Lecture 28 - Novel Analgesics II Flashcards
Type of receptor that CB1 is
GPCR
Where is CB1R found?
Brain, spinal cord, peripheral nerves, fat, muscle, liver
Where is CB2R expressed?
Non-neural tissues, especially microglia
Name for cannabinoids derived from cannabis plants
Phytocannabinoids
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
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
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
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.
How do CB1 agonists enhance activity of inhibitory descending pain modulatory pathways?
Via alpha2 adrenoceptor pathways
Examples of endogenous CB1 agonists
1)
2)
1) Anandamide
2) 2-arachidonylglycerol
Examples of synthetic cannabinoid agonists
1)
2)
1) CP55,940
2) Nabilone
Sativex
1) Oralmucosal spray
2) Combination
THC effects
Analgesic, muscle relaxant, antiemetic, appetite stimulant, psychoactive
Cannabidiol effects
Analgesic, anticonvulsant, muscle relaxant, anxiolytic, antioxidant, antipsychotic, neuroprotective
What can Sativex be used for?
Adjunctive treatment for symptomatic relief of pain in MS, neuropathic cancer-related pain, AIDS neuropathy
How is Sativex administered?
Oralmucosal spray
Self-titrated, as THC and CBD doses are highly variable
Sativex efficacy
41% improvement over baseline, 20% improvement over placebo
Common underlying mechanism of neuropathic pain
Inflammation at site of damaged nerve
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
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
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
Cells that are activated in pain state, and can lead to neuropathic pain conditions
Microglia, astrocytes
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
Cannabinoid receptor particularly expressed by glial cells
CB2R
When is CB2R upregulated in the brain?
In response to infection, inflammation or tissue injury
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
CB2 potential roles
1) MS-related pain and mobility
2) Chemotherapy-induced peripheral neuropathy
3) Neuropathic pain
4) Increased efficacy of opioids
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
Example of drugs with a synergistic effect
CP55,940 and morphine
Example of an alpha2 adrenoceptor agonist
Dexmedetomidine
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
How can it be tested whether a drug combination acts additively or synergistically?
Isobologram
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.
Example of a thermal nociception test that tests supraspinal nociception
Heat plate test
Example of a thermal nociception test that tests spinal reflex nociception
Tail flick test
