Lecture 28 - Novel Analgesics II

Question 1

Type of receptor that CB1 is

Answer 1

GPCR

Question 2

Where is CB1R found?

Answer 2

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

Question 3

Where is CB2R expressed?

Answer 3

Non-neural tissues, especially microglia

Question 4

Name for cannabinoids derived from cannabis plants

Answer 4

Phytocannabinoids

Question 5

Brain distribution of CB1R
1)
2)
3)

Answer 5

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

Question 6

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

Answer 6

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

Question 7

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

Answer 7

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

Question 8

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

Answer 8

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.

Question 9

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

Answer 9

Via alpha2 adrenoceptor pathways

Question 10

Examples of endogenous CB1 agonists
1)
2)

Answer 10

1) Anandamide

2) 2-arachidonylglycerol

Question 11

Examples of synthetic cannabinoid agonists
1)
2)

Answer 11

1) CP55,940

2) Nabilone

Question 12

Sativex

Answer 12

1) Oralmucosal spray

2) Combination

Question 13

THC effects

Answer 13

Analgesic, muscle relaxant, antiemetic, appetite stimulant, psychoactive

Question 14

Cannabidiol effects

Answer 14

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

Question 15

What can Sativex be used for?

Answer 15

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

Question 16

How is Sativex administered?

Answer 16

Oralmucosal spray

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

Question 17

Sativex efficacy

Answer 17

41% improvement over baseline, 20% improvement over placebo

Question 18

Common underlying mechanism of neuropathic pain

Answer 18

Inflammation at site of damaged nerve

Question 19

Normal response to nerve injury
1)
2)

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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

Answer 22

Microglia, astrocytes

Question 23

Astrocyte response to pain state
1)
2)
3)

Answer 23

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

Question 24

Cannabinoid receptor particularly expressed by glial cells

Answer 24

CB2R

Question 25

When is CB2R upregulated in the brain?

Answer 25

In response to infection, inflammation or tissue injury

Question 26

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

Answer 26

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

Question 27

CB2 potential roles

Answer 27

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

Question 28

Why do CB2 agonists increase opioid efficacy?

Answer 28

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

Question 29

Example of drugs with a synergistic effect

Answer 29

CP55,940 and morphine

Question 30

Example of an alpha2 adrenoceptor agonist

Answer 30

Dexmedetomidine

Question 31

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

Answer 31

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

Question 32

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

Answer 32

Isobologram

Question 33

How is an isobologram constructed?

Answer 33

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.

Question 34

Example of a thermal nociception test that tests supraspinal nociception

Answer 34

Heat plate test

Question 35

Example of a thermal nociception test that tests spinal reflex nociception

Answer 35

Tail flick test