Lecture 6: Pain neurochemistry and pharmacology Flashcards
What other species than human has been found to use analgesics?
Orangutans have discovered analgesic as well
How do humans discover medicinal plants?
We do trials with random plants
How would we ideally want to discover analgesics?
-neurochemistry–>pharmacololgy–>drug development
Why are drug mostly developed in pharmaceutical companies?
The limiting step in drug development is medicinal chemistry, and medicinal chemists are very rare and exist only in pharmaceutical companies.
Where is neurochemistry happening that we should be concerned with?
- nociceptor development and maintenance
- peripheral algogens
- transduction
- propagation
- spinal cord presynaptic release
- spinal cord postsynaptic processing
- supraspinal processing
- descending modulation
what are peripheral alogens?
-compounds in the periphery that cause pain
What do you have to play on in neurochemistry to either block or enhance neurotransmitters ?
- neurotransmitter synthesis
- neurotransmitter release
- neurotransmitter degradation
- neurotransmitter reuptake
- receptors
- signal transduction molecules
- ion channels
- transcription factors
- epigenetic processing
What features of “drug targets” are drug companies most interested in?
- “target”: protein that you want to block or enhance
- some proteins are easier to develop drugs for. ex: g-protein coupled receptors.
- ion channels are harder, transcription factors are almost impossible
What is a Nerve growth factor (NGF)?
-One of many neurotrophins
What are neurotrophins?
-Family of proteins that induce the survival, development, and function of neurons
What are the different stages of inflammation?
- rubor, calor: redness, heat
- tumor: swelling
- dolor: pain
- loss of function
What can we say is the main cause of pain aside from nerve damage?
inflammation
Why do we say that inflammation is the root of all evil?
- It is the root of many pain syndromes and diseases
- Even if you can’t see it, it doesn’t mean that it isn’t there.
How can bacteria and other pathogens enter the body?
- wound: broken skin. Skin is meant to prevent bacteria from coming in
- intestines
During the inflammation process, what happens after the bacteria has entered the body?
Platelets from blood release blood-clotting proteins at wound site.
What do mast cells do during the inflammation process?
- secrete factors that mediate vasodilation and vascular constriction.
- delivery of blood, plasma, and cells to injured are increases.
What do neutrophils do during the inflammation process?
-secrete factors that kill and degrade pathogens
What do neutrophils and macrophages do during the inflammation process?
-remove pathogens by phagocytosis
What do macrophages do during the inflammation process? cytokines
-secrete hormones called cytokines that attract immune system cells to the site and activate cells involved in tissue repair.
Does the innate immune system require any prior exposure to start working?
-No, it gets right to work.
What works the best to treat inflammation?
- steroids
- classic one: dexamethasone, can be given orally or injected through the dura (epidural steroid injection)
- very effective
- but side effects
What are the main side effects of steroids?
blurred vision, weight gain, depression, bloody stool, pancreatitis, low potassium, high blood pressure.
What is the other way we an treat inflammation beside steroids?
-NSAIDs: Non-Steroidal Anti-inflammatory drugs
What do broken cells release and they are broke?
- algogens
- substance that causes pain
- Ex: H+, adenosine, ATP
- These bind to receptors for them in the free nerve endings
What does NGF bind to on nociceptors?
Track A.
What are the adequate stimulus for pain?
- noxious heat/cold
- mechanical. that damages cells but also doesn’t.
Why does inflammation cause pain?
- cells migrate to area of wound to kill pathogens
- release chemicals (nTs) to inform brain that smt is happening
- pain is signal that gets you to notice the wound
What does substance P do?
-causes neurogenic inflammation
What is an example of inhibitory system on the membrane of the free nerve ending?
endorphins, which act on mu receptors
Which well-known analgesic works entirely on a biological process of the “inflammatory soup”?
Ibuprofen which acts on PGE2.
what does aspirin come from?
- boiled willow bark
- known since before the common era
- mentioned in 80AD
- probably older
What was aspirin turned into later on?
- salicylic acid
- no longer the most common
What do COX1 and COX2 enzymes do ?
- They both turn arachidonic acid into PH2, prostaglandin H2.
- Then it is turned into other prostaglandines
- They are nt that act on receptors: 4 kinds, IP, TP, EP or FP.
What prostaglandin receptors are we concerned with in this course?
- EPs because they are on nociceptors.
- These are the ones that NSAIDS are trying to act on.
How do NSAIDs act on enzymes to relieve pain?
-Block COX1 and COX2 which in turn blocks cPGES, mPGES and PGE2
How efficace are NSAIDs for postoperative dental pain?
Half your pain
What is the issue with the efficacy of NSAIDs?
They have a ceiling effect, they can only kill so much pain.
What are the potential side effects of NSAIDs?
- Almost no one gets side effects from using a single dose of NSAIDS.
- If you use them everyday, you can get gastritis (inflammation of the gastric lining and dyspepsia (gastric reflux)
Can side effects of NSAIDs be lethal?
Yes (example overdose, don’t forget they are still drugs)
What is the specificity of each COX1 and COX2?
- COX1: constitutively expressed enzyme, always there, housekeeping function, plays roles in stomach intestine and kidney.
- COX2: inducible enzyme, only produced when needed, only in the case of inflammation.
what are examples of NSAID that have been created that only block COX2?
- Rofecoxib, Celecoxib
- Would produce the same analgesia as Ibuprofen but without the gastric side effects.
What was the reason of the Coxib Controversy?
- Increases the risk heart attack or stroke (called APTC event)
- The only coxib left on the market is celecoxib.
- Can’t put drugs on the market that increase the risk of death
What is the difference between acetaminophen (paracetamol) and NSAIDs?
- paracetamol is not an NSAID because it is not anti-inflammatory
- it is also an antipyretic (reduces fever)
How do we think paracetamol works?
- Not sure
- Doesn’t act on COX1 and COX2
- Probably acts on CB1 cannabinoid receptors in the rostral ventromedial medulla
What is sensory transduction?
How physical energies and molecules in the world impact us and are turned into a neural code.
What types of sensory transduction would he have to understand to understand pain?
Sensory transduction of the following stimuli:
- heat
- cold
- touch
- cell lysis
- chemical (acid, base, irritants)
What will activate the TRPA1 channel?
-something colder than 10degrees
How does your brain know what temperature a stimuli is?
By knowing what TRP channel was activated
How is the TRPM8 channel activated?
-cool stimuli between 10 and 20
How is the TRPV1 channel activated?
- heat stimulus higher than 43 degrees: ex capsaicin which is contained in chili peppers.
- noxious heat threshold
- TRPV2 activated at even higher stimuli
what is anandamine?
endogenous cannabinoid nt
What can activate the TRPV1 channel?
- chemical: capsaicin, anandamide
- heat: 42/43 degrees threshold
- voltage
- Other pathways can converge on TRPV1 and activate it
What is an antagonist for the activation of TRPV1 channels?
resiniferatoxin. Possibly an analgesic?
What makes the Ph go down?
inflamed tissue because free protons are release from burst cells
What would happen if we blocked the TRPV1 channel?
-Maybe we would not feel heat
What scientist won a Nobel price in 2021 for their research on the TRPV1 channel?
David Julius
How did the clinical trials of TRPV1 antagonists turn out?
- Most data has never been published
- Might not work
What was the main side effect that TRPV1 antagonists gave?
- fever
- just 1 °or 2 in AVERAGE
- so some people got like 5 degrees more than 37 normal body temperature, which can be lethal
How can capsaicin actually work as an analgesic?
- There is a desensitization period after activation of TRPV1, can last minutes to hours, to forever.
- Capsaicin is an agonist, used topically, activates channel to create desensitization.
- Pain gets worse before it gets better.
How can capsaicin actually work as an analgesic?
- There is a desensitization period after activation of TRPV1, can last minutes to hours, to forever.
- Capsaicin is an agonist, used topically, activates channel to create desensitization.
- Pain gets worse before it gets better.
What scientist won a Nobel prize in 2021 for their work on transduction of mechanical pain? (specifically Piezo)
-Ardem Patapoutian
what can we say about transduction of mechanical pain?
- We don’t know yet how it is transduced
- We have contenders, but no consensus on what exactly transduces pain.
- We do know however that Piezo channels (2 of them) transduce touch
What would be analgesics in regards to sodium and potassium channels?
- Sodium Na+ channel blocker
- Potassium K+ channel agonist
What does Lidocaine do?
- It is a sodium channel blocker
- Local anesthetic: no pain or feeling
What is the problem with lidocaine?
- Can’t use that on a regular basis
- You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
- trying to come up with that
What is the problem with lidocaine?
- Can’t use that on a regular basis
- You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
- trying to come up with that
What is the problem with lidocaine?
- Can’t use that on a regular basis
- You can target only the sodium channel that are in the PNS, which are Na 1.7, Na 1.8 and Na 1.9
- trying to come up with that
What is the challenge in trying to target specific sodium channel for lidocaine use?
If the drug doesn’t have very good selectivity and it blocks Na 1.5, your heart will stop and you will die.
What are some inherited disorders of the SCN9A gene (Na 1.7)?
- HSAN Type V
- Paroxysmal Extreme Pain Disorder
- Primary Erythromelalgia
What does HSAN Type V do to you?
- aka congenital insensitivity to pain
- no pain, no other symptoms
- inability to sweat
- loss of function mutation
- most probably no mental issues
What does Paroxysmal Extreme Pain Disorder do to you?
- comes and goes, not always there
- Gain-of-function disorder
- Hyperactive Nav 1.7 channels
- Very intense Pain
- Usually just in babies
- In and around the rectum
What does primary erythromelalgia?
- Gain-of-function disorder
- Pain and erythema (redness)
- Hand and feet
- Cold water seems to help
Why does the fact that these diseases sometimes cause pain only in specific places or at specific times doesn’t make sense?
-genes are expressed everywhere at all times, so the pain should be everywhere at all times.
