Lecture 7- Pain Neurochemistry and Pharmacology

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what are algogens?
answer

anything causing or referring to pain
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where does neurochemistry happen, what should neurochmists look at when referring to pain? neurochemistry of what?
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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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what features of drug targets are drug companies most interested in?
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– want to target with high specificity – want to target whats drugable – pass certain membranes
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what is inflammation?
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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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is hypersensitivity adaptive?
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yes?
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explain the stages of imflammation
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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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what are 7 inflammatory mediators? (the ones we need to know)
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– bradykinin – prostaglandins -prostaglandins – serotonin – histamine – adenosine – cytokines
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what is a mediator?
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where is bradykinin released?
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from plasma (mast cells and macrophages) after tissue injury
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what does bradykinin do when administered to humans?
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produces pain – sensitivity to heat stimuli
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what channels does bradykinin activate?
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– PKC – TRPV1
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what are the receptors of bradykinin?
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B1 – antagonists- no effect B2 – antagonsits – reduced C fibersensitization
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where do prostaglandins come from?
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– first isolated from seminal fluid (prostate)
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where are prostagladins derived from?
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fatty acids found in the membrane
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where are pros. active and produced?
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– locally active and produced all over
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what are 2 enzymes that are involved in the synthesis of PGE2?
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they are the target of NSAIDS COX1 – baseline prostaglandins COX2- stimulated prostaglandins (inducable form)
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what is the major peripheral effect 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 COX1 enzyme?
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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 the COX2 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 serotonin involved in?
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Descending pain modulation – (different receptors have different effects) – contributes to sensitization
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where is Serotonin released from?
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platelets and mast cells after injury – lots of receptors are on the DRG neurons
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what do 5-HT receptors (serotonin receptors) activate?
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PKA and PKC to open TRPV1 channels and NAv1.8
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What substances cause the release of histamine and from where?
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Substance P and PGE2 and from mast cells
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what are mast cells?
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– its a type of white blood cell – part of the immune system
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what does histamine potentiate (increase power, effect, or likelihood of)?
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– the nocicpetor response to heat and bradykinin
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where does Adenosine bind to?
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A2 receptors
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ATP binds to __________ receptors to iniate __________ production and release
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P2X, cytokine – agonists increase pain, antagonists block pain
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what partially precented the development of allodonya and reversed allodynia after SNI?
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P2X7 antagonist
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what releases interleukins (cytokines) to regulate inflammation?
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macrophages
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what are some major pro-inflammatory cytokines?
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IL-1B, IL-6
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What are some major anit-inflammatory cytokines
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IL-4, IL-10
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there is a _________ on nociceptors or there is is ___________ through other mediators
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direct action, stimulation
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where is a lot of steriod treatment done?
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epidural space of the spine
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explain oral steriods
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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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what the active ingredient in aspirin?
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acetylsalicylic acid
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whats the active ingredient in willow bark?
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salicylic acid
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whats another word for paracetamol?
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acetaminophen
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is acetaminophen an NSAID?
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no
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what will acetaminophen inhibit?
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cox 1 and 2
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whats an antipyretic?
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used to prevent or reduce fever
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what do anitpyretics do?
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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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define transduction
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the action or process of converting something into another form
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how is vision transduced?
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by light
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what are 5 ways pain is transduced?
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heat, cold, pressure, cell lysis, chemical (acid, base, irritants)
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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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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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what do we know about heat and pain?
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there are specific channels that respond only to heat
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what temperature and object does TRPA1 respond to? and what is the tissue distribution?
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<7 degres – horseradish and cinnamon and garlic – sensory neurons
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what temperature and object does TRPFMB 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 TRPV4 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 TRPV3 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 TRPV1 respond to? and what is the tissue distribution?
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– >43 degrees – capsacion – sensory nerons bladder
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what might you want to study TRPV1 for? and why?
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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 is the TRPV receptor?
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ion channel
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why is capsaicin analgesia a paradoxal thing?
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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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how is capsaicin analgesia given?
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patch form
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whats the idea behind the capsaicin patch?
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its gonna desentitize the receptors, TRPV1 is there gonna be non-responsive
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do TRPV1 channels do more than thermal transduction?
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yes
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what 3 channels have been found to transduce mechanical pain?
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– DEG/ENaC and TRP and Piezo
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what is Lidocaine?
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-local anesthetic
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how many SCN genes are there?
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9
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where is Na1.4 expressed?
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skeletal muslcles
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where is Na1.5 expressed?
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cardiac muscles
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whick SNC are the best to target?
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1.7-1.9 because theyre expresed on the PNS
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what happens if theyre not specific?
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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 are 3 inherited disorders of the Na1.7 gene?
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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 is hereditary Sensory Neuropathy, Type V ?
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– no pain – no other symptoms – loss of function mutation
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what is Paroxysmal extreme pain disorder?
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– pain and erythema -rectum area – gain of function mutation – over active channel 1.7
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what is Primary erythmelalgia ?
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– pain and erythema – hands and feet area – gain of function mutation
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why are drug companies so interested by this gene?
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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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whats currently unexplainable about these disorders?
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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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what is opium
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stuff from the poppy plat
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opium vs opiate?
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opiate is anything you can take out of the plant without modifying it
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is heroin an 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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what is Naloxone an antagonsit of?
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Opiates
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what is the tade name of Naloxone?
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Narcan
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what does Naloxone do?
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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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explain the descending modulation of pain with regards to stimulation-produced analgesia
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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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anything that Naloxone reverse must have to be mediated by ___________
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opiates
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if you put morhpine into the PAG it will _______ certain cells in the _____________
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activate, RVM
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if you put morhpine into the _________ it will ____________ certain cells
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RVM, inhibit
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what are 3 opioid receptors?
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– mu opioid receptor – delta – kappa
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what else activates the descending modulation of pain pathway?
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stress
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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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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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RVM input modulates the ____________ input
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DRG
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what are OFF cells?
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always fire until theres pain and then it quiets down
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what are ON 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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which cell does morphine activate and which one does it inhibit?
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activates the OFF cell and inhibits the ON cell
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what kind of channels are opiates?
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inhibitory
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explain the phases of drug development
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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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whats the “file drawer problem”?
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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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define endogenous
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– having an internal cause or origin – growing or originating from within an organism
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whats the goal of the descending pain control pathway?
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