Lecture 29 - Neuropathic pain and analgesia 2 Flashcards
CB1 receptor (for cannabinoids - THC) is one of the most widely expressed ___ in the brain and is also found in peripheral tissues
GPCR
CB2 receptor is found on
non-neuronal tissues, innune cells including microglia
What is the endogenous mediator of CB1 receptor?
anandamide
Unlike opioids rceptors Cb1r have a very low density in the ____
brainstem
What are the 3 main areas where cannabinoids can influence the pain transduction?
- peripheral nerve transmission - CB1 agonists inhibit
- 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 - Descending modulatory (inhibitory) control pathway - CB1 agonists enhance activity
Sativex (mixutre of TH and cannabidiol) is used for
analgesic, muscle relexant
adjunctive treatment for symptomatic relief of pan in MS, neuropathic related cancer pain and AIDS neuropathy
Sativex have a __% improvement over basseline and __% over placebo for treatment of MS
41%
20%
What are the other clinical effects of THC?
anxiolysis
sleep improvement
appetite
psychotropic effects - abuse potential
Glial cells are what percentage of total cells in the brain and SC?
70%
microglia are 5-10% of that
What is the mechanism of inflammation at site of damaged nerve?
cytokines, neurotrophic factors
can activate MICROGLIA and ASTROCYTES located in SC and brain
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
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
Macrohpages move from the ___ within the sheath to the site of injury
DRG
one week after nerve injury, massive ______ activation found in the dorsal horn
one week after nerve injury, massive microglial activation found in the dorsal horn
The activated microglia modulate neuropathic Pain signaling in dorsal horn
How does this happen?
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
what does activation of astrocytes do?
prolongation of a pain state
- more neuro-inflammatory agents secreted in the synaptic cleft
What happens to CB1 and CB2 receptors in neuropathic pain and neuro-inflammation?
CB1 and CB2 receptors upregulated in peripheral and central sensory pathways
also upregualted in microglia/macrophage - like in MS
hence what is the role of CB1 and CB2 receptors in disease?
inhibitor NT release and decreas hypersensitivity and decrease inflammation (CB2R expressed on T cells)
Glial cells express CB1 and mainly Cn2R - secrete ___________
endocannabinoids
What are Cb2R an interesting target for treatment of disorders in which activation of microglial cells is a critical process?
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
Cannabinoids themselves can inhibit entry of what to the brain?
immune cells
through activation of CB2R can also inhibit generation of pro-inflammatory mediators
CBs are also antioxidant molecules meaning they can…
decrease toxicity of ROS
What is the benefit of SELECTIVE CB2 agonists?
you dont get the psychoactivate side effect as they’re not represent in the brain
What applications are relevant for selective CB2 agonists?
MS
chemotherapy
neuropathic pain
increase efficacy of opioids
What is syngery or additivity in relation to prescribing drugs?
(which ideally don’t share a common receptor)
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
What is dexmedetomidine?
a2 adrenoceptor agonist
used in intensive care for sedation
acts to inhibit further release of noradrenaline by taking up the receptor
What are some future directions for cannabinoids, conotoxins and combination therapies?
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
