pccol3022 Flashcards
1
Q
Where does morphine bind
A
preferentially bind to mu opioid receptor
2
Q
Where are mu opioid receptors found
A
dorsal horn of spinal cord, VTA, nucleus accumbens, locus cereuleus
3
Q
Give 2 examples of lower potency mu agonists
A
Codeine and oxycodone
4
Q
What is the mechanism of action for aspirin and non-steroidal anti-inflammatory drugs
A
They produce analgesia by decreasing sensitization. They inhibit the enzyme cyclo-oxygenase 2. COX2 is an important mediator which releases an inflammatory molecule called prostaglanding E2
5
Q
What are 3 ways that an opioid limits pain?
A
1) Opioids inhibit adenylyl cyclase
2) Opioids increase postsynaptic potassium efflux
3) They reduce presynaptic calcium influx
6
Q
How does reducing calcium influx cause analgesia
A
Calcium causes the release of excitatory neurotransmitters such as glutamate in response to an action potential.
This reduces excitatory signals from reaching the post synaptic neurons.
7
Q
How does increasing potassium efflux cause analgesia
A
Potassium efflux causes the post-synaptic neuron to hyperpolarise and therefore less likely to depolarise and cause a symptom
8
Q
How does inhibiting adenylyl cyclase cause analgesia
A
So, basically beta and gamma subunits are important for inhibiting VGCCs or GIRKs.
Moreover, inhibition of voltage dependent pacemaker Ih-cation non-selective current activated at hyperpolarised potentials to depolarise membrane.
9
Q
What are the pharmacokinetics of morphine?
A
It rapidly enters all body tissues, however only a smal percentage crosses the blood brain barrier
10
Q
How does naloxone work
A
Naloxone binds to the mu opioid receptor with a much higher affinity than opioids. It acts as a competitive inhibitor that blocks opioids from binding. Naloxone’s higher affinity means that it can rapidly displace all receptor bound opioids
11
Q
Can we separate the positive and negative side-effects of opioids?
A
No because both the positive and negative side-effects are mediated by the same receptor
12
Q
Which sensory fibres do opioids primarily act on
A
C fibres-
the slow and non-myelinated opioids.
This is why opioids inhibit slow pain, but not fast pain
13
Q
Where are c fibres primarily found
A
C fibres are afferent neurons which terminate in the dorsal horn of the spine.
Mu opioid receptors are also very concentrated in the dorsal horn of the spine
14
Q
What role does norepinephrine and serotonin play in controlling pain?
A
Norepinephrine and serotonin are released from the medulla. They excite enkephalin and inhibit projection neurons and therefore inhibit sensory synpases.
15
Q
What are endogenous opioids
A
These are the enkephalins and endorphins that are primarily produced in the brain. Enkephalin: noradrenaline and sertonin from the medulla excite enkephalin neurons.
16
Q
What are the main kinds of opioid drugs
A
1) opiates-drugs made from opium poppy
agonists
morphine related opioids
opioid agonists
Opioid antagonists
17
Q
Explain mechanism of tolerance
A
(find out more)
As tolerance is likely to depend upon the level of receptor occupancy, the degree of tolerance observed may reflect the response being assessed (e.g. analgesia versus respiratory depression), the intrinsic efficacy of the drug and the dose being administered
Tolerance results in part from desensitisation of the µ receptors (i.e. at the level of the drug target) as well as from long-term adaptive changes at the cellular, synaptic and network levels (see Williams et al., 2013 ). Tolerance is a general phenomenon of opioid receptor ligands, irrespective of which type of receptor they act on. Cross-tolerance occurs between drugs acting at the same receptor, but not between opioids that act on different receptors.
18
Q
Explain synergistic actions with non-opioids to better relieve pain
A
(find out more)
19
Q
Why is heroin so powerful
A
Heroin is a prodrug. It is basically 3,6 acetyl morphine.
Esterification of Heroin means that it can go into the brain extremely fast.
There is a lot of esterases in the brain which forms 6 acetyl morphine and normal morphine
Break down CYP2D6
20
Q
What are the 2 main types of chronic pain
A
1) inflammatory pain or neuropathic pain
21
Q
What is inflammatory pain
A
pain often characterised by tissue injury and inflammatory processes. There is often a nociceptive activity
22
Q
What is neuropathic pain
A
Neuropathic pain is a lesion or disease affecting the somatosensory system. It is caused by lesions to the nerve.
23
Q
What are the symptoms of chronic pain
A
1) spontaneous pain
2) allodynia
3) hyperalgesia
24
Q
What is allodynia
A
normal stimuli perceived as painful
25
What is hyperalgesia
painful stimuli that becomes more painful. Reduced threshold to pain
26
How do we model neuropathic pain in mice
do a peripheral nerve injury-like sciatic nerve ligation.
Give mice chemotherapy drugs like paclitaxel to damage the neurons
Literally stimulate a disease that mimics human chronic pain
27
How do we mimic inflammatory pain in mice
Use intraplantar inflammation: complete Freund's adjuvant is a solution containing mycobacterium in paraffin oil. Inject it into the paws and it causes necrosis and ulceration.
28
How do we measure mechanical allodynia
Use von frey’s filaments to push into paws. The force you use to push into the paw varies.
In the von frey’s test, we are looking for a defensive response
29
How do we measure mechanical hyperalgesia
Randall-Sellito device measures the threshold force
30
How do we measure heat
Hotplate or Hargreaves test
31
Are opioids good for treating chronic pain?
Not very good in chronic pain models.
It causes some reduction in activity in mu opioid receptors but mu opioid receptors not on non-noxious afferents?
No effect on pain transmission from non-noxious afferents
Some reduction in the activation of ascending pain tract neurons
We can’t use drugs like opioids over time, because it can lead to addiction issues
32
Ziconomide
Ziconotide is an N type channel blocker.
It mediates neurotransmitter disease
Generally not approved because these channels expressed in pretty much every afferent pathway which means that it can have severe systemic side effects
33
Ziconomide vs Opioid
Ziconotide vs Opioid:
Better than opioids because it can target allodynia
Channel blocker- so it doesn’t cause as much abuse or tolerance
It is not recommended because of its poor blood brain barrier penetration and its severe side effects
34
What is the current best neuropathic pain medication?
GABA analogues
35
Where do GABA analogues bind
They can pass through the blood-brain barrier and therefore can get into the brain or spinal cord
They bind to the a2delta subunit of L-,N-, P/Q type VGCCs
36
How do GABA analogues work
Decrease VGCC membrane expression in central terminals of afferents AND they are less active
This causes less neurotransmitter release and reduced excitation
This also reduces pain transmission
They alter the trafficking of VGCCs but not the acute inhibition of channel opening
37
Side-effects of GABA analogues
Side-effects: dose dependent dizziness, sedation, incoordination, memory
38
TCA
Block NA and 5 HT transporters to prevent reuptake from the synapse so increase endogenous NA and 5HT and prolong signalling
They are more subtle than globally acting agonists, with fewer side-effects
Can have a few off target effects
TCAs are also channel blockers which can cause alternative analgesic mechanism to target 5HT/NA systems
39
SNRI
Dual noradrenaline and serotonin reuptake inhibitors
40
capsaicin-TRPV1 agonist
TRPV1-senses pain signals above 40C
Located on a major group of nociceptive afferents- in their terminals within the skin
It can cause localised neuropathic pain. Which causes dysfunction of nociceptives
Depletion of nociceptives
41
Where are voltage gated ion channels found
Pretty much everywhere on a neuron; they are found on excitable cells such as neuronal and muscle cells to allow a rapid and coordinated depolarisation.
On a neuron, they are found along the axon and the synapse
42
General structure of a voltage gated ion channel
Each voltage gated ion channel are made out of alpha subunits and beta subunits.
There are 4 main alpha subunits for the sodium voltage gated ion channel which are identical.
Each of these subunits are made out of 6 transmembrane domain called:s1,s2,s3,s4,s5,s6
43
What are the roles of beta subunits
The beta subunits are more diverse accessory units which help change the function of the alpha subunits:
Expression levels
Location
Trafficking
Alter voltage dependence of activation/inactivation
44
How do voltage gated ion channels open?
S4 is positively charged; it is made out of amino acids such as asginine. They play an important role in helping open the pore region which would be explained later. We call them voltage sensors
S5-S6 help form the regions where the pores are. One really important thing to consider is that the pore loop forms between s5 and s6
45
What are the differences between sodium and potassium channels
Difference between potassium and sodium channels is that instead of having 4 alpha subunits, we instead have 4 separate proteins. This is because there is no joining loop between different subunits in the potassium ion channel compared with the sodium ion channel
Different voltage gated ion channels have a pore forming region which have different selectivities for different ions.
Presumably, they have different selectivity filters
46
Describe the different functional states of voltage dependent ion channels
And how they function:
There are three different states of voltage gated ion channels:
1: open state
The pores are open ions can move down the selectivity filter.
After there is a change in membrane potential, the voltage sensor moves in s4 (it is a 25 degree tilt).
The voltage sensor is connected to a linker protein and the linker protein moves outwards and allows the channel to open up
2: closed state:
Opposite of open state
3: inactivated state
This is like the intermediate between a closed and open state. On one hand, the voltage sensor is still in it’s 25 degree tilt and the linker protein is still at an outward location which allows the channel to remain open. However, unlike the open or closed state, there is a ball and chain model for inactivation. This “ball” (inactivation gate) blocks up the open channel. This ball is also an intracellular domain. Helps prevent prolonged open state. Pore is blocked so no cation could move. Only repolarisation could
47
How is ion selectivity between different ion channels achieved
Different amino acids on the pore loops, so different amino acids for S1, S2, S3 and S4 on the S5-S6 pore loop
48
What is the function of a TRPV channel
These are members which are mainly involved in pain perception and also nociception
They are sensitive to
Heat
Acidic pH
Mechanical stimuli
They are relatively non-selective to cations
49
What is the function of a calcium channel?
Basically let calcium from extracellular places in.
Useful statistic to know:
Extracellular Calcium is about 1-5mM whereas intracellular calcium is 0.1-0.2 micromole before opening calcium channels but may rise to 100 micromoles after the opening of calcium channels
```
Calcium entry can affect many intracellular processes:
Muscle contraction
Neurotransmitter
Activation of second messenger systems
Alteration in gene expression
Apoptosis
depolarisation
```
50
Explain the differences in the mechanism of action of benzodiazepines and pentobarbitol on GABA receptors
Phenobarbital increases the channel open time which could mean that a very large amount of sodium could make it into the neuron. That makes it very dangerous
On the other hand, benzodiazepines open the frequency of channel opening, which also allows the chemicals in, but not necessarily that much that it could be lethal
(If it is a GABA receptor, why does it allow sodium ions and stuff in?)
51
Where do benzodiazepine bind?
BZ binding site contains a crucial Histidine residue, which is present on α1, α2, α3, α5
52
Why is pentobarbitone so dangerous
Benzodiazepines are unable to activate GABA receptors themselves whereas Pentobarbitone are able to enhance the actions of GABA or activate GABA receptors themselves.
Phenobarbital increases the channel open time which could mean that a very large amount of sodium could make it into the neuron. That makes it very dangerous
53
How does ethanol modulate the activity of GABA?
Ethanol, enhance the actions of GABA, prolongs the open time of the channel and binds with the transmembrane domain
54
How does general anaesthesia modulate GABA
```
General anaesthetics(e.g propofol)
Enhance the actions of GABA, may directly stimulate receptors at high concentration. Bind at the interface between alpha and beta subunits within the transmembrane region of the channel.
Propofol binds between M1,M2,M3 and m4, presumably keeping it more open?
```
55
How do neurosteroids modulate GABA receptors
Neurosteroids:
Promote channel opening
Sigma subunit most sensitive
56
Suggest ways that GABA receptor subunit diversity can impact on receptor activity and pharmacological modulation of receptor activity
think it means that it greatly impacts the different selectivity of drugs. Some drugs could only bind to homomeric pentameric structures whereas other drugs could only bind to heteromeric pentameric structures
Some drugs like benzodiazepine are selective to GABA receptors which contain a1,a2,a3,a5, or gamma subunits and nothing else.
Some benzodiazepines bind between alpha and gamma subunits so the large variation determines the location where drugs could bind.
57
Explain how AMPA and NMDA work together
NMDA receptors need 2 ligands: glu and glycine whereas AMPA only requires 1 kind of receptor: GLU
NMDA-voltage-dependent block by magnesium ions.
At the resting state, the magnesium bound to NMDA receptors preventing ions from going through.
AMPA starts first and allows cations to enter the cell, which then causes the magnesium in the NMDR to be spat out of the channel, after its released, then the NMDA receptor can then activate.
58
What are monoamines?
Neurotransmitters where an amino acid is connected to an aromatic ring. Tina is notorious for testing examples so know that there are 2 main types of monoamines:
Catecholamines
Indoleamines
59
What are some examples of monoamines?
```
Catecholamines:
Noradrenaline
Adrenaline
Dopamine
I.e, DANiel
```
Indoleamines:
Serotonin
Melatonin
60
Where are monoamines synthesised?
Monoamines are synthesised from decarboxylated amino acids and catalysed by cytosolic enzymes typically on the presynaptic neuron
61
How are monoamines synthesised?
So to synthesise the catecholamine your starting amino acid is L tyrosine
L tyrosine=> dopamine=> noradrenaline=>adrenaline in that order.
```
N.b indoleamines are synthesised in a completely different way.
I.e, serotonin:
Starting amino acid: tryptophan
Intermediate: 5 hydroxytryptophan
End product: serotonin
```
62
Where are monoamines stored
The monoamines are stored in vesicles at the presynaptic neuron
So..they are actively transported into vesicles or something?
63
How are monoamines released?
The neuron gets depolarised
Calcium channels open and calcium enters
Calcium ion entry promotes fusion of vesicles to terminal membrane
Causes exocytosis of monoamine from vesicles
Alternative:
Varicosities
64
Gas subtype
stimulates adenylyl cyclase
65
Gai
inhibits adenylyl cyclase
66
Gao
limited effects of a subunit
67
Gaq
activates phospholipase C, increasing production of second messengers
68
Gbeta gamma
activates potassium channels
inhibit voltaged gated calcium channels
Activate GPCR kinases
interact with adenylyl cyclase and phospholipase C beta
69
cAMP function
it regulates kinases such as protein kinase A. pROTEIN KINASE CAN DO LOTS OF THINGS SUCH AS PHOSPHORYLATE VOLTAGED GATED ION CHANNELS TO INCREASE THE AMOUNT OF CALCIUM.
70
phospholipase C/inositol phosphate system
hospholipase C/inositol trisphosphate (IP 3 )/diacylglycerol (DAG):
– catalyses the formation of two intracellular messengers, IP 3 and DAG, from membrane phospholipid;
– IP 3 acts to increase free cytosolic Ca 2+ by releasing Ca 2+ from intracellular compartments
– increased free Ca 2+ initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarisation;
– DAG activates various protein kinase C (PKC) isoforms, which control many cellular functions by phosphorylating a variety of proteins.
71
What do beta gamma subunits of Gi and G o do?
Direct G protein–channel interaction, through the βγ subunits of G i and G o proteins, appears to be a general mechanism for controlling K + and Ca 2+ channels. In cardiac muscle, for example, mAChRs enhance K + permeability in this way (thus hyperpolarising the cells and inhibiting electrical activity; see Ch. 22 ).
72
What are the phases of migraine?
1) Interictal phase
2) Prodrome and Aura
3) Headache
4) Termination
5) Postdrome
73
What does interictal mean?
ictal refers to a physiologic state/event such as a seizure or a stroke.
Interictal refers to period between seizures or convulsions
74
What does prodrome mean
```
The pre headache that marks the beginning of the migraine
Characterised by
1) Irritability
2) Depression
3) Fatigue
4) Nausea
```
75
What does an aura mean?
1) visual disturbances
2) temporary loss of sight
3) numbness and tingling on part of the body
vertigo
aphasia
76
What is the pathogenesis of a migraine headache?
The headache originates from extracerebral structures-such as the meninges/large arteries. They are innervated by nociceptive sensory nerves of the trigeminal pathway
77
What causes migraine?
environmental triggers
Potentially genetic-but polygenic mutations
involve genetic mutations in calcium channel or sodium/potassium/ATPase
78
Where is the cause of migraine?
1) In the trigemino-cerebrovascular system
- There are trigeminal nerves/ganglia
- There were major vessels for regulating cerebral blood flow
- There were smaller vessels in the meninges
79
What is the neurogenic inflammatory theory of migraine?
1) Unknown trigger
2) Causes intracranial blood vessels to constrict
3) constriction detected by ophthalmic division of trigeminal nerve.
4) Trigeminal ganglion releases vasodilatory cytokines such as CGRP and NO
5) Vasodilation causes plasma protein leakage
6) This causes inflammation which lead to neurogenic inflammation and peripheral sensitisation
Mast cell degranulation and the secretion of serotonin, bradykinin, histamine and prostaglandin also plays big role.
80
5HT1 receptors
- are they inhibitory?
- do they cause vasoconstriction or dilation?
inhibitory
Gi protein coupled
isoforms:a,b,c,d and e
Cause vasoconstriction
81
5HT2 receptors
- are they inhibitory?
- do they cause vasoconstriction or dilation?
Excitatory
Gs coupled
isoforms a,b,c
Causes indirect vasodilation
82
What evidence may suggest that serotonin plays a role in migraine?
There is a sharp increase in the urinary excretion of the main 5-HT metabolite, 5-HIAA, during the attack. The blood concentration of 5-HT falls, probably because of depletion of platelet 5-HT.
2 Many of the drugs that are effective in treating migraine are 5-HT receptor agonists or antagonists. See Fig. 16.3 and the clinical box below for further information
83
How does serotonin play a role in migraine?
5HT2 receptors on meningeal blood vessels might contribute to vasodilation of intracranial and meningeal blood vessels.
This causes further neurogenic inflammation and further dilation
84
Why is NSAIDs used to treat acute migraine?
NSAIDs inhibit prostaglandin synthesis and decrease inflammation by inhibiting COX2.
The logic is that prostaglandin is a vasodilator
85
Why are Ergotamines used to treat migraines?
Stimulates vasoconstriction.
| It does so by agonising 5HT1D which is an agonist
86
Triptan function in reducing migraine
1) They inhibit the release of neuropeptides like CGRP, and NO from trigeminal ganglia
2) They inhibit trigeminal ganglia activation by acting on 5HT1
They also inhibit trigeminal nucleus caudalis activation
They inhibit trigeminal transmission
87
What are some important considerations with using triptans?
5HT1B is found on coronary arteries.
This can be devastating if the guy has cardiovascular disease due to vasoconstrictor properties
88
What is the definition of drug addiction
A state where drug use continues in spite of serious potential or actual harm to the user and others
89
What is the reward centre of the brain?
VTA- the ventral tegmental area and the nucleus accumbens are important parts of the brain.
90
tolerance
you need more drug to achieve the same effect
91
withdrawal
You start feeling bad when the drug wears off
92
craving definition
You start wanting the drug all the time
93
Prefrontal cortex and anterior cingulate cortex
Cognitive control
94
Nucleus accumbens and VP
Reward prediction and pleasure
95
Orbitofrontal cortex
motivation drive and salience attribution
96
HIP and amygdala
learning and memory
97
What are 2 characteristics of a highly addictive opioid
1) quick entry to the brain
| 2) efficacious agonist
98
How does heroin stimulate the reward pathway?
Disinhibition
| Basically, it acts on the GABA neurons and this prevents GABA from being released to inhibit the release of dopamine
99
Why does Opioid cause nausea, respiratory depression, etc
Because it affects the medullary mu opioid receptors
100
Explain how neuroadaptations causes withdrawal effects in opioids
For an opioid like morphine, some adaptations include increased amounts of adenylyl cyclase and decreased amounts of phosphodiesterase. These effects do not go away even after removing the opioid, meaning that the person now suffers from the symptoms of increased amounts of adenylyl cyclase and decreased amounts of phosphodiesterase.
Phosphodiesterase degrade the second messenger molecules cAMP and cGMP, regulating the localisation, duration and amplitude of cyclic nucleotide signaling within subcellular domains.
adenylyl cyclase is an enzyme that makes cAMP.
cyclic AMP functions as a second messenger to relay extracellular signals
101
Drug for rapid detox of opioid
Clonidine, benzodiazepine.
They help reduce symptoms, but cause high relapse rate.
102
mu opioid agonist
mu agonist with long half life- time=22 hours
Users don't like it as much as heroin
It stops withdrawal
Can cause drug overdose
methadone
103
partial mu opioid agonist for addiction
Buprenorphine occupies the receptor and prevents full agonists like heroin producing effects.
The partial agonism should reduce craving
There is much less overdose risk compared with methadone
It can prevent withdrawal in all but the most addicted.
104
Mu antagonist for opioid addiction
methadone
Orally active antagonist
occupies receptor and prevents agonist binding
Need to detox before use
Poor compliance
105
In what kind of people is tobacco usage more popular
It tends to be higher use in 40-49 year old males, low SES , aboriginal/torres strait islander, remote communities, mental health issues
106
Tobacco/nicotine
nicotine increases the release of adrenaline from adrenal glands
- this causes increased blood pressure
- increased heart rate
- increased respiration
- increased blood glucose
107
How does nicotine stimulate the reward pathway
nicotinic receptors found directly on dopamine neurons, and can cause excitatory or inhibitory effects on the dopamine neurons
108
Why are cigarettes unhealthy
financial stress
| 4000 chemicals
109
Agonist therapy/nicotine replacement therapy
Eliminates smoke exposure
agonist at receptor reduces craving
110
Partial agonist for nicotine replacement therapy
Varenicline, cytisine
reduces craving, reduce smoking satisfaction
causes nausea and sleep issues
111
Name a antagonist for nicotine
Mecamylamine
- blocks nicotine reward but no effect on craving
- side effects cause significant drowsiness, dizziness and constipation
- some evidence may help reduce smoking when combined with NRT
112
What is the best approach for long term abstinence
widely used anti-depressant
causes modest reduction in craving
appears to have similar efficacy to NRT
lowers seizure thresholds and causes sedation
113
What are 3 strategies for long term abstinence of nicotine
1) use antidepressants like buproprion
Other antidepressants
Behavioral therapy.
114
What does alcohol do
Enhance GABAergic and Glycinergic synaptic transmission
- inhibition of calcium channels
- activation of potassium channels
- inhibition of glutamate receptor function
- inhibition of adenosine transport
115
How can we block alcohol reward/craving
The reward feeling is partially due to endogenous opioids
Naltrexone is an opioid receptor antagonist
So, either oral daily or extended injection monthly
116
What can we do to make alcohol unpleasant?
Disulfiram-very unpleasant flush, palpitations, nausea, daily dose but complaince poor
117
Topiramate effect on alcohol
•Topiramate- alter phosphorylation of Na+, Ca2+, GABA & glutamate receptor/channels.- Unclear mechanism in addiction- may increase GABA and reduce glutamate synaptic transmission- Significant reduction in drinking but variable results- Some evidence that people with polymorphisms in kainatereceptors have better treatment outcomes.
118
Acamprosate effect on alcohol
may act via inhibition of NMDA receptor (possibly alter plasticity)- may also act to change GABA or glutamate synaptic transmission-- Similar efficacy to naltrexone
119
phytocannabinoids
synthesised in plants
120
synthetic cannabinoid
synthesised in the lab
121
endocannabinoid
synthesised in humans
122
Street cannabis THC and CBD characteristics
Street cannabis has high THC and low CBD
123
Functions of endocannabinoid
Endocannabinoids comprise a homeostatic regulatory system and subserve normal physiological functions
They are synthesised on demand to maintain balance
They activate receptors in a lock and key fashion which regulate cell function in different organs of the body
Levels of endocannabinoids are tightly regulated by synthetic and catabolic enzymes
The optimal function of the endoCB system maintains health
124
Where does THC bind
It binds to CB1 cannabinoid receptors which are found in
1) cortex
2) hippocampus
3) striatum
4) ventral midbrain
5) cebrebellum
125
What does endocannabinoid signalling do?
It stimulates the activity of G proteins with Gi function
This causes cell hyperpolarisation and inhibition of adenylate cyclase
126
Fatty acid binding protein
1) transport 2 AG from the post synapse to pre synapse
2) transport AEA (anandamide) intracellularly to FAAH for degradation.
FAAH is fatty acid amide hydrolase
127
Anandamide
is a fatty acid neurotransmitter and endocannabinoid. It binds to same receptors that THC in cannabis acts on.
128
2 Arachidonoylglycerol (2AG)
is an endocannabinoid, endogenous agonist of CB1 and primary endogenous ligand.
129
DAGL
2 Arachidonoylglycerol enzyme
130
EndoCB function
sleep and circadian rhythm
131
Where are CB1 receptors found?
largely presynaptically
132
What are endocannabinoids made from
lipids
133
EndoCB: retrograde messengers
travels backwards from post-synaptic to presynaptic
with things like epilepsy, lots of release of glutamate
if you have excessive activation of mGluR to release 2 AG which inhibits GI protein, and inhibits calcium entry to stop glutamate from releasing.
134
homeostatic functions of EndoCB system?
```
Sleep and circadian rhythms
analgesia
positive mood
energy balance
stress coping
```
135
FAAH
degrades anandamide
136
What happens with Jo cameron and her faah mutation
feels no pain
no worry or stress
increased blood anandamide detected
