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PHAR324 > Cannabis 1 > Flashcards

Cannabis 1 Flashcards

1
Q

What are the 3 families of cannabinoids?

A

endocannabinoids
phytocannabinoids
synthetic cannabinoids

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2
Q

What are examples of endocannabinoids?

A

anandamide (AEA)
2-arachidonyl glycerol (2-AG)

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3
Q

What are examples of phytocannabinoids?

A

cannabidiol (CBD)
tetrahydrocannabinol (THC)

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4
Q

What are examples of synthetic cannabinoids?

A

WIN
CP

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5
Q

How were cannabinoids originally described in the 1970s?

A

as “false steroids”
-the theory was they mimicked the effect of steroids in the body

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6
Q

What was the theory regarding cannabinoids in the 1980s?

A

cannabinoids modulate membrane fluidity
-thought that they mimic cholesterol

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7
Q

Why are cannabinoid actions receptor dependent?

A

because:
-modulate intracellular signal cascades
-temperature dependent
-saturable

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8
Q

What was discovered regarding cannabinoids in 1993?

A

CB2 receptors present on immune cells

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9
Q

What are the components of the endocannabinoid system?

A

receptors
-ex: CB1, CB2, GPR, TRPV1, PPAR
enzymes
-ex: DAGL, FAAH, MAGL, NAPE-PLD, ABDH, COX
signaling molecules
-ex: 2-AG, AEA

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10
Q

Describe the CB1 receptor.

A

Gi/o-coupled G-protein-coupled receptor
most abundant GPCR in the CNS

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11
Q

How is the CB1 receptor activated?

A

2-AG and AEA
THC (the high)
spice/K-2 compounds

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12
Q

How is the CB1 receptor inhibited?

A

rimonabant
CBD (indirectly)

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13
Q

Describe the CB2 receptor.

A

Gi/o-coupled G protein-coupled receptor
expressed and induced at immunomodulatory cells

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14
Q

How is the CB2 receptor activated?

A

2-AG and AEA
THC
CBD

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15
Q

How is the CB2 receptor inhibited?

A

SR144528

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16
Q

What is an orphan receptor?

A

a receptor for which we do not know the endogenous ligand

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17
Q

What are the the 3 orphan GPCRs that respond to exogenous cannabinoids?

A

GPR55
-expressed predominantly in immune cells and osteoclasts/blasts
-activated by THC
GPR18
-expressed in microglia
-activated by THC and CBD
GPR119
-expressed in pancreas and gut
-activated by derivates of 2-AG and AEA

18
Q

Describe TRPV1.

A

ligand-gated Ca2+ channel expressed on central and peripheral neurons
activated by AEA and capsaicin

19
Q

How is AEA synthesized and broken down?

A

synthesized by NAPE-PLD
broken down by FAAH
secondary break down by COX-1/2

20
Q

How is 2-AG synthesized and broken down?

A

synthesized by DAGL
broken down by MAGL
secondary break down by COX-1/2 and ABHD-6/12

21
Q

What is the best studied endocannabinoid system polymorphism?

A

FAAH
-most ECS genes show polymorphisms that may be clinically relevant

22
Q

What occurs with FAAH polymorphisms?

A

C/A or A/A genotype show less anxiety, greater propensity to SUD and obesity, and heightened pain perception

23
Q

What occurs with CB1 levels in the brain with aging?

A

areas of the brain where CB1 is most abundant changes with aging

24
Q

What are the physiological roles of endocannabinoids?

A

memory
voluntary movement
stress & anxiety
nociception
thermoregulation
appetite
metabolism
immune function
reproduction

25
Q

Describe memory as a physiological role of endocannabinoids.

A

activation of CB1 impairs long-term potentiation in the hippocampus & reduces short-term memory
CB1 activates neurogenesis in the dentate gyrus and subgranular zone
cannabinoids can facilitate short-term depression via CB1 vs long-term depression via TRPV1

26
Q

Describe stress & anxiety as a physiological role of endocannabinoids.

A

activation of CB1R habituates the HPA-axis
-AEA decreases corticosterone secretion
-2-AG inhibits excessive glucocorticoid release
activation of CB1R in the amygdala is anxiolytic
-in GABAergic neurons this improves socialization, NORT, and exploration (mice)
-in glutamatergic neurons this reduces aggression and excessive arousal
-2-AG and AEA levels are also circadian, peaking during slow-wave sleep

27
Q

Describe nociception as a physiological role of endocannabinoids.

A

CB1R activation inhibits GABAergic interneuron transmission, which disinhibits descending, pain-attenuating pathways from the brainstem
TRPV1, GPR55, and PPRA are also involved
1 possible mechanism for acetaminophen is inhibition of AEA catabolism

28
Q

Describe thermoregulation as a physiological role of endocannabinoids.

A

in humans and non-human primates TRPV1 regulates temperature through hypothalamic and vasodilatory mechanisms
in other mammals CB1R also contributes to thermoregulation with CB1R activation –> hypothermia

29
Q

Describe appetite as a physiological role of endocannabinoids.

A

acute activation of CB1R stimulates appetite
chronic stimulation of CB1R reduces appetite
inhibition of CB1R reduces food intake and weight
the effect of CB1R inhibition on food intake has implications for addiction as well

30
Q

Describe metabolism as a physiological role of endocannabinoids.

A

cannabinoids act on their receptors through a paracrine or autocrine mechanism in:
-adipocytes: activation of CB1R increases lipogenesis
-hepatocytes: activation of CB1R increases fatty acid oxidation, VLDL-TG clearance, de novo lipogenesis, chronic activation of CB2R stimulates fibrosis
-GIT: activation of CB1R decreases GI motility and permeability
-skeletal muscle: TRPV1, PPAR, and CB1R activations increases insulin sensitivity
-pancreas: CB1R activation stimulates insulin release
-hypothalamus: CB1R activation stimulates leptin release, decreases adiponectin release

31
Q

Describe immune function as a physiological role of endocannabinoids.

A

CB1R < CB2R limits TNFa and pro-inflammatory cytokines
-CB2R upregulated in response to inflammation
-esp in macrophages & mast cells
utility in MS
-CB2R activation increases oligodendrocyte survival & growth, microglial proliferation, and Schwaan cell survival and growth

32
Q

Describe reproduction as a physiological role of endocannabinoids.

A

in females:
-CB1R lvls rise and fall alongside progesterone, which may help to initiate menses
-CB1R expressed on sensory and sympathetic fibres throughout the uterus
in males:
-CB1R expressed at high lvls on spermatocytes and sperm
-cannabinoids inhibit sperm maturation, motility, acrosome reaction, and mitochondrial function
in both sexes:
-exogenous cannabinoids are sex hormone mimetics that inhibit the activity of testosterone and augment the activity of estrogen

33
Q

What is the key structural piece found in all endocannabinoids?

A

arachidonic acid
also all are lipids

34
Q

How do you get high?

A

through THC which is a CB1R and CB2R partial agonist

35
Q

What is the mechanism of action of cannabidiol?

A

multiple mechanisms of action:
-CBR1 modulator
-CB2R partial agonist
-5HT1A partial agonist

36
Q

What is the entourage effect?

A

the idea that cannabis as a plant is superior to THC or CBD on their own
-theres other constituents along for the ride and we dont know how they impact eachother

37
Q

Why are synthetic cannabinoids very potent?

A

they are full agonists
-very efficacious at activating CB1 in particular

38
Q

What is ligand bias?

A

when a ligand prefers one pathway over another
-in theory receptor signaling can be directed toward a preferred pathway and away from an unwanted pathway

39
Q

What is the most common example of allosteric modulation?

A

benzos

40
Q

What is allosteric modulation?

A

binding to specific sites on receptors to either increase or decrease signalling

PHAR324 (7 decks)

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