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Pharmacology II > Ion Channels and Pain > Flashcards

Ion Channels and Pain Flashcards

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1
Q

5 receptor types

A 
Lipid-soluble ligand
Enzymatic reaction
Tyrosine Kinase activation
Ion channel activation
G protein-coupled receptor
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2
Q

Ion channels provide a _____ route for ions through _____ _____ membranes

A

Permeable

Hydrophobic lipid

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3
Q

Ion channels consist of ____ folded into ________

A

amino acids

complex structures

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4
Q

Ion channels are made from 3-6 similar ______ or ______

A

proteins

structural subunits

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5
Q

Can ion channels be selective to specific ions? non-selective?

A

Yes

Yes

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6
Q

Definition of gating

A

open and close in response to specific chemical, electrical or mechanical signals

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7
Q

Ion channels conduct ions across _____________

A

plasma membrane

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8
Q

Ion channels regulate ________ ________ of cells

A

membrane potential

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9
Q

5 types on ion channels

A 
Resting K+ channel
Voltage-gated channel
Ligand-gated channel
Signal-gated channel
Mechanically-gated channel
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10
Q

Ions that cross through voltage-gated channels?

A

Na+, K+, Ca2+, Cl-

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11
Q

How many transmembrane segments are in the voltage-gated ion channels?

A

6

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12
Q

Voltage-gated ion channels open in response to changes in what?

A

membrane potential

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13
Q

2 domains in voltage-gated ion channels?

A 
Voltage sensor domain (S1-4)
Pore Domain (S5-6)
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14
Q

3 major superfamilies on Ligand-Gated Ion channels?

A

Cys-Loop Receptors
Ionotropic Glutamate Receptors
P2X Receptors

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15
Q

Ligand-Gated Ion Channels : transmembrane domains are important for? (2)

A

pore formation

ion selectivity

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16
Q

Ligand-Gated Ion Channels : what is important for ligand binding? (determines which ligand can bind to it)

A

extracellular domains

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17
Q

Extracellular domain of Cys-Loop receptors?

A

Disulfide bridges of cysteine residues

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18
Q

Extracellular domain of Ionotropic Glutamate receptors?

A

Ligand binding domain (segment and 2)

N-terminal domain

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19
Q

Two ways a cell can sense a mechanical stimuli?

A

Direct gating by physical opening of channel

Indirect by activation of GPCR then opening of TRP channels

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20
Q

What happens in regard to action potential when activating a ligand-gated ion channel?

A

Opening, Na+ influx, nerve depolarisation

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21
Q

Effect of a mild mechanical stimulation

A

Opening of only a few ion channels, but firing isn’t highly activated, relatively few action potentials

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22
Q

Effect of noxious mechanical stimulation

A

Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves

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23
Q

Effect of noxious mechanical stimulation

A

Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves

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24
Q

Resting membrane potential value?

A

-70mV

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25
Which complex helps the transport of cations and anions to normalize the membrane potential?
Na+/K+ exchange pump
26
Concentration gradients of Na+ and K+ in extracellular and intracellular?
Extracellular: K + 4.5 mM Na+ 145 mM Intracellular K+ 120 mM Na+ 15 mM
27
What causes sodium to enter channel? what happens to action potential?
stimulus | depolarization (spike in voltage)
28
When sodium leave the cell and ion channel closes, what happens to action potential? What does this do to ADP-ATP?
repolarization | Exchange ATP for ADP
29
Example of Cys-Loop Channel?
Nicotinic Ach Receptor
30
Nicotinic Ach Receptor : subunits?
two alpha one beta one gamma one delta
31
Nicotinic Ach Receptor requires how many Ach molecules for activation? Which ion influxes once the pore opens
2 | Na+
32
Nicotinic Ach Receptor functions? (4)
1. Skeletal muscle contraction 2. Smooth muscle relaxation 3. Inhibits cardiac muscle contraction 4. Nerve depolarization
33
What dictates the location and pharmacology of Nicotinic Ach Receptors?
Subunit composition
34
What causes depolarizing blockade? (Nicotinic Ach Receptor)
Excess Ach and Nicotinic Receptor Agonists
35
Depolarizing blockade : what are the effects of continuous activation of nicotinic receptors?
Muscle excitation and fasiculations in myocytes and then flaccid paralysis
36
Depolarizing blockade : what are the effects of prolonged agonist bound nAchRs?
neuron desensitization
37
Depolarizing blockade : what are the effects of continuously depolarized membrane?
Affects inactivation of voltage-gated sodium channels (nerve less likely to fire)
38
nAch Receptors located where?
DRG | Dorsal horn of spinal cord
39
Ach sensitizes about 50% of ___ fibres for heat but not ________ pain
C | mechanical
40
Analgesics for nAch Receptors and Pain? (4) | They inhibit what? (2)
Botulinum toxin, alpha-7 blockers, epibatidine, nicotine Inhibits inflammatory neuropeptide and cytokine release
41
GABAARs Cys-Loop Receptor : what type of receptor? allows passage of what ion?
Inhibitory (hyperpolarization) | Cl-
42
Composition of GABAAR?
Heteropentameter with variable subunits
43
GABAARs activated by what?
GABA
44
GABAARs are found where?
Dorsal horn of spinal cord
45
Roles of GABAAR? (2)
Inhibits pain transmission by hyperpolarizing second order neurons Inhibits substance P release form primary afferent neurons
46
Which drugs potentiate GABA-mediated synaptic inhibition? (2)
Benzodiazepines | Barbiturates
47
GABA binds where on GABAAR?
alpha-beta interface
48
Benzodiazepines binds where on GABAAR?
alpha-gamma subunit interface (allosteric binding site)
49
Barbiturates interacts with what on GABAAR?
Pockets in the transmembrane domain
50
Acute pain?
warning system for harmful stimuli
51
chronic pain lasts more than _____ months and it is __________
3 | maladaptive
52
the Nervous system can change in response to pain because it is _______
plastic
53
4 steps to the pain pathway
1. Nociception 2. Neurotransmission 3. Sensation, Cognition, Emotion 4. Neuromodulation
54
5 types on fibres in the sensory nerves Which one is unmyelinated? Biggest to smallest diameter? Biggest to smallest conduction velocity?
``` A-alpha A-beta A-gamma A-delta C - unmyelinated ``` From top to bottom : - biggest to smallest diameter - fastest to slowest conduction velocity
55
Function of A-alpha fibre
proprioception
56
Function of A-beta fibre
mechanosensation
57
Function of A-gamma fibre
Motor fibre to muscle spindle
58
Function of A-delta fibre
mechanosensation nociception
59
Function of C fibre
temperature nociception
60
3 types of pain
Nociceptive Inflammatory Neuropathic
61
5 factors that activate nociceptors
``` Mechanical Heat Cold Pathogens Chemical ```
62
What activates TPRV1 and what does this lead to?
Capsaicin Mustard Oil Formalin H+ Opens channel, Na+ an Ca2+ enter free nerve ending, depolarisation
63
What causes neuropathic pain in the periphery? (4)
Trauma Metabolic Infection Chemo induced neuropathy
64
What causes neuropathic pain centrally?
Spinal cord injury Stroke Multiple sclerosis
65
3 classes on analgesics
Non-opioid analgesics Opioid analgesics Adjunct analgesics
66
3 types of adjunct analgesics
Anti-convulsants Anti-depressants Biologics
67
3 types of anti-depressants
TCAs SSRIs SNRIs
68
TCAs are highly effective for _____ neuropathic pain
chronic
69
Example of a TCA and what is their MOA?
Amitriptyline Blocks neuronal uptake of NA and 5-HT in spinal cord, increases descending inhibition Also blocks NMDA receptors, Na, K, Ca channels
70
What is the major effect of Amitriptyline (TCA)?
Analgesic effect is independent of mood change
71
Examples of SNRIs? (2)
Duloxetine | Venlafaxine
72
Examples of SSRIs?
Fluoxetine | Fluvoxamine
73
SSRIs have fewer side effects because of ___________
high selectivity
74
SSRIs have low efficacy for __________ neuropathic pain
diabetic
75
SNRIs have fewer side-effects than TCAs because they __________________
do not block NMDA receptors
76
More efficient : TCA, SSRIs of SNRIs?
TCA > SNRI > SSRI
77
More side effects : TCA, SSRIs, or SNRIs>
TCA > SNRI > SSRI
78
anti-convulsants are used for ______ and they interfere with _______
epilepsy | neuronal excitability
79
2 examples of anticonvulsants? Effective for which diseases? (3) Side effects? (4)
gabapentin pregabalin Postherpetic neuralgia, diabetic neuralgia, fibromyalgia Side-effects : drowsiness, dry mouth, weight gain, dizziness
80
MOA of gabapentinoids? What does it inhibit? It also modulates what?
MOA : binds to alpha-2-delta subunit of Ca2+ channel - Inhibits release excitatory NTs - Also modulates Na, K activity : altered neuronal excitability
81
Gabapentin is given ___
locally
82
Gabapentin reduced _____ in normal AND inflamed joints
mechanosensitivity
83
In inflamed joints, gabapentin doesn't seem to reduce __________
neuronal activity
84
is gabapentin ideal for inflammatory pain?
No
85
Inflammation may alter gabapentin binding to what?
alpha-2-delta subunit of Ca2+ channel
86
Na+, K+ and Ca2+ are involved in nerve ________ and _______. | Also in electrical _________ along ______
depolarization communication transmission axons
87
Voltage-dependent conformational change in ion channels results in what?
open state
88
Voltage-gated Sodium Channels (VGSC) : Classification of VGSC? Derived from what?
Tetrodotoxin (TTX) | Derived from puffer fish
89
TTX sensitive channels are found where? (2)
Muscle, CNS
90
TTX resistant channels are found where?
Some sensory neurones
91
Types of VGSC? (9)
Nav1.1-Nav.9
92
Which VGSC isoforms are involved in nociception?
Nav1.7, Nav1.8 and Nav1.9
93
Which Nav isoforms are predominantly in the CNS?
Nav1.1, Nav1.2 and Nav1.3
94
Where is Nav1.4 found? What is their role?
skeletal muscle | skeletal muscle contractility
95
Where is Nav1.5 found? What is their role?
Heart | Cardiac function
96
Where is Nav1.6 found?
Mainly in large diameter neurons, motor neurons, also in CNS
97
Where are Nav1.7, Nav1.8 and Nav1.9 found?
PNS
98
Which Nav isoforms have a slow inactivation rate?
Nav1.8 and Nav1.9
99
Which Nav isoforms have a low TTX sensitivity?
Nav1.8 and Nav1.9
100
Which Nav isoform has an intermediate TTX sensitivity?
Nav1.5
101
Which Nav isoforms are brain type sodium channels and unlikely to be involved in pain?
Nav1.1, Nav1.2, Nav1.3, Nav1.6
102
Role of Nav1.7?
Peripheral sodium channel subtype. Excellent target for pain control
103
Role of Nav1.8? (3)
- Action potential electrogenesis - Redistribution along intact axons after nerve injury may promote sensory hypersensitivity - Excellent target for pain control
104
Role of Nav1.9?
May modulate resting potential of DRG and response to subthreshold stimuli.
105
Nav1.7 gain of function disease?
Mutation in SCN9A gene Familial erythromelalgia Burning, intense pain
106
Nav1.7 loss of function disease?`
Loss of function of SCN9A gene Congenital insensitivity to pain Self harm, unknown injuries
107
What is a local anaesthetic that acts on sodium channels? Does is activate or inactivate Na channel? Where does it bind? Is it selective?
Lidocaine Inactivation Intracellular pore Not selective
108
What is an antidepressant that acts on sodium channels? Inactivate or activate Na channel? Where does it bind? Is it non selective for ______ subtypes so it can affect _____ and _____ activity
- Amitriptyline - Interacts with local anaesthetic binding site and binds to inactivated channel, keeps them in inactive state - Na+ channel subtypes - Cardiac and skeletal muscle
109
What is an anticonvulsant that acts on sodium channels? It inhibits which Na+ channels? (2) Non-selective for _____ subtypes so can affect _____ and ______ activity
Carbamazepine Binds to inactive channel, keeping them in inactive state -Inhibits TTX-resistant and TTX-sensitive Na+ channels -Na+ channel subtypes -Cardiac and skeletal muscle activity
110
When testing NON-SELECTIVE VGSC blockers, do we get negative or positive side-effects?
Negative | Ex: cardiac arrhythmias
111
When testing Nav1.8 blocker on joint pain, does it increase or decrease pain?
decrease
112
Where do Nav1.8 blockers act?
in periphery
113
Cav1.1 - Cav1.4 | Tell me their current, inactivation and tissue localization
Cav1.1 : L, Fast, skeletal muscle Cav1.2 : L, Fast, Cardiac Myocytes and Neurons Cav1.3 : L, Fast, Cardiac Myocytes and Neurons Cav1.4 : L, Fast, Retinal Cells
114
Role of Cav1.1
Excitation contraction coupling
115
Role of Cav1.2
Excitation-contraction coupling | Synaptic integration
116
Role of Cav1.3
Cardiac pacemaker | NT release
117
Role of Cav1.4
NT release from photoreceptors
118
Cav2.1-2.3 | Tell me their current, inactivation and tissue localization
Cav2.1 : P/Q, Slow, Neurons Cav2.2 : N, Slow, Neurons Cav2.3 : R, Slow Neurons
119
Role of Cav2.1
NT release
120
Role of Cav2.2
NT release
121
Role of Cav2.3
Nerve firing
122
Cav3.1-3.3 | Tell me their current, inactivation and tissue localization
Cav3.1 : T, Fast, Neurons and Cardiac Myocytes Cav3.2 : T, Fast, Neurons and Smooth muscle Cav3.3 : T, Fast, Neurons
123
Role of Cav3.1
Repetitive Nerve firing | Cardiac pacemaker
124
Role of Cav3.2
Repetitive Nerve firing | Contractile response
125
Role of Cav3.3
Repetitive Nerve firing
126
Name 2 L-Type drugs that act of calcium channels | What do they do?
Nifedipine Verapamil Decrease substance P release and pain
127
Name 2 N-type drugs that act on calcium channels, what do they do?
conotoxin : decreases substance P release and pain | Knockout animals : decreases inflammatory and neuropathic pain
128
Name a P/Q type drug that acts of calcium channels | What does it do?
agatoxin : decreases substance P release and migraine
129
Name a R type drug that acts of calcium channels | What does it do?
SNX-482 | Decreases substance P release
130
Name a T type drug that acts of calcium channels | What does it do?
Mibefradil | decreases pain
131
How is a voltage gated calcium channel classified? | How is it subclassified?
Classified based on type of voltage required to activate them Subclassified based on alpha-1 pore forming subunit structure and pharmacological properties

Pharmacology II (21 decks)

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