Lecture 8 Flashcards
what are the 4 neurotrophins?
- NGF
- Brain derived neurotrophic factor (BDNF)
- N 4/5
- N 3
- These neurotrophins bind to one of 3 receptors (Trk A B or C)
how does NGF work? (increasing pain)
- In periphery: causes peripheral sensitization
- In Dorsal root ganglion: can increase substance P, CGRP, Na channels, bradykinin receptors
- In CNS: cause central sensitization
explain the biology of inflammation (simpler terms)
- inflammation is body’s response to wound
- Wounds cause bacteria to enter body
- Inflammation is how our immune system recognizes where to act
when immune system is activated, what does it bring in?
brings in macrophages, mast cells, platelets
why do histamine, serotonin, prostaglandin, ATP, etc hurt when they’re injected?
hurts when injected because they activate nociceptors
what are algogens?
- things that activate nociceptors
- Algogens released during inflammation are known as “inflammatory soup”
what are the important ions channels in the inflammatory soup?
- TTX - resistant sodium channels
- TRPV1
These ion channels cause neuron firing
what can change the number of receptors?
gene regulation
The firing of a nociceptor is dependent on:
amount of excitatory/inhibitory receptors
function of aspirin
Aspirin interferes with algogens of inflammatory soup
- works entirely in the periphery
how was aspirin discovered?
Aspirin arose from discovery that willow tree bark helps w pain
** willow bark tree is hard on stomach
difference between aspirin (ASA) and salicylic acid
ASA has same effects of salicylic acid but isn’t as hard on the stomach
what is COX?
COX: cyclooxygenase
- Turn arachidonic acid into PGH2
explain PGE2 and EP receptors
- PGE2 binds to a type of receptor called EPs
- EP receptors are found in brain, kidney, vascular smooth muscle cells, platelets, mast cells, nociceptors
how do NSAIDs work? (and what do they stop)
NSAIDs work by blocking production of PGE2 because NSAIDs are inhibitors of COX1 and COX2
- NSAIDs stop pain and inflammation but have many side effects and have ceiling effects
which inhibitors are more COX 1 / COX 2 specific?
COX1: naproxen, ibuprofen
COX2: rofecoxib, celecoxib
explain coxib controversy
- latest data suggest that coxibs may not actually reduce risk of serious GI events over standard NSAIDs
- Merck execs didn’t want to fund a study to test vioxx (associated with heart problems)
how does chemical transduction work?
conversion of energy in environment or molecule environment into neural firing
what are TRP channels?
TRP channels are expressed by sensory fibres (not all nociceptors, but they are all primary afferents)
- Sensory fibres express molecules and allow us to know what temperature our skin is
- Evolutionarily, we have TRP channels for temperature
* plants evolve ability to activate these TRP channels
which TRP channel is most activated with cold?
TRPA1
which TRP channel is most activated when skin temp reaches level of painfully hot?
TRPV1
what is capsaicin?
makes chili pepper hot
- topical cream (TRPV1 helps with pain)
what is resiniferatoxin?
lab drug
what is anandimide?
endogenous cannabis
what are protons?
acid
explain TRPV1 channels
discovered by David Julius
- TRPV1 channels can be opened up indirectly by many other things
decrease in pH is associated with:
inflammation
what side effects did TRPV1 antagonists produce?
feeling hot, nausea, headache, fatigue, hyperthermia (small fever, very important, mainly why it was dropped)
- didn’t work better than the NSAIDs
TRPV1 agonists cause pain, so why would we put them on our skin? (capsaicin cream)
- Desensitizes the TRPV1 ion channel
- Ion channel is closed and will stay closed until the
channel is recycled - Overuse of a channel can kill the channel until it’s
recycled - Stops TRPV1 channels for a few hours bc receptors cant be activated
what is piezo?
transducer of mechanical touch
what does pain need to propagate?
Need both transduction and propagation of action potential for it to make it to the spinal cord
blocking/enhancing which channels has analgesic effects?
Blocking Na channels and enhancing K channels has analgesic effects
local anesthetics prevent:
Na channels from opening (inhibit action potentials, therefore inhibiting somatosensation
explain xylocaine
- Really really works
- Nerve blocks are v effective temporarily
explain Inherited Disorders of the SCN9A (Nav1.7) Gene
Caused by mutations of SCN9A gene (gene that produces NAV1.7 type of sodium channel)
what is Hereditary sensory autonomic neuropathy
type 4?
feel no pain and have no other effects
* NAV1.7 doesn’t work
what is paroxysmal extreme pain disorder?
-pain and erythema
-rectum
-usually only in babies
-gain-of-function mutation
what is Primary Erythromelalgia?
-pain and erythema
-hands and feet
-gain-of-function mutation
- NAV1.7 works too much (more active than it should be)
* Causes pain for no reason
what’s unexplainable about Inherited Disorders of the SCN9A (Nav1.7) Gene?
Why would gain of function be localized? (Place on body and time period of onset/disappearance)
explain Gene Expression in the DRG Changes After Nerve Injury (+ what genes are expressed more/less)
- DRG is where cell bodies of nociceptors are
- After nerve injury, some genes will be expressed more or less in nociceptor cell bodies
- Genes that are expressed more: neuropeptide Y, galanin
- Genes that are expressed less: CGRP, substance P
what is the potential analgesic strategy for Gene Expression in the DRG Changes After Nerve Injury?
reduce levels of genes that were expressed more after injury, and/or increase levels of genes that were expressed less after injury
opioid receptors exist in:
periphery and in dorsal horn
THC binds to:
CB1
presynaptic and post synaptic AKA:
pre: primary afferent
post: dorsal horn neuron
what does pregablin do?
blocks voltage gated calcium channels, causing analgesia
* Nothing released if Ca channel is inhibited
Glutamate acts on 3 diff types of receptors:
- ampereceptors
- MGluRs
- NMDA
(NMDA involved in learning)
what is ketamine?
ketamine is NMDA receptor blocker (therefore ket is
analgesic)
in the Spinal Cord Neurochemistry of Pain, which activity is analgesic and pro-algesic?
analgesic: inhibitory (top)
pro-algesic: excitatory (bottom)
Gabapentin and pregabalin are:
anticonvulsants
Gabapentin (and pregabalin) blocks:
a subunit of Ca channel: alpha delta
- 2 subunits
* need subunit to make working calcium channels
why does pregabalin exist if gabapentin works just as well?
- pregabalin works at lower doses
- Patent on gabapentin ran out
what could be a target to develop a drug that could be an analgesic?
anything downstream of a glutamate receptor or opioid receptor
why is Thalamocortical Neurochemistry of Pain studied so little?
it’s a lot more complicated, we don’t know enough
opium is a component of:
the milk of opium poppy
difference between opium and opiates
- opioids: things in your body
- opiates: anything that is similar to opium in
structure and function (some compound you would ingest)
what are agonists?
substances that bind to and activate a receptor in the same way that an endogenous transmitter would
what are antagonists?
substances that can “fit in the lock but not turn the key”
what is potency?
how much drug in mg do you need to start getting effects (study graph in slides)
what is PVG (PAG)?
grey matter around ventricles in midbrain
- area where if electrode is placed and stimulated, most likely to cause stimulation-produced analgesia
- Sometimes reversed by naloxone
can get analgesia from either electrical stimulation or from morphine/other opioids in:
◦PAG
◦RVM
◦Directly into the spinal cord
why would there be descending system from
midbrain to spinal cord?
so that stress-induced analgesia can work
what are opioids acting on, and what are they endogenously activated by?
Opioid receptors
* mu
* Delta
* Kappa
explain the difference of rats in cold vs warm water
- Rats in warm water: produces naloxone-reversible stress induced analgesia
- Rats in cold water: produces naloxone-insensitive stress induced analgesia
explain the results of tail flick and exposure to cats
Eliciting tail response (stress response) with shock
* When exposed to a cat, almost triples amount of shocked required for rat to show stress response
explain the results of intruder vs resident rat test
- loser of rat fight becomes analgesic
- Intruder rat usually loses
- X axis - number of bites the intruder gets from the resident
- More bites/longer experiment goes on: tail flick delay of intruder goes up (analgesic)
- “Defeat stress”
Descending inhibition can become descending facilitation:
- if stress is mild
- if stress is chronic
- after injury
- after prolonged exposure to opioids
Opioid-Induced Hyperalgesia is _____ demonstrated in animals but _______ to show in humans
Easily; harder
T or F: after opioids, can become more sensitive to stimuli
true bishhh
does Morphine increase time amount to return to normal threshold?
yes
Opiates can bind to opioid receptors, but receptors are designed for _________________
endogenous ligand
all 3 subtypes of opioid receptors are:
G protein coupled receptors + inhibitory
Essentially all of the analgesic effects of analgesic drugs occur on:
mu receptors
- but acting on mu receptors also cause most side effects
kappa used to be used for:
labour pain
what are kappa agonist side effects?
dysphoria, pupil constriction, analgesia (spinal level), respiratory depression
what do opioid receptors in the intestines do?
cause constipation
difference between peptides and receptors
Peptides: short amino acid chains formed by gene expression
Receptors: proteins (many amino acids)
what is POMC?
POMC produces wide variety of important peptides (AlphaMSH)
what is peculiar about endomorphins?
no evidence these are being produced because cannot find gene associated with peptide
what is the RVM?
Rostroventral medulla
explain the off-cell vs on-cell
- off-cell: when analgesic, goin crazy (ex: stops when heat starts)
- on-cell: when analgesic, doesn’t fire (ex: starts when heats starts)
what is most efficacious complementary modality?
acupuncture
explain how Acupuncture analgesia is naloxone-reversible
- naloxone: opioid receptor antagonist
If something is naloxone reversible, implies that opioid receptors must have been involved - If opioid receptors are involved, what could be activating them? -> endogenous opioids
what is amitrimptyline?
- Lowest NNT for neuropathic pain
- Old school antidepressant
what is the problem with depression?
problem is imbalance of monoamine transmitters
(norepinephrine, serotonin, dopamine)
- Antidepressants are used to increase the levels of these transmitters
what are SNRIs?
selective norepinephrine reuptake inhibitor
◦Cymbalta
what is tramadol?
a combination opioid/SNRI
Antidepressants are thought to amplify:
the descending inhibitory effect of the descending inhibitory system
what is the end result of antidepressants?
To inhibit the second order spinothalamic neuron (projection neuron) from firing through release of norepinephrine (locus cerulius) or serotonin (RVM) in spinal cord
* antidepressants act as agonists so that more serotonin/norepinephrine is released or has longer action
what is CB1?
receptor that gets you high
why is the analgesic drug development graph inaccurate?
- patent ran out on Lyrica
- Oxy isn’t making as much due to lawsuit
explain the market share of certain types of drugs
- strong opioids: 29%
- NSAIDs: 28%
- anti-convulsants: 13%
- anti-depressants: 11%
- weak opioids: 7%
explain drug development process
PHASE 0: animal testing
- in vitro screening
- molecular biology studies
molecule discovery and characterization
PHASE 1: assess toxicity
- evaluate route of administration
- determine safe dosage
PHASE 2: evaluate effectiveness
- determine side effects
PHASE 3: validate effectiveness of treatment
FDA APPROVAL
___ % of drugs fail because they lack efficacy
46%
what is the file drawer problem?
when your study doesn’t work/failed, you’re less likely to publish it
what is the receptor for substance p?
NK1
explain the failure of NK1 antagonists
- all trials failed except one
- problem may be with the trials themselves
explain cone snails venom
- venom is very deadly
- it’s an omega conotoxin - blocks calcium channels (works like gabapentin)
- without calcium channels, you don’t get vesicle migration
- got improved as analgesic (beat placebo by 7%)
- BUT, Elan (the company) lost money bc you can only give it through an intrathecal pump
explain tanezumab
- it’s an antibody that blocks nerve growth factor
- had a huge effect (beat placebo by a lot)
- some patients arthritis got worse
- FDA put a stop on the trials
- some thought it alleviated OA pain so well people over used their joints (dancing in the streets hypothesis)
- REAL problem was when tanezumab was combined with NSAIDs (interaction)
- without NSAIDs it doesn’t beat placebo as much (10 points as usual)
- due to worry about side effects and reputation, drug wasn’t approved
how do you know that something is a monoclonal antibody?
when it ends with mab
what are prophylactic drugs?
prevent the thing from happening
what is glutamate?
major excitatory NT
what is NMDA?
- involved in learning
- affected very much by depolarization
- ketamine blocks it
what happens if you block voltage-gated calcium channels?
glutamate or substance p aren’t released
(action potential already happened)
name strong, moderate, and weak opioid agonists
strong: morphine
moderate: codeine
weak: tramadol
explain what drugs bind in the spinal neurochemistry
- Substance p —> NK1
- Glutamate —> AMPA, mGluR, NMDA
- Ketamine —> NMDA (blocks)
- THC –> CB1
what are mu receptor agonist effects?
- analgesia
- respiratory depression
- nausea
- miosis
- euphoria
- reduced gastrointestinal motility
what is naloxone?
opioid antagonist
explain where different NTs (serotonin and norepinephrine) in anti-depressants work in the body
serotonin: RVM
norepinephrine: locus cerulius
