Midterm 2 Flashcards

Question

What's another rating scale concept we use in pain research?

Answer 1

- Uses 2 VASs - One of them asks about intensity and the other one about unpleasantness - Ex: one scale is from no pain to most intense imaginable and the other scale is from not unpleasant to most unpleasant imaginable - Mostly these are correlated - Visceral pain is usually more unpleasant than intensity

Answer 2

- Scales using 0-10 ratings with very detailed descriptions of each level - Ex: 0-10 scale of pain severity with description of experience at each severity level - Problem with these: the descriptions are completely arbitrary and they put them in a specific order (who says that's the order of these descriptions?) - Someone's asserting that the descriptions on the higher numbers are worse than the descriptions on the lower numbers - You can't just come up with a scale - You have to validate these and show people that it works

Answer 3

1) Pain Ratings as a Communications Strategy * What a person giving you a rating is aiming at is probably not the same thing as why you're asking them for a rating * You want an objective depiction of their pain * Patients usually are sending you a message about what they want from you * Want to be taken seriously and want good treatment * Patients will often say their pain is an 11 on a scale of 0-10 or it's "too serious for numbers" 2) Pegs * This has been used to explain why women are more sensitive to pain * It's true that they're more sensitive to pain * If we're using the peg "worst pain imaginable" on a VAS scale, people substitute the worst pain with the worst pain they've ever experienced themselves * Women will hence often put childbirth which is much more painful than most pain experiences of males * Women therefore probably have much bigger scales than men * When using these scales, it hence often seems like men are experiencing greater pain, but it's only because the pain women are feeling is much smaller relative to their much larger pain scale that they've experienced in real-life * Although it seems like men are experiencing greater pain, women are actually experiencing greater pain

Answer 4

* Asked people that had these pain experiences to rate them and asked people that hadn't had these experiences to estimate them through their imagination * Findings show that people imagine these to hurt much more than they do * One exception: childbirth * People have rated this lower than it actually hurts * Closest approximation to experienced rating was for sprained ankle, athletic injury, menstrual cramps and ingrown toenail * Furthest approximations to experienced rating were for electric shock, dog bite or small mammal bite and stepping on nail or glass in bare feet

Answer 5

- Ratings from Montreal General Hospital patients - Most painful: 1) Causalgia (8.5) 2) Digit amputation (8.25) 3) Childbirth (no training = 7.5 and training = 6.8) - Least painful: 1) Sprained ankle (3.25) 2) Laceration (3.4) 3) Arthritis (3.9)

Answer 6

- Ratings from chronic pain patients - Comparing clinical pain to experimental pain (temperature from thermode) - Most painful: 1) Childbirth (8.75) 2) 51 degree Celsius thermode (7.5) 3) Causalgia (6.75) - Least painful: 1) 43 degree Celsius thermode (2.75) 2) 45 degree Celsius thermode (2.9) 3) Myofascial pain (4.25)

Answer 7

- Ratings from 115 University of Florida undergraduates - Most painful: 1) Dental drilling (without anesthetic) (7.75) 2) Fall from 6-foot ladder onto cement (7.5) 3) Boiling water spill on hand (7.1) - Least painful: 1) Throat examination during check-up (1.75) 2) Dental examination (1.8) 3) Mosquito bite (1.9)

Answer 8

- Ratings from 187 University of Florida undergraduates - Most painful: 1) Childbirth (9.25) 2) Knife wound (8.9) 3) Cancer (advanced) (8.75) - Least painful: 1) Eye exam (1) 2) Mosquito bite (1.5) 3) Walking on gravel (1.75)

Answer 9

- These painful events differ in things other than pain intensity: - Differ in their duration - Digit amputation is very bad, but it only hurts for as long as it lasts (couple hours?) - Neuralgia can last months - Childbirth and labour pain goes up and down in pain throughout time - Some pains last longer than others, some are shorter, some come and go - Also if comparing experimental pain to clinical pain, a 51 degree thermode you can only apply to someone for a few seconds because it'll cause a burn - So issue with comparing this for a few seconds compared to longer chronic pain

Answer 10

- Most to least: - Functioning (anxiety/depression, sleep disturbance, cognitive) - Allodynia (punctate, dynamic, cold, heat) - Ongoing pain (burning, lancinating, stabbing) - Hyperalgesia (mechanical, thermal) - Even if you get a pain score (ex: clinical pain score of 8), and you could trust the overall number, you don't know what's driving this pain - How much of it is spontaneous or ongoing pain, how much of it is allodynia - Patients often don't sleep because of the pain and it makes their brain foggy and their anxiety and depression is worse and these will all factor into their pain number - Not only about the pain - This is telling us what we want to know but with a lot of ambiguity - Pain ratings have lots of problems but it's the best system we have right now

Answer 11

* Instantiations of ratings * Use on babies * This is a rating scale where the person in pain is not self-reporting * This is now a rating by others (almost always a nurse) * Used pretty commonly * FLACC: 1) Face: 0 = no particular expression or smile, 1= occasional grimace or frown, withdrawn, disinterested, 2 = frequent to constant frown, clenched jaw, quivering chin 2) Legs: 0 = normal position or relaxed, 1 = uneasy, restless, tense, 2 = kicking, or legs drawn up 3) Activity: 0 = lying quietly, normal position, moves easily, 1 = squirming, shifting back and forth, tense, 2 = arched, rigid, or jerking 4) Cry: 0 = no crying (awake or asleep), 1 = moans or whimpers, occasional complaint, 2 = crying steadily, screams or sobs, frequent complaints 5) Consolability: 0 = content, relaxed, 1 = reassured by occasional touching, hugging, or being talked to, distractible, 2 = difficult to console or comfort

Answer 12

* Another way of rating pain of someone else * Paul Ekman was the first to have the insight that emotional expressions are pretty constant across cultures, individuals, species * The face has a finite number of muscles that can only move in certain ways * FACS: Facial Action Coding System * He coded all the muscles on the face, what they do and what the result is on the face * Score their facial expression * Found that rage is a reliable sequence of facial muscles doing a certain set of things * You can look for changes in the face that are caused by specific musculature * Video-ing the person and then later someone can turn their facial expressions into numbers * Prkachin (1992) depicted the facial expressions and facial muscle movements that depict increasing amount of pain * Demonstrated a sequence of facial changes showing the emergence of the 4 principal facial actions: 1) Onset of action 2) Brow lowering, orbit tightening, and levator contraction 3) Brow lowering, orbit tightening, and eyelid closing 4) Mouth stretch (not consistently related to pain)

Answer 13

* Ron Melzack at McGill * Started by coming up with a whole bunch of descriptors that anyone anywhere have used to describe pain (whole bunch of adjectives) * Then divided those into categories * Main categories: sensory, affective and evaluative * Temporal adjectives: what pain does through time * Change in intensity over a small amount of time * Spatial: pain moving from place to place on the body * Punctate pressure: pressure at a particular point * Incisive pressure: pressure at a particular point that goes through the skin * Constrictive pressure: when you put pressure on something * Traction pressure: when you pull on something * He then asked both doctors and patients to put them in order within each category * Where the most severe adjective should go at the bottom and least severe should go at the top * Very good concordance between doctors and patients

Answer 14

* Temporal (between 1 and 3 in intensity): 1) Flickering (least) 2) Quivering 3) Pulsing 4) Throbbing 5) Beating 6) Pounding (most) * Spatial (between 2 and 4): 1) Jumping 2) Flashing 3) Shooting * Punctate pressure (between 1 and 4): 1) Pricking 2) Boring 3) Drilling 4) Stabbing 5) Lancinating * Incisive pressure (between 3 and 4): 1) Sharp 2) Cutting 3) Lacerating * Constrictive pressure (between 1 and 4): 1) Pinching 2) Pressing 3) Gnawing 4) Cramping 5) Crushing * Traction pressure (between 2 and 4): 1) Tugging 2) Pulling 3) Wrenching * Thermal (between 2 and 5): 1) Hot 2) Burning 3) Scalding 4) Searing * Brightness (between 1 and 3): 1) Tingling 2) Itchy 3) Smarting 4) Stinging * Dullness (between 1 and 3): 1) Dull 2) Sore 3) Hurting 4) Aching 5) Heavy * Miscellaneous (between 1 and 4): 1) Tender 2) Taut 3) Rasping 4) Splitting

Answer 15

- Tension (between 2 and 3): 1) Tiring 2) Exhausting - Autonomic (between 2 and 4): 1) Sickening 2) Suffocating - Fear (between 3 and 5): 1) Fearful 2) Frightful 3) Terrifying - Punishment (between 3 and 5): 1) Punishing 2) Grueling 3) Cruel 4) Vicious 5) Killing - Miscellaneous (between 3 and 4): 1) Wretched 2) Blinding

Answer 16

1) Mild (least intense) 2) Annoying 3) Discomforting 4) Troublesome 5) Miserable 6) Distressing 7) Intense 8) Horrible 9) Unbearable 10) Excruciating

Answer 17

* Melzack & Katz (2012) * He turned the Pain Descriptors by Intensity into the McGill Pain Questionnaire * 20 categories of adjectives and you pick the one that's most representative of the pain that you have * Put down where on your body the pain is happening * PPI: present pain index * Use 6-point verbal rating scale (VRS) for this * These adjectives would provide a signature that doctors could diagnose what problem that you have * This is very popular but it doesn't really work * But it works well for neuropathic pain that has a lot of heat components and electrical components to it where people use a lot of relevant adjectives for it * Inflammatory pain is very dull * You can tell the difference between these 2 from this questionnaire * This has as many citations or more than the gate control theory * He had the most cited pain research career ever

Answer 18

* Melzack & Katz (2012) * Short form of McGill Pain Questionnaire * Now people use the short form of this questionnaire * It's kind of a different thing * List of 15 of the adjectives that people rate (from 0 to 3, none = 0, mild = 1, moderate = 2, severe = 3) * Why did Melzack want to make a short form of the MPQ? Why is there a need for short forms of questionnaires? * In clinical settings, people don't have time to let patients take 10 mins on this * Original MPQ takes 10 mins and the short form takes ~1 min * Scientists like the original MPQ but clinicians like the short form

Answer 19

* Bouhassira, D. (2005) * Douleur Neuropathique 4 * Consists of 4 questions * Consists of a patient interview and a patient examination * 10 points total * You get a point for each item you answer yes to and then get a score out of 10

Answer 20

Fancy word for numbness

Answer 21

* Haegg (2007) * Has one section about pain (section 1 - pain intensity) * Asking people how much pain they have in the presence of pain killers * Kind of getting at pain intensity * Rest of the sections are about disability * Demonstrates the impact of the pain on disability

Answer 22

- Catastrophizing is a combination of rumination, magnification, and helplessness - Rumination: can't stop thinking about something - Magnification: building something up to being bigger than it is - Helplessness: feeling like you can't do anything about it

Answer 23

* Sullivan et al. (1995) * Super important * Developed at McGill * Short scale * 13 Questions * Meant to quantify catastrophizing * Either respond 0 = not at all, 1 = to a slight degree, 2 = to a moderate degree, 3 = to a great degree, 4 = all the time * You can catastrophize about things other than pain but this is about pain * Pain catastrophizing is both a trait and a state * There are a lot of psychological constructs that can predict pain * None works as well as this scale * This has the best predictive power

Answer 24

* Sometimes rating scales are aimed at particular disease states * Specific, not general * Specifically developed for arthritis * Measures 3 things: pain, stiffness, and disability * Section A (pain): for arthritis sufferers these will all cause very different ratings * Ex: going up stairs is very hard for people with Knee OA

Answer 25

* Svendsen et al. (2007) * Threshold and tolerance * Strange thing happening in the pain world: * People got very frustrated with ratings and thought maybe they could get useful info by doing lots of thresholds and ratings and doing it carefully and systematically (QST) * 2 ways to do QST: at the bedside (faster) or true QST (everything is perfectly calibrated and repeatable) * Ways to fake it at the bedside

Answer 26

1) Mechanical stimuli: - Dynamic Touch - Static Touch - Punctate stimuli - Method: - Stroking skin with a paintbrush/cotton swab - Gentle pressure with fingertip - Pinprick 2) Thermal stimuli - Cold - Warm - Method: - Metallic thermal roller kept at 20 degrees Celsius - Acetone/menthol - Metallic thermal roller kept at 40 degrees Celsius

Answer 27

1) Mechanical stimuli: - Tactile detection threshold - Tactile pain threshold - Pressure pain threshold - Pressure pain tolerance threshold - Method: - Von Frey Hair - Pressure Alogometry 2) Thermal stimuli - Cold detection threshold - Warm detection threshold - Cold pain threshold - Heat pain threshold - Heat tolerance threshold - Method: - Thermotest (using a thermode)

Answer 28

* If you're going to do QST, you have to consider that you'll apply stimuli at different pain intensities * In what order do you present stimuli? * Psychophysics: * There are ways and orders to do things * Up-down games (Gracely & Eliav, 2009) * Sensory detection regions: start small and go up until detection and then start high and go down until no detection * Pain threshold region: go up in intensity until pain is felt

Answer 29

- 4 subjects were tested for their pain thresholds - Line represents skin temperature (extremities are colder than core) - Tested their cool threshold, warm threshold, cold pain threshold, heat pain threshold - Findings: - Cool threshold: 31.1 degrees Celsius - Warm threshold: 37.7 degrees Celsius - Cold pain threshold: 13.8 degrees Celsius - Heat pain threshold: 43.5 degrees Celsius - People won’t call it pain until it goes down to about 14 degrees and until it gets hot to up to 43.5 degrees - Something that's just a bit more or less hot than 44 degrees: hot tubs - Evolutionarily heat pain is at 43.5 degrees because proteins start to breakdown higher than that (they denature) - If your skin gets to that temperature, then your core gets to that temp and proteins breaking down leads to death - Evolutionarily cold pain is at 14 degrees because frostbite and core being too cold (hypothermic) which leads to death

Answer 30

- Quantitative Thermal Sensory Testing of Inflamed Skin - Heat pain thresholds (degrees Celsius) in human models of experimental inflammation - Testing what certain injuries will do to your heat pain threshold 1) Burn: - Baseline = 44.5 - Inflamed skin = 39.7 - Change in threshold = -4.8 2) Capsaicin (injection): - Baseline = 42.5 - Inflamed skin = 33.7 - Change in threshold = -8.8 3) UV - Baseline = 44.5 - Inflamed skin = 36.7 - Change in threshold = -7.8 4) Freeze - Baseline = 42.5 - Inflamed skin = 37.1 - Change in threshold = -5.4 5) Mustard oil - Baseline = 42.1 - Inflamed skin = 36.5 - Change in threshold = -5.6 - In all of these cases, these caused the threshold to go down by 4.8 to 8.8 degrees - People's ratings may or may not correspond to how hyperalgesic they've become

Answer 31

* Experiment that did QST on a neuropathic pain patient * 3 things were done: * Used a cotton wisp * Used a Qtip * Used a paint brush * Dynamic mechanical allodynia * Didn't look for pain threshold * They simply did this on the side of the body of the patient with pain and on the unaffected side of the body * On affected side of the body (in pain) they had mechanical allodynia * What's surprising: the pain rating was the same in each case even through using different tools

Answer 32

* Rolke et al. (2006) * Pinnacle of QST: data that were generated by a bunch of German pain researchers * Being able to do what the McGill pain questionnaire couldn't do * Can we use QST to differentiate one type of pain from another type of pain * Splitting exercise * 14 QST types * They trained everyone in this network very seriously * Made sure everyone was using these precisely in the same way * Gave these to non-pain patients * Got a normal distribution of all of these pain thresholds * An individual pain patient had a problem if they were above or below each of these * Studied 2 patients with postherpetic neuralgia * These have the same diseases but have 2 complete different QSTs * Maybe these people have completely different diseases * Looking back, this effort largely failed * Turns out that QST is really good at determining who has neuropathy but not good at determining who has neuropathic pain * Doesn't tell you anything about their pain, just tells you about the diseases they have that causes their pain

Answer 33

* If you pay people a bit more money, you can get them to agree to let them test their pain directly in the muscle * You can electrically stimulate the muscle, do deep mechanical in the muscle and inject chemicals (all of these activating the muscle nociceptor and triggering exogenous muscle pain) * Chemical (ex: hypertonic saline, bradykinin, capsaicin, glutamate, substance p) * Mechanical (pressure and tourniquet pressure) * Electrical (intramuscular and intraneural) * Miscellaneous (heated isotonic saline and focused ultrasound) * You can also test visceral pain in people (ex: inflating balloons in their colon, oesophagus, or bladder)

Answer 34

- Self-report (through scales and interviews) - Observe behaviour and infer - Indirect physiology

Answer 35

* Pain measurements are subjective * People hate this * Everyone thinks that life, the world and pain research would be better if we had some sort of objective biomarker for pain * Biomarker: something you can measure the levels, size or density of * You can infer how much pain people were in from that biomarker without asking them anything * Problem: you would only be certain that something is a biomarker if it agrees with self-report * Dependent on agreement with self-report * Some people are incapable of self-report (ex: babies, people with dementia) * People also lie sometimes (however #1 rule is believe the patient) -> patients in general won't go through the trouble of driving to the hospital and telling you they're in pain when they're not * But sometimes they would (ex: maybe they're an opioid addict, man lying about not being in pain, legal actions -> getting money for pain and suffering) * There are circumstances where there's reason to believe people are lying * Biomarkers would solve the problem

Answer 36

- Tissue Damage (bigger wounds don’t necessarily mean more pain) - Cardiovascular (ex: heart rate, blood pressure, heart rate variability) -> it's true sometimes that people in pain have higher heart rates and increased blood pressure but not always true - Stress-Related (ex: cortisol and galvanic skin response) - Neural (ex: EEG, microneurography, imaging (functional, structural, chemical)) -> a lot of people are putting their money on brain imaging - Chemical (in blood or CSF) (ex: substance P, b-endorphin, cystatin C, C reactive protein, nerve growth factor) -> chemicals in the blood that have been indicated as being pain biomarkers - Molecular (ex: DNA variants and mRNA levels) - Problem with DNA variants: you have a DNA variant from the moment of conception and that doesn't tell you very much (it's always there) but biomarkers are used to tell you what's going on right now - Problem with mRNA: invasive, it's specific to the tissue in question (DRG, spinal cord, cingulate, insula)

Answer 37

- Rated pain rating on a VAS - Wide range of ratings - Took people with the 6 highest ratings and 6 lowest ratings in an imager - High raters had high activation (in SI and ACC) - Low raters had low activation - Their brains agreed with their ratings - Evidence that could be used as a biomarker

Answer 38

* The jury is still out on this * People range on a continuum between fMRI will maybe be a biomarker it just has to improve a little and others who say fMRI won't work for pain

Answer 39

- Studied the brain activation of Ps with physically-induced pain, hypnotically-induced pain and imagined pain - Found there was pretty big overlap (especially between PI pain and HI pain) suggesting that the same areas of the brain are going to activate if you experience physically-induced pain and are hypnotized to imagine it

Answer 40

- Can conduct causation experiments (can't do a causation experiment in humans, only correlation which is useful but causation is better and impossible to keep everything the same in every one thing for humans but in rats and mice, you can do essentially the same thing in all -> can hold things constant) - Can stimulate/lesion any tissue - Can assay, record from, or extract any tissue - Can give unapproved drugs - Can alter gene expression (temporarily or permanently) - Can turn particular types of neurons in particular locations on or off at will - Can control environmental pre-exposures (ex: housing, diet) - Cheaper, faster, less highly regulated - No malingering (to try and get more drugs), no stoicism/machismo, no demand characteristics (confound of human experiments where people sort of intuit what the right answer in an experiment is and they supply it to increase the chances that the research will work and the experimenter will be happy)

Answer 41

- Most common to least common: 1) Rat (800) 2) Mouse (600) 3) Dog (500) 4) Cat (300) 5) Rabbit (200) * In the 70s, these 5 species were pretty common in pain research * In 1980-1985, the rat took off and became very popular in pain research * Why rats? * They're small which means they're cheap (they cost less to feed, you can house them in a much smaller space -> can fit them in a room) * Later the mouse took off and became very popular and caught up to rats * #1 species in biomedical research * Something that happened in the late 1990s for this to happen: transgenetics (alter gene expressions) * There was a while where that technology only worked with mice * So a lot of people switched over from rats to mice

Answer 42

- “The best material model of a cat is another cat, preferably the same cat.” - Arturo Rosenblueth (1945) - Meaning it's hard to model things with things that aren't the same - They’re the “wrong” species - They don’t talk - They’re prey (rats and mice are prey species and they have reason to hide their pain from us as we're much bigger) - They’re a lot tougher than we are (not used to comfort in the way humans are, put up with a lot and the kind of things that'll get us to complain, they'll need more to complain) - Ethical issues (ex: deontological vs consequentialist ethics)

Answer 43

- Deontological Ethics: the normative ethical position that judges the morality of an action based on the action’s adherence to a rule or rules - Relies on rules put out prior - If there's a rule that you shouldn't inflict pain on animals, then you can't inflict pain on animals - Consequentialist Ethics: the normative ethical position holding that the consequences of one’s conduct are the ultimate basis for any judgment about the rightness of that conduct - Utilitarianists are a subset of consequentialists - Whether you do something depends on the consequences of that conduct - What matters are the consequences

Answer 44

- Types of pain measurement in rodents: 1) Chemical 2) Cold 3) Electrical 4) Heat 5) Mechanical 6) Spontaneous (pay attention to ear position changes, orbital tightening, cheek bulging, nose bulging, and whisker changes)

Answer 45

* Heat used to be the dominant type of measurement in 1980s and 90s * We spend a lot less time measuring heat overtime and spend a lot more time measuring mechanical overtime * Mechanical allodynia and pain is a much more important clinical problem (much harder to avoid) * Whereas heat hyperalgesia and allodynia is easier to avoid

Answer 46

- Hot-plate test - Tail-flick test - Hargreave's test

Answer 47

- von Frey filaments - Randall-Selitto test - Weight bearing (indirect) - Grip force (indirect) - Gait changes (indirect)

Answer 48

- Writhing test - Formalin test

Answer 49

- Thermal Assay - Hot plate analgesia meter - Put a rat or mouse on a hot plate - What happens when you put a rat on 50 degrees plate - 2 seconds after you put them on the plate, nothing happens - Why? - Their skin is at ~ 32 degrees - It takes a few seconds before hind paw skin gets to 50 degrees - They'll usually pick up the hind paw and shake it really fast or they pick up their paw and put it in their mouth - As soon as the animal does a jump, lick or shake, you take them off the hot plate - The ones with the longer latencies had the longest thresholds

Answer 50

- Tail-flick analgesia meter - 2 ways of doing this: 1) Shine a heat light on the rats tail 2) Dip their tail in hot water (50 degrees Celsius) - As soon as their tail gets to the heat threshold, they'll flick their tail

Answer 51

- Tail-flick test is a reflex - Hot-plate test is not a reflex because they're thinking to themselves this is no longer a warm, this is a pain, what should I do? - 2 ways of measuring acute thermal pain: 1) Only requires the spinal cord: tail-flick test 2) Requires the brain supra spinal: hot-plate test

Answer 52

- AKA “radiant heat paw-withdrawal” test or “toe-toaster” test (not really) - Invented by Ken Hargreaves - IITC Plantar Test Analgesia Meter System - You put animals on a glass floor and once they stop moving, then you shine a high intensity heat lamp aimed at the plantar surface of the hind paw and you measure the amount of time it takes for the animal to hop away - The hot plate test, you don't have any control over the left or right paw because they're both on the hot plate - This test you can isolate either paw and choose to test the ipsilateral or contralateral pain - No one knows if this is spinal (reflex) or supra spinal (brain)

Answer 53

* Bioseb von Frey Filament Set * Von Frey filaments were meant for humans to test neurological functioning in humans * It was realized that if you use smaller fibers, then you can do the same thing in mice that you do in humans * Set of fibers that are calibrated such that when they bend, they're exerting a particular amount of force and no more force than that * You find the fiber that cause withdrawals 50% of the time * Can test mechanical allodynia where they withdraw with smaller fibers after they're given an injury

Answer 54

* IITC Digital Randall-Selitto Paw Pressure Test * Another way of measuring mechanical pain * Generally only works with rats since rats allow people to hold them in position necessary for this test * A force will drop on the rats paw and the force gets bigger and bigger and eventually the force gets big enough that the rat squeaks or wiggles away which indicates their pain threshold * Von Frey and Randall-Selitto are direct ways of measuring mechanical stimulation

Answer 55

- Mechanical assay - Positioning the mouse so it has to put its weight on its hind paws - Measures how much weight the mouse is putting on the right vs the left hind paw

Answer 56

- Mechanical assay - If the mouse is holding onto something and you pull them on the tail, they'll hold on for a while - Measure how much time they can hold on for

Answer 57

* Chemical Assay * Test developed in 1950s * Abdominal constriction test * Inject a chemical substance in their belly (either acetic acid, magnesium sulfate, hyper-/hypotonic saline, bradykinin, etc.) * This causes the animal to have abdominal pains * This only lasts about 30 mins but you can stop the pain easily with aspirin * Can identify abdominal pain by the way the mouse drags their belly to the floor

Answer 58

* Chemical assay * Inject 5% formalin substance in the hind paw and it causes inflammation * The nociceptive behaviour is licking -> the animals lick their hind paw * The more they lick the more pain they're in * Measure C-fiber response and DH neuron response * Early/acute phase and late/tonic phase * Also interphase/quiescent period * People are more interested in late phase because whenever something lasts longer, it's a good comparator to clinical pain

Answer 59

* More modern techniques * This is what people generally do today * Inflammatory Thermal Hyperalgesia (inject chemical substance in hind paw then do Hargreaves' test) * Inflammatory Mechanical Allodynia (inject chemical substance in hind paw then do von Frey filaments test) * Inflammatory Cold Allodynia (inject chemical substance in hind paw then inject acetone -> if you bubble a drop of acetone on the skin, it'll immediately evaporate and cool the skin -> cool under normal circumstances but hurts mouse with cold allodynia) * For inflammatory pain, you want to inject an inflammogen that produces effects that last from days to weeks * Terms allodynia and hyperalgesia are not right, because we're measuring thresholds and not allodynia or hyperalgesia * Mechanical and cold = allodynia * Thermal = hyperalgesia * What they're referred to in the field

Answer 60

- Carrageenan - Complete Freund’s adjuvant (CFA) - Zymosan - Mustard oil

Answer 61

* Surgical * Measures: * Thermal hyperalgesia * Mechanical allodynia * Cold allodynia * Different ways of causing injuries to the nerves from the foot * Interested in the sciatic nerve because it serves the foot * You can put a cuff, create ligatures or cut some but not all of the sciatic nerve as it branches out to go out to the foot * Sciatic nerve breaks into 3 * If you cut all of these, you get phantom limb pain * Neuropathic pain is caused by partial nerve injury * Causes thermal hyperalgesia, mechanical allodynia, cold allodynia

Answer 62

* Another nerve that comes from the foot: the saphenous nerve * If you want no info to go from the foot to the spinal cord, you have to cut the sciatica and saphenous * Behaviour that this causes is autotomy (mice starts biting off their toes and you measure this by counting how many flanges have come off) * Create wounds by excessive self-grooming with automutilation (autotomy) of denervated limb -> high autonomy score following nerve transections * Autotomy studies not allowed to be done anymore except for in one pain lab in the world * This is not done much anymore because there's lots of blood that comes from this (messy and disturbing)

Answer 63

- Chronic neuropathic assays 1) Sciatic Nerve Transection (ScNT) - Nature of injury: transection and ligating of sciatic nerve - Clinical correlate: nerve trauma, iatrogenic nerve injury 2) Partial Sciatic Nerve Ligation (PSL) - Nature of injury: partial ligation of sciatic nerve - Clinical correlate: partial peripheral nerve injury 3) Spinal nerve ligation (SNL) - Nature of injury: ligation of the L5 and L6 spinal nerves - Clinical correlate: proximal peripheral nerve damage (ex: after disc prolapse) 4) Spared Nerve Injury (SNI) - Nature of injury: ligation and transection of 2 of 3 distal sciatic nerve branches - Clinical correlate: partial peripheral nerve damage 5) Chronic constriction injury (CCI) - Nature of injury: loose ligature of the sciatic nerve with chromic gut suture - Clinical correlate: nerve entrapment (ex: carpel tunnel syndrome) 6) Sciatic inflammatory neuropathy - Nature of injury: perineurial injection of immune activator (zymosan or CFA) - Clinical correlate: peripheral neuritis 7) Peripheral nerve demyelination - Nature of injury: Immune or toxin-mediated demyelination - Clinical correlate: demyelination (ex: diabetic neuropathy) 8) Diabetic neuropathy - Nature of injury: Streptocotocin, diet, genetic models (can give animals diabetes through diet, genetic models, and injecting streptocotocin) - Clinical correlate: Diabetic neuropathy 9) Viral neuropathy (neuropathy from virus) - Nature of injury: herpes simplex virus, varicella zoster virus, HIV (gp120) - Clinical correlate: zoster-associated pain, postherpetic neuralgia, HIV-associated neuropathy 10) Drug-induced neuropathy - Nature of injury: Vincristine, paclitaxel, ciplatin (3 of the most common chemotherapeutics) - Clinical correlate: polyneuropathy caused by tumour chemotherapy - It would be better to use higher doses of these to kill the cancer but we can’t because they cause neuropathic pain

Answer 64

- Depending on age and gender - Back pain - Headache - Osteoarthritis

Answer 65

- Back pain - Headache - Osteoarthritis - Diabetic Neuropathy - Post-Herpetic Neuralgia - Fribomyalgia et al. - These are the things we're trying to model in animals

Answer 66

- Is injecting something inflammatory or cutting through nerves in mice's hindpaw really osteoarthritis? - The Problem with “Better” Algesiometric Assays: * It's possible to make a better pain assay (pain testing) * Animal model of vulvodynia (one of the most common pain syndromes) (Farmer et al., 2011) * Syndrome where the symptom largely is allodynia of the vulvar vestibule (of the vulva) * Affects ~20% of pregnant women * A better assay * Women with vulvodynia have a fair share of yeast infections * Giving mice yeast infections and then treating the yeast infection *Confirm that it's gone and then give another yeast infection * After 3 rounds of yeast infections, mice become allodynic * No one has ever used this assay because it's very long * 90 days to get only 40% of mice to show allodynia * A lot of time and work and expensive

Answer 67

1. Reflexive vs conditioned measures - All our measures are not like human clinical pain 2. Pain-affected measures (ex: sleep, anxiety, attention) - We haven't measured this in animals for most of history 3. Symptom epidemiology vs dependent measure use - Disconnect between the symptoms common in humans and symptoms common in animals

Answer 68

- People have come up with the idea of using conditioning methods to get the animal to think about the pain and have it make some decisions - Operant (Reinforcement) Conditioning: - Learned escape from pain from electric shock and from noxious heat/cold - Learned analgesic self-administration - Motivational conflict (between pain vs food/water) - Method of measuring or inferring pain by using operant conditioning - Inject carrageenan in mice's cheek - Would expect this to create mechanical or heat allodynia - Made a machine where the animal can go get a sweetened solution (reward solution) but to do so, it has to press its inflamed cheek on a heated coil (Neubert et al., 2005) - If the animal drinks less of the reward solution than it would without the heated coil, you can infer that it hurts to drink the solution so it's doing it less - Problem: this is complicated - Maybe the animal is drinking less of the solution because it's in pain or maybe it's not thirsty or maybe it doesn't like the sweetened solution as much, or maybe it's too sedated - Classical (Pavlovian) Conditioning: - Conditioned place avoidance (to chamber where pain is experienced) - Conditioned place preference (to analgesic-paired chamber) - Training phase where you put the rat or mouse into another of these chambers and you put it in there and let it walk around for a while (King et al., 2009) - Left and right of chamber is very different so rat can tell the difference - On one side you give them an analgesic and on another you give them a saline - Then eventually you open the door and let them choose where to go - If the animal spends more time in the analgesic side, then the animal must be in pain because why else would they be there - Conotoxin worked against von frey mechanical allodynia, compared to sham surgery and baseline surgery - Conotoxin is not a drug that gets you high and the rat preferred this side so sciatic nerve ligation (SNL) causes pain because if the rat prefers this side, there's no other reason to explain this other than pain - Problem: could be pain, or could be memory or movement

Answer 69

- You can measure this in animals and people have started measuring these things too - Modern pain research doesn't only try to measure pain but also these other comorbidities - Anxiety: Suzuki et al. (2007) ran a study that seems to demonstrate heightened anxiety in mice in pain in an open field test and elevated plus maze test - Attention: Millecamps et al. (2004) found significantly lower attention level in colitic mice compared to healthy mice - Sleep: Anderson & Tufik (2003) found mice in pain experienced significantly lower sleep efficiency than mice who got a sham

Answer 70

Prevalence of chronic pain symptoms in humans (Backonja & Stacey, 2004): 1) Spontaneous pain (continuous and/or paroxysmal) = 96% 2) Mechanical hypersensitivity = 64% 3) Thermal hypersensitivity = 38% - If you ask how bothersome these are, they also come up in this order Prevalence of dependent measures in animal models (Mogil & Crager, 2004): 1) Thermal hypersensitivity = 48% 2) Mechanical hypersensitivity = 42% 3) Spontaneous pain = 10% (claim to measure this 10% of the time (doesn't mean they actually are measuring it))

Answer 71

- A measure of spontaneous pain in mice - A way of measuring pain in mice the same way you do it in babies - 5 action units as defined by the facial action coding scale by Eckman - Looks at orbital tightening (eyes closing), nose bulge, cheek bulge, ear position, and whisker change coded/on a scale of 0 = not visible, 1 = somewhat visible, 2 = very visible - Then give the mouse a score from 0-10 - This works pretty well - Works so well that there are now grimace scales for 12 other mammals

Answer 72

- Mouse - Rat - Cat - Horse - Bunny - Otter - Lamb - Monkey - Sheep - Donkey - Pig - Cow - Ferret

Answer 73

- Mammals meet all criteria - Evidence that birds do most of these - Amphibians and reptiles have about 1/2 of these

Answer 74

* Clifford Woolf discovered central sensitization when he was in London * He published this study in 1983 * Sole-authored study * He was testing behaviourally and recording from rats and was measuring the flexor reflex of the leg (movement of the leg when they try to withdraw from some noxious stimulus) * Found that the threshold for that rat to withdraw from a mechanical stimulus, after the injury plummets down * After a few hours, they're extremely allodynic * He was measuring from WDR (2nd order) neurons in the spinal cord and before the burn injury they fire and after the injury they fire more and then it lasts for a lot longer * The surprise: he also found when recording WDR neurons in spinal cord following a noxious stimulus before and after a burn injury to the hind paw that the neurons were firing on the contralateral side as well * Injury was on the left side but when he simulated the other side of the body, he also got a firing response * Only way to explain that WDR neurons are also being activated by stimuli on the other side of the body is if the WDR neurons themselves had changed * The 2nd order neurons had to change such that a stimulus that normally wouldn't be painful before the injury would fire * This was revolutionary in 1983 * People thought changes in the periphery causes changes in the periphery but not in the CNS * If the changes found here in the flexor reflex parallel changes in the sensory input to the brain then pain hypersensitivity following injury may be due to changes within the CNS as well as at the site of the injury

Answer 75

* Electrophysiological recordings can measure peripheral sensitization and central sensitization * If there's only peripheral sensitization, then regardless of where you're recording from (peripheral or CNS), you're going to see the same thing * After sensitization, you're going to get more firing * All things being equal, even if there's no sensitization, the periphery fires faster * You would expect to see a similar pattern of responding peripherally and centrally * If there's only central sensitization, you wouldn't see any changes in the periphery * In central sensitization, it's the spinal cord that has changed * In peripheral sensitization, the nociceptor will be activated more often

Answer 76

* Part of Central Sensitization * You can measure this in people * This is what it would look like in a rat or a mouse * Every second, they're given the stimulus (maybe a pinch or heat pulse) * The spinal cord neuron you're recording from is firing * As you go further, that same neuron is firing more times * Temporal summation: summation in time * "Wind-up": that stimulus is winding up * If the stimuli are far enough apart such that they don't produce wind up (ex: 4 seconds apart), then you'll have a normal rate of firing * However if you're doing this many times in a short period of time (ex: 1 second apart) then the pain intensity adds up and becomes more intense with time (with the same stimulus) and the pain threshold goes down

Answer 77

* If you put many noxious stimuli close enough to each other that the stimuli summate with each other, then the ratings goes up and up and by the end the ratings are way above their threshold * Their second order neurons are simply firing more to the stimulus

Answer 78

* Sensitization produces hyperalgesia and allodynia * Primary hyperalgesia: the thing that happens at the site of injury * You can easily show that within the zone of injury, you get hyperalgesia and allodynia * Can get it for heat and mechanical stimuli * If you get away from the site of injury and enter the secondary zone (uninjured tissue) you can show mechanical allodynia and hyperalgesia but not heat

Answer 79

* Secondary hyperalgesia is mechanical only * 2 types of mechanical stimuli: poking (static) vs brushing (dynamic) * 2 types of secondary hyperalgesia: 1) Stroking hyperalgesia (allodynia) * Adequate stimulus: light stroking * Area: small * Duration: short * Central sensitization 2) Punctate hyperalgesia (static hyperalgesia) * Adequate stimulus: punctate stimuli * Area: large * Duration: long * Central sensitization * How they measure this, they give someone an injury and then start poking them from areas further away from the injury and draw out a map * From this they can draw a circle or oval * In doing these experiments they found that if they use stroking stimuli, the area of hyperalgesia doesn’t go as far * But if they use static punctate hyperalgesia, it goes further * The evidence that it's central sensitization, is mirror pain * Seeing allodynia and hyperalgesia on the other side of the body from the site of the injury and local desensitization/analgesia doesn’t block it

Answer 80

1) Rubor: redness (ruby) 2) Calor: heat (calorie) 3) Tumor: swelling (tumour) 4) Dolor: pain (douleur) 5) Loss of function - These all happen until you form a scab

Answer 81

- Because inflammation either causes or exacerbates: - Neurological diseases - Diabetes - Cancer - Cardiovascular - Alzheimer's disease - Pulmonary diseases - Arthritis - Autoimmune diseases - All of these things are happening as a side product of the immune system - It's the chronic low level inflammation that you can’t see that's the root of all evil - The obvious inflammation that you get after injury is probably the good one

Answer 82

- Ibuprofen (41%) - Acetaminophen (25%) - Aspirin (18%) - Naproxen (10%) - Other (5%)

Answer 83

* Derives from the bark of the willow tree * Chemical that comes from the bark of the willow tree is salicylic acid * Bayer company figured out how to turn salicylic acid into acetylsalicylic acid (ASA) * This was much gentler on your stomach than taking salicylic acid

Answer 84

- Meyer et al. (2012) - From coolest temperatures to hottest - TRPA1 ion channel responds to cinnamon, horseradish, and garlic, mustard oil - TRPM8 ion channel responds to mint/menthol - TRPV4 ion channel responds to BAA - TRPV3 ion channel responds to camphor - TRPV1 ion channel responds to chili peppers, capsaicin, protons

Answer 85

* David Julius * Won the nobel prize for it in 2021 * TRPV1 will activate to capsaicin * It can be blocked by resiniferatoxin * People are testing resiniferatoxin as an analgesic, found evidence that it works as an analgesic in dogs * There to respond to heat (anything 43 degrees or up will activate it) * Not just heat that activates it, but also protons (acid) * State associated with decreases in pH: inflammation, when tissues get acidic, partially because of the wound itself * Inflamed tissue is acidic * Once TRPV1 was discovered, people realized there are all sorts of receptors that affect TRPV1's excitability * Even if heat isn't there, all of this stuff can still activate TRPV1 * TRPV1 is also found in the olfactory bulb * Side effect that you may predict if something's in the olfactory bulb and you're going to block it: might interfere with smell * If you don't smell very well, then you don't taste very well * There was a time when there were 23 different drug companies in the world trying to develop drugs to block TRPV1 * Plants would want to evolve the ability to develop TRPV1 so animals leave them alone * A lot of plants want to be eaten by animals (especially birds) because the animal eats the plant including the seeds, flies out somewhere else and then poops out the plant somewhere else, covered in fertilizer which helps it grow somewhere new * The chili pepper plant does indeed want to be eaten but specifically wants to be eaten by birds, because it figured out that there's something about bird biology that the TRPV1 in birds responds to heat and protons in a normal way but don’t respond to capsaicin, so they can consume capsaicin * Example of co-evolution

Answer 86

* Transduction of Mechanical Pain * Mechanical pain has been much harder to understand * Today we also don't really understand mechanical pain * Ardem Patapoutian won the Nobel prize in 2021 for piezo * Piezo is the mechanical touch transducer * Also the gene that is suspected to be involved in masochism * It's been very hard to figure out the mechanical pain transducer, it may or may not be TACAN or TRP or TMC or DEG/ENaC * Everyone is working hard to figure out that any one of these is the mechanical transducer

Answer 87

- Mast Cells secrete 5HT (binds to 5HT), Histamine (binds to H1), PGE2 (binds to EP - part of COX), Bradykinin (binds to B2/B1) - Macrophages secrete Bradynikin (binds to B2/B1), IL1-Beta (binds to IL1-R), NGF (binds to TrkA)

Answer 88

Transformation of info from the environment into neural firing

Answer 89

- Heat - Cold - Touch - Cell lysis - Chemical (acids, bases, irritants)

Answer 90

- Cannabinoids receptors in the Rostral Ventromedial Medulla - Serotonergic mechanism (serotonin) - Odd that for such a popular drug, we don't know the mechanism or whether it binds to a receptor and which one

Answer 91

Cancer deaths

Answer 92

1) Gastritis Erosive (38%) 2) Dyspepsia (27%) 3) Gastric Ulcer 4) Gastritis (14%) ... 12) Erosive Esophagitis and Hiatus Hernia (6%) 13) Diarrhea, Nausea, Duodenal Ulcer (5%) 14) Upper Respiratory Tract Infection (4%)

Answer 93

1) Cancer (cancer pain) 2) Stroke (shoulder pain) 3) Diabetes (painful diabetic neuropathy) 4) Trauma (causalgia) 5) Shingles (post-herpetic neuralgia) 6) Stroke (post-stroke pain) 7) Surgery (chronic post-surgical pain ~7%) 8) Fracture (complex regional pain disorder)

Answer 94

- Organismic: - Genetic background - Sex - Psychological traits - Age (infants feel most pain and elderly women) - Circadian rhythms - Environmental: - Past experiences - Gender - Psychological states - Diet - Social factors

Answer 95

- Most heritable clinical pain (between 50 and 60%): 1) Rheumatoid Arthritis 2) Menstrual Pain 3) Migraine 4) Back/Neck Pain 5) IBS - Most heritable experimental pain (50-55%): 1) Punctate Hyperalgesia Area 2) Cold-Pressor Pain Intensity 3) Heat Pain Threshold

Answer 96

Most to least (between 65 and 75%) 1) Acetic Acid Constriction Test 2) Paw Withdrawal Test 3) Tail-Clip Test 4) von Frey Test 5) Autotomy

Answer 97

* Famous study (hidden-open study) * Placebo effect was being instituted * At min 25 using a hidden design, people were either given saline in which case the placebo continued or they were given proglumide which blocks CCK which lead to placebo getting even stronger * Means CCK is working in the opposite direction of placebo so it’s producing nocebo * Placebo and nocebo are working simultaneously but in opposite directions * If you do something in a negative direction to placebo, then you can infer nocebo effect * Proglumide is a blocker of CCK * Enhancing placebo is the equivalent of blocking nocebo * They concluded the proglumide was blocking nocebo therefore the CCK

Answer 98

- Subjectivity vs objectivity of measure (pain or depression vs. wound healing or Parkinson’s) - Nature of the verbal suggestion (“It can be either a placebo or a painkiller” to “It’s a powerful painkiller”) - Previous experience - Belief/expectation/desire of patient and clinician - Patient-clinician interaction (the “therapeutic context”): - “Bedside manner" (enthusiasm, reassurance, empathy, communication) - White coats - Deep voices - Physical properties of placebo itself: - Sham surgery > i.v. placebo > i.m. placebo > big pill > small pill - Expensive pill > cheap pill - Personality variables (ex: trait optimism)