Lecture 29 - Neuropathic pain and analgesia 2

Question 1

CB1 receptor (for cannabinoids - THC) is one of the most widely expressed ___ in the brain and is also found in peripheral tissues

Answer 1

GPCR

Question 2

CB2 receptor is found on

Answer 2

non-neuronal tissues, innune cells including microglia

Question 3

What is the endogenous mediator of CB1 receptor?

Answer 3

anandamide

Question 4

Unlike opioids rceptors Cb1r have a very low density in the ____

Answer 4

brainstem

Question 5

What are the 3 main areas where cannabinoids can influence the pain transduction?

Answer 5

1. peripheral nerve transmission - CB1 agonists inhibit
2. Dorsal horn - CB1 agonists inhibit activity of relay neurons
   - negative coupling via G protein with N-type Ca2+ channels- leads to decrease in Ca2+ entry and release of excitatory NTs
   - hyperpolarisation of postsynaptic neuron due to activation of K+ channels
3. Descending modulatory (inhibitory) control pathway - CB1 agonists enhance activity

Question 6

Sativex (mixutre of TH and cannabidiol) is used for

Answer 6

analgesic, muscle relexant

adjunctive treatment for symptomatic relief of pan in MS, neuropathic related cancer pain and AIDS neuropathy

Question 7

Sativex have a __% improvement over basseline and __% over placebo for treatment of MS

Answer 7

41%

20%

Question 8

What are the other clinical effects of THC?

Answer 8

anxiolysis

sleep improvement

appetite

psychotropic effects - abuse potential

Question 9

Glial cells are what percentage of total cells in the brain and SC?

Answer 9

70%

microglia are 5-10% of that

Question 10

What is the mechanism of inflammation at site of damaged nerve?

Answer 10

cytokines, neurotrophic factors

can activate MICROGLIA and ASTROCYTES located in SC and brain

Question 11

macrophages, T cells and ___ cells invade lesion site and spread around distal stumps of injured nerve fibres. _____ cells begin to proliferate and dedeffierentiate to guide regenerating axons

Answer 11

macrophages, T cells and mast cells invade lesion site and spread around distal stumps of injured nerve fibres. Schwann cells begin to proliferate and dedeffierentiate to guide regenerating axons

Question 12

Macrohpages move from the ___ within the sheath to the site of injury

Answer 12

DRG

Question 13

one week after nerve injury, massive ______ activation found in the dorsal horn

Answer 13

one week after nerve injury, massive microglial activation found in the dorsal horn

Question 14

The activated microglia modulate neuropathic Pain signaling in dorsal horn

How does this happen?

Answer 14

The activated microglia modulate neuropathic pain signaling in dorsal horn

ATP binds to receptors on microglial surface - increase in IC Ca2+ which induced p38 MAPK pathway

This initiates transcription of various neuroinflammatory agents including cytokines, neurotrophic factors and NTs into the synaptic cleft - these cause depolarisaion and sensitisation = PAIN

Question 15

what does activation of astrocytes do?

Answer 15

prolongation of a pain state

• more neuro-inflammatory agents secreted in the synaptic cleft

Question 16

What happens to CB1 and CB2 receptors in neuropathic pain and neuro-inflammation?

Answer 16

CB1 and CB2 receptors upregulated in peripheral and central sensory pathways

also upregualted in microglia/macrophage - like in MS

Question 17

hence what is the role of CB1 and CB2 receptors in disease?

Answer 17

inhibitor NT release and decreas hypersensitivity and decrease inflammation (CB2R expressed on T cells)

Question 18

Glial cells express CB1 and mainly Cn2R - secrete ___________

Answer 18

endocannabinoids

Question 19

What are Cb2R an interesting target for treatment of disorders in which activation of microglial cells is a critical process?

Answer 19

CB2R, although scarce in healthy brain, are up-regulated in idfferent glial elements, mainly reactive microglia cells, in response to infection, inflammation or tissue reponse

This response related to process of microglial recruitment (proliferation and migration) at the lesioned sites AND to generation of several micro-glia derived mediates, both processes being regualted by CBR2

Question 20

Cannabinoids themselves can inhibit entry of what to the brain?

Answer 20

immune cells

through activation of CB2R can also inhibit generation of pro-inflammatory mediators

Question 21

CBs are also antioxidant molecules meaning they can…

Answer 21

decrease toxicity of ROS

Question 22

What is the benefit of SELECTIVE CB2 agonists?

Answer 22

you dont get the psychoactivate side effect as they’re not represent in the brain

Question 23

What applications are relevant for selective CB2 agonists?

Answer 23

MS

chemotherapy

neuropathic pain

increase efficacy of opioids

Question 24

What is syngery or additivity in relation to prescribing drugs?
(which ideally don’t share a common receptor)

Answer 24

additivity (a +b) - drug combination leads to mathematically predicable effect of the two drugs

synergy (greater than a + b) - drug combination leads to effects of exaggerated intensity

Question 25

What is dexmedetomidine?

Answer 25

a2 adrenoceptor agonist

used in intensive care for sedation

acts to inhibit further release of noradrenaline by taking up the receptor

Question 26

What are some future directions for cannabinoids, conotoxins and combination therapies?

Answer 26

w-conotoxins - potential clinical utility in low doses or in combinatin therapy

Cannabinoids - could be used as CB2 agonsits due t efficacy and lack of CNS side effects

combination therpaies in general to be pursued - decreases side effects and tolerance