Lecture 7- Pain Neurochemistry and Pharmacology – Flashcards
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anything causing or referring to pain
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what are algogens?
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- nociceptor development and maintence (neurotrophic factors) - peripheral algogens ("inflammatory soup") - transdction (TRP channels...etc) - propagation ( ion channels) - "presynaptic release (e.g. glutamate, substance P) - "postsynaptic" processing (e.g. NMDA-Rs, GABA-Rs) - supraspinal processing (e.g. AC1, PKM) - descending modulation what: - neurotransmitter synthesis - neurotransmitter degradation - neurotransmitter reuptake - receptors - signal transduction molecules - ion channels - transcription factors
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where does neurochemistry happen, what should neurochmists look at when referring to pain? neurochemistry of what?
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- want to target with high specificity - want to target whats drugable - pass certain membranes
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what features of drug targets are drug companies most interested in?
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the bodys response to damage in order to remove the stimuli (infection/pathogen) and start the healing process
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what is inflammation?
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yes?
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is hypersensitivity adaptive?
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injury- ex. by a thorn Rubor, Calor - rubor is colour change, calor is heat tumor - swelling, by product of all the cells infultrating the one area dolor- pain loss of function
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explain the stages of imflammation
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- bradykinin - prostaglandins -prostaglandins - serotonin - histamine - adenosine - cytokines
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what are 7 inflammatory mediators? (the ones we need to know)
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from plasma (mast cells and macrophages) after tissue injury
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where is bradykinin released?
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produces pain - sensitivity to heat stimuli
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what does bradykinin do when administered to humans?
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- PKC - TRPV1
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what channels does bradykinin activate?
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B1 - antagonists- no effect B2 - antagonsits - reduced C fibersensitization
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what are the receptors of bradykinin?
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- first isolated from seminal fluid (prostate)
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where do prostaglandins come from?
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fatty acids found in the membrane
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where are prostagladins derived from?
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- locally active and produced all over
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where are pros. active and produced?
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they are the target of NSAIDS COX1 - baseline prostaglandins COX2- stimulated prostaglandins (inducable form)
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what are 2 enzymes that are involved in the synthesis of PGE2?
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- to sensitize neurons to noxious stimuli, modulated through PKA and activity of NaV 1.8
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what is the major peripheral effect of PGE2?
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- it is a consitutively expressed enzyme - its in the platelets, , stomach, intestine, and kidneys - they produce normal functions "housekeeping"
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what is COX1 enzyme?
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- when tissue damage occurs - its inducable - comes from macrophages, synoviaocytes, cells in the urogenital tract and in the CNS, endothelial cells - present in imflammation, regulgation in electrolyte balance and fertility
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what is the COX2 enzyme?
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Descending pain modulation - (different receptors have different effects) - contributes to sensitization
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what is serotonin involved in?
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platelets and mast cells after injury - lots of receptors are on the DRG neurons
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where is Serotonin released from?
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PKA and PKC to open TRPV1 channels and NAv1.8
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what do 5-HT receptors (serotonin receptors) activate?
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Substance P and PGE2 and from mast cells
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What substances cause the release of histamine and from where?
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- its a type of white blood cell - part of the immune system
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what are mast cells?
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- the nocicpetor response to heat and bradykinin
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what does histamine potentiate (increase power, effect, or likelihood of)?
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A2 receptors
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where does Adenosine bind to?
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P2X, cytokine - agonists increase pain, antagonists block pain
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ATP binds to __________ receptors to iniate __________ production and release
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P2X7 antagonist
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what partially precented the development of allodonya and reversed allodynia after SNI?
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macrophages
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what releases interleukins (cytokines) to regulate inflammation?
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IL-1B, IL-6
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what are some major pro-inflammatory cytokines?
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IL-4, IL-10
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What are some major anit-inflammatory cytokines
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direct action, stimulation
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there is a _________ on nociceptors or there is is ___________ through other mediators
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epidural space of the spine
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where is a lot of steriod treatment done?
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will take the pain to zero BUT there alot of side effects such as blurred vision, wieght gain, depression, bloody stool, HBP
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explain oral steriods
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acetylsalicylic acid
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what the active ingredient in aspirin?
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salicylic acid
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whats the active ingredient in willow bark?
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acetaminophen
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whats another word for paracetamol?
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no
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is acetaminophen an NSAID?
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cox 1 and 2
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what will acetaminophen inhibit?
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used to prevent or reduce fever
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whats an antipyretic?
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they cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in the reduction of a fever.
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what do anitpyretics do?
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the action or process of converting something into another form
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define transduction
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by light
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how is vision transduced?
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heat, cold, pressure, cell lysis, chemical (acid, base, irritants)
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what are 5 ways pain is transduced?
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heat- we know well cold- a bit pressure - no idea cell lysis- the hypothesis is that they release protons chemical - a bit with the irritants but not really
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out of the 5 wyas which ones do we know for sure and which ones do we not know?
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there are specific channels that respond only to heat
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what do we know about heat and pain?
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<7 degres - horseradish and cinnamon and garlic - sensory neurons
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what temperature and object does TRPA1 respond to? and what is the tissue distribution?
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- 8-23 degrees - mint - sensory neurons
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what temperature and object does TRPFMB respond to? and what is the tissue distribution?
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- >27 degrees - extract of a plant BAA - sensory neurons, Kidney
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what temperature and object does TRPV4 respond to? and what is the tissue distribution?
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>31 OR 39 degrees - Camphor, vix vvapour rub - sensory neurons
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what temperature and object does TRPV3 respond to? and what is the tissue distribution?
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- >43 degrees - capsacion - sensory nerons bladder
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what temperature and object does TRPV1 respond to? and what is the tissue distribution?
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for its acid properties because it will reach a wider range of people. also it is modulated by a lot of things so you would want to study it
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what might you want to study TRPV1 for? and why?
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ion channel
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what is the TRPV receptor?
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because it makes the area more sensitive and hurt more, but only for a little bit of time
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why is capsaicin analgesia a paradoxal thing?
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patch form
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how is capsaicin analgesia given?
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its gonna desentitize the receptors, TRPV1 is there gonna be non-responsive
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whats the idea behind the capsaicin patch?
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yes
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do TRPV1 channels do more than thermal transduction?
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- DEG/ENaC and TRP and Piezo
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what 3 channels have been found to transduce mechanical pain?
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-local anesthetic
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what is Lidocaine?
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9
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how many SCN genes are there?
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skeletal muslcles
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where is Na1.4 expressed?
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cardiac muscles
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where is Na1.5 expressed?
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1.7-1.9 because theyre expresed on the PNS
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whick SNC are the best to target?
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the trouble is targeting 1.7, its very hard to do that and if theyre not specific then it can target 1.5 which is very bad
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what happens if theyre not specific?
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- hereditary Sensory Neuropathy, Type V (type four has other things too such as anhydrosis) - Paroxysmal extreme pain disorder - Primary erythmelalgia
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what are 3 inherited disorders of the Na1.7 gene?
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- no pain - no other symptoms - loss of function mutation
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what is hereditary Sensory Neuropathy, Type V ?
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- pain and erythema -rectum area - gain of function mutation - over active channel 1.7
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what is Paroxysmal extreme pain disorder?
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- pain and erythema - hands and feet area - gain of function mutation
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what is Primary erythmelalgia ?
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because if they can find a way to target this then they have a good pain treatment
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why are drug companies so interested by this gene?
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- the localization... how are they so localized? and the fact that these people have flare ups as well - if the 1.7 gene is in all DRGs then why is it so localized (ex. hands and feet fot primary erythmelalgia)
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whats currently unexplainable about these disorders?
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stuff from the poppy plat
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what is opium
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opiate is anything you can take out of the plant without modifying it
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opium vs opiate?
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no its a opioid because heroin is not something you can take straight out of the plant
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is heroin an opiate ?
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Opiates
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what is Naloxone an antagonsit of?
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Narcan
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what is the tade name of Naloxone?
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its used in overdoses because it will help reverse the overdose because it competitive. it works quickly
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what does Naloxone do?
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-implanted an electrode into a mouses head, let the animal recover, then they did a surgery (visceral insition with no anesthetic) and there was no pain, a mild current stimulating the PAG was sufficient enough to cause an analgesic effect. - depednign in the type of surgery the electrodes are in a different place.
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explain the descending modulation of pain with regards to stimulation-produced analgesia
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opiates
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anything that Naloxone reverse must have to be mediated by ___________
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activate, RVM
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if you put morhpine into the PAG it will _______ certain cells in the _____________
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RVM, inhibit
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if you put morhpine into the _________ it will ____________ certain cells
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- mu opioid receptor - delta - kappa
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what are 3 opioid receptors?
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stress
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what else activates the descending modulation of pain pathway?
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a mouse is living in its home and you get a stranger to enter and then they get teritorial and aggressive. the more bites the intruder got the longer the took to do a tail flick
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explain the stress-induced analgesia in rates, mice and athletes with regards to the resident-intruder paradigm
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DRG
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RVM input modulates the ____________ input
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always fire until theres pain and then it quiets down
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what are OFF cells?
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theyre quiet until the pain threshold has been reached. Fine when we have the tail flick. ON cells fire right before and after pain threshold is exceeded
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what are ON cells?
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activates the OFF cell and inhibits the ON cell
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which cell does morphine activate and which one does it inhibit?
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inhibitory
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what kind of channels are opiates?
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phase 0 : 1-4 yrs...usually 20 yrs, animal trials, in vitro screening, moldular biologystudies, 5-20 compounds phase 1: YEAR 3-6 , access toxicity, evaulate route of administration, deterimine safe dosage, 2-5 compounds ~50 healthy subjects phase 2: YEAR 5-9, evaluate effectiveness of treatment, determine side effects, 2 compunds ~250 pateints phase 3: YEAR 8-12 , validate effectiveness of treatment, 1 compound ~3000 patient FDA approved : market introduction
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explain the phases of drug development
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not showing the studies that dont work. because youre more likely to publish with positie results, no one wants to publish negative results therefore those just get kept in the "drawer"
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whats the "file drawer problem"?
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- having an internal cause or origin - growing or originating from within an organism
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define endogenous
