Lecture 29 - Neuropathic Pain I Flashcards Preview

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

Flashcards in Lecture 29 - Neuropathic Pain I Deck (32):
1

What is the active component of cannabis?

How does it act?

THC: tetrahydrocannabinol

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

2

Which endogenous molecule acts on CB1 and CB2?

Anandamide

  • an 'endocannabinoid'

3

Outline the various molecules that act on CB receptors

  • 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

4

Where is CB1 expressed?

  • 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

5

What effects does activation of CB1 bring about?

Describe how these effects are brought about

  • 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

6

What physical property of cannabinoids is important?

Highly fat soluble

Results in slow residual elimination

7

What is Sativex?

  • Effects
  • Use

  • 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

8

What is the general role of CB2 R?

Where is is expressed?

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

9

What are microglia?

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

10

Importantly, which receptor is expressed on microglia?

CB2 R

11

Outline the various glial cells in the CNS

  • Microglia
  • Macroglia
    • Oligodendrocytes
    • Astrocytes

12

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

Damage to nerves

13

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

  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

14

What is the role of astrocytes in neuropathic pain?

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

15

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

p38 MAPK

16

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

What is the implication for therapy?

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

Which cells make endocannabinoids?

Glial cells

  • Made on demand

18

What is the role of CB2 R on glial cells?

  • 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

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

  • 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

What is the effect of glia on opioids?

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

21

Outline the actions of cannabinoids

  • 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

Why are selective CB2 agonists needed?

CB2 receptors don't induce the psychoactive effects

  • Restrists effects to those that are wanted *

23

Differentiate between synergy and additivity

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

Describe the interaction between morphine and the cannabinoid CP55,490

  • 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

What is Dexmedetomidine?

Describe the MOA and clinical use

  • 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

Compare the action of the following in analgesia:

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

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

How is a dose-response curve generated?

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

28

What is ED50?

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

29

What is an isobol?

  • 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

Compare ED50 of the following drugs:

  • Morphine
  • CP55,940
  • Dexmed.

From highest to lowest:

  • Morphine
  • CP55,940
  • Dexmed.

31

Compare ED50 of the following drug combinations:

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

Is this synergy or additivity?

What conclusions can be made?

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

Compare the tail flick and hot-plate assays

Tail flick:

  • Purely spinal reflex

Hot plate reflex:

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