
          • Microglia
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2
Q

Which endogenous molecule acts on CB1 and CB2?

A

Anandamide

  • an ‘endocannabinoid’
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3
Q

Outline the various molecules that act on CB receptors

A
  • Phytocannabinoids
    • Naturally occurring, from cannabis plant
    • There are very many, but only two are well characterised
      • THC
      • CBD: Cannabidiol
  • Endocannabinoids
    • ​Anandamide
    • 2-arachidonylglycerol
    • Made on demand
  • Synthetic cannabinoids
    • ​Nabilone
    • CP55
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4
Q

Where is CB1 expressed?

A
  • CNS
    • Pain pathways in brain and spinal cord
    • Hypothalamus
    • Cortex
    • Hippocampus
    • Cerebellum
    • Low density in brain stem
      • ​Lack of serious respiratory or cardiotoxicity
  • Periphery
    • ​1° sensory afferents
    • Vasculature
    • Urogenital tissues
    • Gut
    • Skin
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5
Q

What effects does activation of CB1 bring about?

Describe how these effects are brought about

A
  • Analgesia
    • Inhibition of:
      • Primary sensory neurons
      • Relay interneurons in dorsal horn
        • ​Decreased Ca2+influx ⇒ decreased release of excitatory neurotransmitters
        • Hypopolarisation of the relay neuron
    • Activation of:
      • ​Descending modulatory pathways
        • ​Via a2-adrenoceptors
  • Disruption of:
    • ​Motor coordination
    • Cardiovasculature system
    • Memory
  • Anti-emesis
  • Appetite stimulation
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6
Q

What physical property of cannabinoids is important?

A

Highly fat soluble

Results in slow residual elimination

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7
Q

What is Sativex?

  • Effects
  • Use
A
  • Oromucosal spray
  • Mixture of THC and CBD
  • Well tolerated, few AEs
  • Effects:
    • ​Analgesic
    • Antiemetic
    • Muscle relaxant
    • Increased quality of sleep
    • etc.
  • Use:
    • Therapeutic dose differs between individuals
    • Symptomatic relief of pain in:
      • MS
      • AIDS
      • Cancer pain
  • Availability
    • ​UK, US, Australia, many central European countries
    • Approved for:
      • ​Spasticity in MS
      • Neuropathic pain in MS and cancer
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8
Q

What is the general role of CB2 R?

Where is is expressed?

A
  • Role in the immune & inflammatory systems
  • Expressed:
    • in Microglia
    • Normally at low levels, but is upregulated in various glial cells in response to injury
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9
Q

What are microglia?

A
  • Macrophage equivalents in the CNS
  • BM derived
  • One of the glial cells
  • Function:​
    • Insulation
    • Protection
    • ​Nutrients
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10
Q

Importantly, which receptor is expressed on microglia?

A

CB2 R

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11
Q

Outline the various glial cells in the CNS

A
  • Microglia
  • Macroglia
    • Oligodendrocytes
    • Astrocytes
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12
Q

What is the common mechanism that leads to development of neuropathic pain?

A

Damage to nerves

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13
Q

Describe the role of microglia in nerve damage and development of neuropathic pain

A
  1. Damage to nerve
  2. Release of ATP
    • Recruitment of cells
  3. Inflammation:
    • ​Recruitment of macrophages, T cells and Mast cells to site of lesion
  4. ​​Microglia attracted to site of lesion by ATP
  5. Activation of microglia
    1. ​Ramified ⇒ migratory ⇒ activated
  6. Microglia localise around pain-sensing neuron
  7. ATP activation of microglia:​​
    • ATP binds** P2X4 R​**
    • Ca2+ influx
    • Translocation of NFKB to nucleus
    • Induction of p38 MAPK pathway
  8. Release various neuroinflammatory factors into the synaptic cleft
    1. Cytokines
      1. IL-1B
    2. ​Neutroptopic factors:
      1. ​BDNF, NGF
    3. ​Neurotransmitters
      1. ​ATP, Substance P
  9. These factors act on receptors on various neurons
    1. ​Ca2+influx
    2. Depolarisation
    3. Neuron sensitisation
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14
Q

What is the role of astrocytes in neuropathic pain?

A

Prolongation of the pain state:

  1. ​​Nerve damage
  2. Neuroinflammation from factors released by activated microglia
  3. Astrocytes become activated
    • ​​Factors bind to surface receptors
    • Influx of Ca2+
    • NFKB translocation to nucleus
    • Activation of astrocytes
  4. Hypertrophy
  5. Production of neuroinflammatory agents
  6. Increased Ca2+ influx into neurons
    • ​​Depolarisation of neurons
  7. Sensitisation of neurons
  8. Potentiation of the pain state
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15
Q

Which signalling pathway is important in microglial activation after nerve damage?

A

p38 MAPK

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16
Q

Outline the changes to CB1 and CB2 expression in various disease states

What is the implication for therapy?

A

Neuropathic pain

  • Upregulation of both receptors
    • CB1 R inhibit neurotransmitter release, inhibiting the hyper-sensitivity of the nerve pathways
    • CB2 R inhibits inflammation

Neuroinflammation

  • eg diseases like MS
  • CB2R upregulated in MS microglia
    • ​Decreases inflammation

Therapy:

  • Enhanced analgesic response to cannabinoids
17
Q

Which cells make endocannabinoids?

A

Glial cells

  • Made on demand
18
Q

What is the role of CB2 R on glial cells?

A
  • Upregulated on glial cells in response to various types of injury
    • ​Infection
    • Inflammation
    • Tissue damage
  • Role in **recruitment **of the glial cells:
    • ​Proliferation
    • Migration
  • as well as generation of mediators
    • ​Cannabinoid binding to CB R inhibits inflammation
19
Q

What is the significance of cannabinoid receptors in neuropathic pain therapy?

A
  • CB Rs represent a therapeutic target in neuropathic pain
    • ​Play a role in the recruitment of microglia
    • Microglia play a role in setting up the neuroinflammation which leads to the neuropathic pain
20
Q

What is the effect of glia on opioids?

A
  • Glia oppose the action of opioid analgesia
  • Enhance tolerance & dependence
21
Q

Outline the actions of cannabinoids

A
  • Act on CB R on glia
    • ​Inhibition of inflammatory molecule production
    • Stimulation of anti-inflammatory molecule production
    • Inhibition of migration into the brain (past BBB)
  • Act as antioxidants
    • Decrease toxicity of ROS
    • (CB R independent)
22
Q

Why are selective CB2 agonists needed?

A

CB2 receptors don’t induce the psychoactive effects

  • Restrists effects to those that are wanted *
23
Q

Differentiate between synergy and additivity

A

Simple additivity:

  • Drug combination leads to a mathematically predictable effect

Synergy:

  • Drug combination leads to effects of exaggerated intensity
  • Potency greater than calculated from individual potencies
24
Q

Describe the interaction between morphine and the cannabinoid CP55,490

A
  • Combination of cannabinoid (CP55,940) and morphine resulted in a far greater analgesic effect than either in isolation
  • Tested with a tail-flick assay
  • Thus, the relationship is synergy, not additivity
25
Q

What is Dexmedetomidine?

Describe the MOA and clinical use

A
  • a2 receptor agonist
    • Receptor present on the pre-synaptic neuron
    • Inhibits pre-synaptic neuron via inhibition of Cav channels
    • Decreased Ca2+influx
    • Decreased release of NA
    • Inhibition of nociceptive transmission
  • Used in intensive care:
    • Sedation, axiolysis, analgesia
  • Cardiovascular and respiratory side effects
26
Q

Compare the action of the following in analgesia:

  • α2-ADR agonists
  • μ receptor agonists
  • CB R agonists
A

α2-ADR agonists

  • Inhibits Cav channels, thus decreasing Ca influx
  • Inhibits the release of NA, thus blocking nociceptive transmission
  • Weak anti-nociceptive effect

μ receptor agonsits:

  • Agonised by opioids
  • Similar MOA as α2-ADR agonists

CB R agonists:

  • Agonise CB Receptors
  • Stimulate K+ channels
  • Increase efflux of K+ from neurons
27
Q

How is a dose-response curve generated?

A
  • Tail-flick assay
  • Increasing doses of the drug are administered
  • The maximum response for each conc. is taken
  • Construct a curve
28
Q

What is ED50?

A

Effective dose for 50% of the maximum effect of the drug

29
Q

What is an isobol?

A
  • Graph that allows analysis of synergy or additivity
  • If the drug combination falls on or above the line, then this is an additive effect, not a synergistic effect
  • If the drug is in the lower quadrant, it is a synergistic effect
  • Axes:
    • Drug doses on each of the axes
    • Line: ED50 of the two drugs
  • Fixed ratios of the drugs are used:
    • 1.0 ED50 (for eg) must be used for each drug
30
Q

Compare ED50of the following drugs:

  • Morphine
  • CP55,940
  • Dexmed.
A

From highest to lowest:

  • Morphine
  • CP55,940
  • Dexmed.
31
Q

Compare ED50 of the following drug combinations:

  • CP & morphine
  • CP & dexmed.
  • Dexmed. & morphine

Is this synergy or additivity?

What conclusions can be made?

A

From lowest to greatest arbitrary ED50:

  • CP & morphine
    • From isobol, synergistic combination
  • Similar for the other two combinations:
    • CP & Dexmed
      • Synergy with hot-plate assay
      • Additivity with tail flick assay
    • Morphine & dexmed.
      • ​Additivity on both assays

Conclusions:

  • CP & morphine
    • ​Synergistic for supraspinal & spinal reflex
  • CP & dexmed.
    • ​Suprespinal syngery
  • Morphine & dexmed:
    • ​Independent action
32
Q

Compare the tail flick and hot-plate assays

A

Tail flick:

  • Purely spinal reflex

Hot plate reflex:

  • Supraspinal mechanism
  • Pain signal goes into cortex
  • Mouse ‘decides’ to remove pax

BIOM30001 - Frontiers in Biomedicine (35 decks)

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