Lecture 28 - Novel Analgesics II Flashcards Preview

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Flashcards in Lecture 28 - Novel Analgesics II Deck (35):
1

Type of receptor that CB1 is

GPCR

2

Where is CB1R found?

Brain, spinal cord, peripheral nerves, fat, muscle, liver

3

Where is CB2R expressed?

Non-neural tissues, especially microglia

4

Name for cannabinoids derived from cannabis plants

Phytocannabinoids

5

Brain distribution of CB1R
1)
2)
3)

1) Dense in hypothalamus, cortex, hippocampus, cerebellum
2) Low density in brainstem
3) Present in pain pathways of brain and spinal cord

6

Effects of cannabinoid agonists
1)
2)
3)
4)
5)
6)

1) Analgesia
2) Motor coordination impairment
3) Memory disruption
4) Anti-emesis
5) Anxiolysis
6) Cardiovascular effects

7

Parts of pain pathways that endocannabinoids modulate
1)
2)
3)

1) Primary sensory afferents - CB1 agonists inhibit
2) Dorsal horn - CB1 agonists inhibit activity of relay neurons
3) Descending modulatory control pathway (inhibitory pathway) - CB1 agonists enhance activity

8

How do CB1 agonists inhibit activity of dorsal horn relay neurons involved in ascending pain pathway?
1)
2)

1) Interaction with N-type calcium channels leads to decreased calcium entry into neuron. Reduced neurotransmitter release
2) Activates potassium channels on post-synaptic neurons, hyperpolarises them.

9

How do CB1 agonists enhance activity of inhibitory descending pain modulatory pathways?

Via alpha2 adrenoceptor pathways

10

Examples of endogenous CB1 agonists
1)
2)

1) Anandamide
2) 2-arachidonylglycerol

11

Examples of synthetic cannabinoid agonists
1)
2)

1) CP55,940
2) Nabilone

12

Sativex

1) Oralmucosal spray
2) Combination

13

THC effects

Analgesic, muscle relaxant, antiemetic, appetite stimulant, psychoactive

14

Cannabidiol effects

Analgesic, anticonvulsant, muscle relaxant, anxiolytic, antioxidant, antipsychotic, neuroprotective

15

What can Sativex be used for?

Adjunctive treatment for symptomatic relief of pain in MS, neuropathic cancer-related pain, AIDS neuropathy

16

How is Sativex administered?

Oralmucosal spray
Self-titrated, as THC and CBD doses are highly variable

17

Sativex efficacy

41% improvement over baseline, 20% improvement over placebo

18

Common underlying mechanism of neuropathic pain

Inflammation at site of damaged nerve

19

Normal response to nerve injury
1)
2)

1) Nerve injury provokes recruitment, activation of immune cells at site of injury, dorsal root ganglia, ventral, dorsal spinal cord horns
2) Macrophages, T lymphocytes, mast cells cluster around distal stumps of nerve to guide neuronal regeneration

20

Neuropathic response to nerve injury
1)
2)
3)
4)
5)

1) Peripheral nerve injury.
2) Synaptic projection of a pain-sensing neuron in the spinal cord releases ATP
3) Nearby microglia are drawn to ATP, activated
4) Fully activated microglia localise around pain-sensing neuron, release neuroinflammatory agents
5) These agents lead to increased calcium, chlorine ions in the neuron, depolarising it, leading to sensitisation

21

How does ATP activate microglia?
1)
2)
3)
4)

1) Binds P2X4R on microglial surface.
2) This leads to increased intracellular calcium levels
3) This leads to NF-kB translocation to nucleus, p38 MAPK pathway stimulation.
4) This leads to increased transcription of neuroinflammatory agents

22

Cells that are activated in pain state, and can lead to neuropathic pain conditions

Microglia, astrocytes

23

Astrocyte response to pain state
1)
2)
3)

1) Pro-inflammatory cytokines activate astrocytes
2) Activated astrocytes undergo hypertrophy, release neuroinflammatory agents.
3) Neuroinflammatory agents depolarise neurons, leading to sensitisation

24

Cannabinoid receptor particularly expressed by glial cells

CB2R

25

When is CB2R upregulated in the brain?

In response to infection, inflammation or tissue injury

26

Cannabinoid effects on neuroinflammation
1)
2)
3)
4)

1) Inhibit immune cell entry into the brain
2) CB1R agonists prevent excitotoxicity by reducing glutamate release
3) CB2R agonists reduce glial release of pro-inflammatory molecules and promote glial release of anti-inflammatory molecules
4) Cannabinoids are anti-oxidants, and reduce toxicity of ROS

27

CB2 potential roles

1) MS-related pain and mobility
2) Chemotherapy-induced peripheral neuropathy
3) Neuropathic pain
4) Increased efficacy of opioids

28

Why do CB2 agonists increase opioid efficacy?

Glial activation opposes opioid analgesia, enhances opioid tolerance and dependence.
CB2 agonists reduce release of glial pro-inflammatory agents

29

Example of drugs with a synergistic effect

CP55,940 and morphine

30

Example of an alpha2 adrenoceptor agonist

Dexmedetomidine

31

Role of alpha2 adrenoceptor agonists
1)
2)
3)
4)

1) Weak antinociceptive efficacy in acute pain
2) Located in dorsal horn of spinal cord
3) Associated with N-type voltage-gated calcium channels
4) Role in neuropathic pain

32

How can it be tested whether a drug combination acts additively or synergistically?

Isobologram

33

How is an isobologram constructed?

On each axis place ED50 of a drug, draw a line between them.
If a drug combination acts additively, ED50 will be on this line.
If acts synergistically, ED50 will be closer to zero.

34

Example of a thermal nociception test that tests supraspinal nociception

Heat plate test

35

Example of a thermal nociception test that tests spinal reflex nociception

Tail flick test