1. Hand out has most everything I want you to know on it
Hand out has most everything I want you to know on it. Today and tomorrow, cover a subject we cant begin to cover. If you were to pick up a text book of pain and management of pain, put out by international association for study of pain its very thick. If you go to any of the international pain meetings, tremendous research to the study of pain. Interestingly the sort of formal study of pain is not that old. Physician at university of Washington, John Vineta (??), realized in 1950’s that medicine’s ability to treat patients with chronic pain, to address issues of palliative care, terminal end of life decisions, was totally inadequate, no systematic study of pain. Since then they have been the leading sort of route to initiate and foster idea that pain must be studied in systematic and integrative way. You cant study pain and talk about it without approaching from integrative standpoint. Physiology of neurons and nociceptors is exactly the physiology of any other neuron, already seen that sort of thing. What becomes interesting from the standpoint of someone who has pain is that how one responds to pain how one actually feels and perceives pain, intensity and emotional content of that pain is dependent on not just straight neurophysiology, hardwiring of spinal chord and brain, but also social background, emotional state, many things. Will try to point out these as we go along. What id like to start out with is think about history of pain and anesthesia. For you, you will be involved in one, treating patients who come in with pain, tooth bothering them so they seek treatment, will be involved in relieving pain, but also be involved with preventing pain, idea that you give local anesthetic, aren't doing preps on un-anesthetized teeth. When I was little, first dentist had slow speed hand piece and didn’t believe in local anesthesia. Also in the practice, may run across more difficult kinds of pain cases, chronic pain cases, patients come in who might have trigeminal neuralgia, may also sufferer from other chronic pain. Those will be difficult to deal with in terms of diagnosis and management, will require referral to specialist. Other kind of patients that you have, fits of phobic pains, who not only don’t like coming to you but will claim they are in pain no mater how deeply anesthetized they are. We will talk about why a phobic patient has such a problem with pain.
To begin. On the top left, Horace Wells. Was for a long time credited with being discoverer of surgical anesthesia. A dentist in Connecticut, in 1840’s and he used to go to party, where parlor tricks would provide nitrous oxide or ether, and have frolics. Traveling shows were great, they would get people on stage, under influence of nitrous oxide, they would do stupid things like stumble around. Horace Wells noted that one person on stage, badly injured leg and didn't respond to the injury. No pain? Went back and under influence of nitrous oxide he had a colleague remove a tooth of his. Felt no pain. Painless tooth removal! YAY! Does more cases and is about to take it out to the world, Massachusetts general hospital, sets up experiment in operating theater to remove tooth of person under nitrous. He didn’t not get the patient anesthetized completely, patient wakes up and starts screaming, and they start laughing. Ended up in New York depressed and angry, put in jail for throwing acid at prostitutes. In prison, he anesthetized himself with chloroform and killed himself.
The one on the top right. William Thomas Green Morton, was a student of his. Saw what wells was doing, that wells was on the right track. Rather than going with nitrous, chose ether as the gas. In October of 1846 at Massachusetts general hospital, performed experiment. This time a success, came out looking like the winner. Horace wells was the discoverer, William Morton stole the idea. That’s the beginning. Few years later what was found out was that the man who really discovered it was the one in the middle. Crawford Williamson long, that began experimenting with ether 4 or 5 years earlier.

2. Definition of Pain (IASP)
Nociception and Pain
Definition of Pain (IASP)
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”
Talk about two things, nociception, and pain. They are two different things. Very common to read about pain pathways ,pain as physiological response, but pain is perception. Definition that IASP came up with is: all of these things are required for something to be called pain, unpleasant sensory and emotional experience associated with actual or potential. Potential tissue damage or described in such terms. That is the accepted definition of pain as a perception. Pain is in some ways related to couple of other sensations which are annoying or can be annoying, tickle and itch. Don’t often think of either tickle or itch as unpleasant but annoying.

3. Nociception vs Pain Tranduction* Conduction Spinal Processing
Perception
Begin to ask what is diff between nociception and pain, how do you tease out what’s going on in terms of tissue damage, to brain saying ouch. We can think of nociception as this ability to sense actual or potential tissue damage. Three steps. Transduction. At a receptor ending in skin, just as visual receptor or other sensory receptor, have to have stimulus that’s transuded into electrical signal conducted along the neuron. Transduction. Here point out that with nociceptors, use that terms as the receptor involved in sensing tissue damage. Specific subset of peripheral sensory receptors, you don’t have something that would normally transmit just pressure or light touch and by over stimulating it get pain. Nociceptors, those nerve en dings that actually sense tissue damage are specific receptors specialized for that sort of reception. You would have transduction in periphery, nerve endings here of nociceptors, responds to physical injury or very hard pressure, rapid increase or decrease in temp, or presence of chemical. This would then lead to depolarization, and conduction of the signal back into central nervous system. Notice that basically afferents involved are C fibers and A delta fibers. This comes back to dorsal root ganglion, for you the ganglion most important is trigeminal ganglion. That conduction then, transduction of physical or chemical signal, into an electrical potential, conduction back to CNS, and within the CNS the signal is passed onto higher centers. One thing that we will look at and talk about is something that goes on in dorsal horn, or equivalent of dorsal horn in trigeminal nerve, that within the spinal cord that it isn't just one to one passage of signal, release of NT synapse and then conduction via projection neuron into brain. Actually processing of signal that goes on. This processing is very important. It doest a couple things one it prevents just any old signal from being passed on, not always ouch ouch ouch, because of accidental firing. Also ways of changing what information is allowed through there, a gate. Talk about gate theory. That is involved in how spinal chord recognizes when an injury or a potential injury is severe enough to alert you to that as a problem. This spinal processing is extremely important. From spinal cord or trigeminal spinal nucleus, signal passed to second neuron to thalamus in brain. Its at the thalamus that you first have initial actual perception of pain, actually sense pain, cant localize. If all you had was thalamus and no cortex, no localization. At thalamic, can sense pain. Know something is wrong. Perception, all of this was nociception. Transduction conduction and spinal processing. This was nociception. Just a way of detecting and passing along information that yes there has been injury in periphery. Now in thalamus and to the cortex, also projections into limbic and reticular system, all of that then is pain. Pain as a perception. Nociception, all this normal cellular physiology, then perception, realizing that making some sense of it, pain, and knowing what hat means is perception
At thalamus you will be aware of pain but wont be able to localize it or to make anything of it, to respond to it or have emotional effect or anything like that. At thalamus, there is an awareness of pain as opposed to how you think about it.
*Nociceptors are a specific subset of peripheral sensory organs which respond to noxious stimuli.

4. Categories of Pain Physiological Clinical Persistent
In order to really make sense of pain, have to divide pain into categories. Notice that for today and tomorrow I will divide it into three categories. Allows us to think of just the basic four steps, but also to think clinically about what can go wrong, or what happens under differing types of circumstances that make pain a different creature for different people. Physiological pain, this is what I showed there, you bang thumb or paper cut, you feel it, respond to it, no great consequence. That is what it is. You feel it, aware, respond, take some action to it. That physiological pain is a protective mechanism. Its good pain. Because if you put hand on hot stove or you accidentally put hand on some broken glass, respond to it, immediately fixed on looking at what's happened if you haven't already pulled away. You will be motivated to take some action, to remove yourself from whatever danger or object is causing that pain. This is a reflex mechanism , protective. Its something that we all depend on, a great deal. If you don’t have that protective mechanism, some people don’t, disease where you lose the ability, no longer have protective ability to feel pain, leprosy, lose peripheral receptors, and also diabetics check their feet a lot, is that they sometimes lose sensation in their feet, cant feel it, injure foot, untreated injury. Get gangrene in worst case. Other times, “gee when did I do that?” not because you lose ability to feel pain, but part of that spinal processing, can get people to ignore pain signals.
This is what we will talk about first, looking at this idea of how do you take physical tissue injury and translate that into not only perception of pain but response to that. C
Clinical pain, this falls into category of what happens after injury and you have inflammation. Injure and severe enough to get inflammation at site of injury. Other example is surgical pain, post surgical, where there has been an injury and now you have pain that has to be taken care of in some way thorough analgesic.
Persistent pain, this is the really big problem in the world of pain. Sometimes you have injury or even if you cant find any organic cause for it, person experiences pain. Persistent stays around for a long time, like chronic back pain, migraine headaches trigeminal neuralgia, myofacial pain, multiple pain sites around the body and person experiences pain when you touch. Cancer pain, age related pain, all kinds of sorts of persistent ain that are an enormous problem for clinician.
Physiological pain, initial transduction of message, clinical mostly thinking about what happens in state of inflammation and continuing peripheral stimulation of nociceptors ,ad persistent with variety of causes at peripheral and central level that in some cases we don’t understand at all.

5. Physiological Pain “Fast” pain – carried by Ad fibers Sharp
Well-localized
“Slow” pain – carried by C fibers
Aching
Poorly localized
First if we think about the idea of what type of nerve fibers carry pain. These are things that you should remember from pulp. We can talk about fast pain or first pain, carried by A delta fibers, medium to small size neurons that are lightly myelinated, they are myelinated. If you remember from other lectures conduction velocity is 12 to 30 m per second. When we talk about fast pain, characteristic is that its very sharp. Quick on and off pain. You know it, feels sharp. Epicritic is also used. Generally well localized, so this is the pain that gets your attention when you have paper cut, immediately know where it is.
Also experience of other pain, slow pain, after you have banged your thumb, really hurts, then gradual onset to peak and then off of dull ache, throb. Problem is its not well localized. Low pain or second pain. It is slow, carried by C fibers which conduction velocity is only half a meter to two meters per second. 10 times to 20 times slower than the signal that is carried by an A delta fiber. When you think about physiological pain, think about quick alert focused pain, fast pain, and then slow second pain, dull throb. In general, that’s how we describe two types of physiological pain.

6. Nociceptor Activation
Heat  VR1
nucleus
Ca+2
Glutamate
ATP  P2X2
H+  ASIC
Na+/Ca+2 ?
PKA/PKC 
Bradykinin 
Mechanical
What's happening at receptor. Think about the cellular physiology of those receptors. Just picture accidental incision, acid on hand, etc. This is kind of what you have. Cartoon of the nociceptor. This is the cell body, what I haven't shown is that coming off is all sort of peripheral processes leading out. Three nerving endings out in the skin or dental follicle or gingiva. Out one side is free nerve endings, then moving back into CNS, another process, going central. This drawing is not anatomical. Think abut what goes on in terms of activating nociceptor. What kind of chemical and physical signals will lead to nociception. One of the things, interesting about nociception compared to just a plain sensory neuron picking up light touch. Dealing with A beta fiber, general sensory, large fiber. For general sensation, those have low thresholds for activation, doesn't take much to activate a general sensory neuron. A nociceptor is different, has high threshold of activation, really takes a signficant push to get these things to fire. Don’t want them going of at any old thing. Difference between sensory fiber like A beta, low threshold, vs nociceptor, high threshold.
What kinds of things can do that? Heat is one thing, all of these channels basically involve opening of a calcium or non specific cation channel. Unlike the channels that are involved in propagation of action potential, these are chemically gated, not voltage gated. Physical distortion or chemical transmitter, chemical compound to actually get these to work. Heat receptor, involved that is vanilloid receptor, interesting because it was discovered, because people noticed that if you eat chili pepper it feels hot. Then isolate compound in chili that is responsible for feeling of heat, capsaicin. Basically it interacts with vanilloid receptors, beginning of understanding some way heat is responsible for opening these receptors up, let in calcium, depolarize neuron, open voltage gated channels and action potential occurs. Based on that process. Heat can activate a neuron, vanilloid receptor, also components like ATP. Damage the cell, what leaks out? A lot of ATP, ATP floating around, purinergic receptor bind it and lead to activation of the nociceptor. Acid in the sense that there is acid sensing ion channel will do the same sort of thing. Hydrogen ions activate that. All of these thing will lead to depolarization of cell, initiation of action potential, propagation of that action potential then back to CNS to e processed. Notice on the same slide, point out that mechanical.
Know that there are some cells that respond to deformation of plasma membrane fibroblasts will deform the membrane open group calcium channels. Potential is that if you deform the plasma membrane are channels that respond to that deformation. Lead to transduction of mechanism of the signal. Still sort of a big question. Bradykinin will cause intense pain, produced in an area of injury, acts in slightly different manner, not an ion channel the way hydrogen ion or ATP or heat might act. Acts through protein kinase. A or C which by activating those two protein kinases will lead to increase in intracellular calcium. All mechanisms lead to increase in intracellular calcium or opening of something that allows sodium in.
Bradykinin is chemical compound, kininogen in blood, broken down, made in liver, circulates, and in area of cell injury will break down to bradykinin, not only will it cause pain but increase vascular permeability etc.
VR1= vanilloid receptor
ASIC=acid sensing ion channels
P2X2=purinergic receptor

7. Nociceptors in Teeth 1. A fibers thermoreceptors mechanoreceptor
2. C fibers
polymodal (chemoreceptors)
Back to teeth, remind you were we were about that. Nociceptor in teeth, a delta fibers, those are thermo receptors or mechano. A delta basically if you are A delta you are either mechano or thermo receptor, do one or the other. But also, nociceptors that are C fibers, these are polymodal, will respond to heat, but most of all to chemical compounds. Chemo receptors for most part, but respond to a a lot of chemical compounds, often called polymodal. Nociceptors, this is what you have. In terms of sensory innervation of the tooth, any time you activate any of these things if its thermo receptor or mechano, don’t feel pressure in pulp or increase in temp, feel pain, perception. That’s because there are nociceptors and not other kinds of sensory receptors involved in sensation. In PDL also nociceptors, too much pressure on that or if you have braces and move wires too much, can hurt. These in teeth are very important, mostly within the pump chamber itself and pulp horns particularly. Remind you that we talked about hydrodynamic mechanism, nociceptor ,A delta fiber, that

8. Hydrodynamic Mechanism of Dental Pain
Odontoblast
Predentin
Dentin
Odontoblastic Process
Subodontoblastic Nerve Plexus
A Fiber
Axon Terminal in Tubule
If in some way its disturbed mechanically or thermally, if its disturbed mechanically by changes in fluid pressure, get sharp pain associated with a delta fiber. If in prep of tooth you crate inflammation because of deep caries, that inflammatory soup with those chemicals can activate C fibers and you have patient coming in with dull ache that covers whole jaw.

9. Substantia Gelatinosa
Spinal Processing
Nociceptive nerve endings synapse in the spinal cord (substantia gelatinosa) or medulla (nucleus of the spinal tract of CN V).
Information passed to thalamus through the activation of secondary (projection) neurons.
Spinal Nucleus (C.N. V)
Have activation now of nociceptor, that can be either through thermoreceptor, nociceptor detects rapid changes, increase in temp or rapid decrease through sensing of chemical in environment of nociceptor, mechanical deformation, deep sharp heavy pressure, conduction of signal into CNS, along the axon, and then within the spinal chord then you have synapsing on something called projection neuron. Projection neuron is second neuron of pain pathway. In the case of somatic sensation in general body, you have receptors coming in from viscera or skin through dorsal root ganglion and synapsing in dorsal horn. Several different anatomical layers of the dorsal horn, that are involved in different kinds of sensory reception. One of the ones that’s important for a pain pathway is substantia gelatinosa, in general spinal cord. Analogous thing happens in oral structures in trigeminal system, but in this case not to dorsal root ganglion but through trigeminal, as you come into ganglion general sensation will go to main sensory nucleus but the pain pathways, neurons that will be involved in projecting this nociceptive info to higher levels are found in area called spinal nucleus of five. Pons, medulla, come down to level of C1, have very long nucleus called spinal nucleus. Its in the spinal nucleus, in this caudal region of spinal nucleus that you have most of the secondary neurons that are involved in passing trigeminal nociceptive info into thalamus. Whether its coming into spinal cord or spinal nucleus of trigeminal spinal nucleus in medulla, this information is relayed up to the thalamus. Within this thalamus you have another synapse, three neuron process. From there you have this thalamic synapse then you have neurons that will go to the somatosensory cortex, from there you begin to localize and think about what kind of pain. Other projections to reticular and limbic systems. This is the spinal process.
Interesting here, going to digress, you have sensory from blood vessel, like viscera, gut or heart. Will talk about topic of pain from viscera projected to other regions. Referred pain.
Substantia Gelatinosa

10. Referred Pain Visceral Nociceptors
Fibers usually run with autonomic fibers
Large receptive fields
Converge on neurons that receive somatic input
Lots of theories about why you have this referral of pain. If you have heart attack, left arm, to mandible. Sometimes esophagus problems ,is between shoulder blades. One of the things to keep in mind about this idea of referred pain is that visceral nociceptors are an odd creature. In the sense that you may even remember from gross anatomy, in terms of sensory fibers, they very often run along with the autonomic fibers, going along in that same pathway. Other thing is that if you think about visceral nociceptor, cutaneous nociceptors have very small receptive field. Have well localized perception of pain on the skin. But, the receptive fields for visceral nociceptors are very large. Will cover a lot. One nociceptive neuron sends branches ot larger area. True for not only gut but teeth. One of problems as dentist, pain, cant tell which tooth it is. Reason they cant say its 19 or 18 is because nociceptor neurons began in the dorsal root ganglion might send branches to all three teeth. Brain gets confused. Other thing that plays into that, not only large receptive field, but what becomes important from standpoint of referred pain, visceral nociceptors converge on those that receive somatic input. You have skin neuron coming, cutaneous from same dermatome to one level, and visceral ending at the same projection neuron. Cutaneous and visceral nociceptors end up synapsing on the same neuron or sets of neurons, so pain fools your brain and you get referred pain. Same in head and neck.
Fact that you can confuse sinus pain and tooth pain. Also the case that you can have pain in one part , which in fact if you hit part that has inflammation, pain is felt in different region. In oral medicine, you will talk about idea that sometimes diagnosing pain in head and neck is difficult if you cant find periapial abscess or deep carious lesion. Remember guy with every tooth was endodontic procedure, so they kept filling. That was not a problem of tooth pain, but problem of persistent pain conditions, atypical adontalgia (sp??). If dentist is not thinking about it, they get fooled and over treat a patient.

11. (a-Amino-3-hydroxy-5-methylisoxazole-4-proprionic acid)
AMPA Receptor
(a-Amino-3-hydroxy-5-methylisoxazole-4-proprionic acid)
Natural agonist is glutamate
Permeable to Na+ and K+, but not Ca2+
Channel opening short (10 ms)
Glu
Na+ K+ Ad SP C PN
When you get into the spinal chord, how is the signal then passed. Don’t like the text book, only talk about substance P, transmitter in pain pathway it is a transmitter, but its not the only one. Not even the most important. The most important neurotransmitter in the CNS in terms of nociceptive transmission is glutamate. In the case of physiological pain, in particularly from A delta fiber of C fiber, the compound released in greatest quantity is glutamate. Here is projection neuron, sends info to thalamus. Then primary neurons, releasing glutamate. They act on one of several sort of glutamate receptors. One involved in physiological pain is AMPA receptor (don’t remember long name). Be aware that here are several receptors for glutamate, one involved in physiological pain, that’s sharp and also from C fibers is AMPA receptor, interesting channel, opens up, and you get ,permeability to sodium, characteristic, short on short off, on off, that allows for quick signal to be passed. This is what is then involved in physiological pain.

12. Ascending CNS Pathways Spino- and trigemino-thalamic tracts
Thalamus (sensory-discrimination)
Reticular/limbic systems (motivational-affective)
Cortex (cognitive-evaluative)
Think about this problem. We know that there are ascending pathways. Come up and go to thalamus, but why is it hat not every injury, firing of nociceptive neuron actually makes it up into the pathway, why aren’t you constantly bothered by a barrage of nociceptive info and always in pain.
To understand pain, must understand pharmacology, sociology, anatomy, psychology etc. Very complex function. Yesterday I ended up in the spinal cord, we had the transmission of the nociceptive signal from primary nociceptive afferent cross into the secondary neuron in that pathway, projection neuron going ascending to higher center. That transmission is largely due to the release of glutamate from a delta and C fibers acting on AMPA receptor, one of the three kinds of receptor glutamate. Goes to channel that goes rapidly on and rapidly off. Once that signal has been transmitted across that synaptic junction in spinal chord, to perceive the pain, signal has to ascend to the higher centers. Could also create a reflex, with spinal cord and spinal nucleus and get muscle response, like when you put your hand on something hot and don’t feel pain until your hand is away. In terms of anatomy, important from standpoint of physician, once you are in the spinal cord after projection neuron is activated, then that fire ascends through spino-thalamic tract and goes to synapse within the thalamus. The analogous pathway is from the spinal nucleus of trigeminal nerve through the trigeminal thalamic tract, both ascend through spinal cord through midbrain and synapse on thalamus, the relay station for everything that takes place after that, here that first awareness of pain as perception takes place, form that point the signal can be sent to many different regions, mentioned the definition that pain is unpleasant experience, emotional associated, can change affect and mood of indivi8dula and motivates people to do something. That is all taken care of by the fact that from the thalamus there are tracts that go into limbic and reticular system, here is where motivational and affective aspects of response to noxious stimulus come about. We also know that part of the pain response is you can localize it and two you can think about it, evaluate it, is it serous pain, consider something other than feeling it, a higher function in the cortex. Cognitive functions associated with perception of pain. Pain in terms of perception and the response to it and changes in mood and emotion that it sort of insights then the result of nerves going to many regions of the upper CNS, thalamus reticular limbic and cortex. One of the problems yesterday, say you have a few nociceptive neurons firing, not every nociceptive incident, not every noxious stimulus is perceived, you can have small injury, involving a few nociceptive neurons and you wont perceive that, it would be too low a stimulus. Not everything gets through. Problem is why does that occur, what sort of keeps us from always constantly feeling like we are n pins and needles, are constantly or by accidentally causing damage to few nociceptive neurons, concept that came up was much like you have door keeper or gate keeper, allowing who can come in and leave, there is a gate keeper in spinal chord or spinal nucleus known as gate control theory of pain.

13. Gate Control Theory of Pain
(Melzack and Wall, 1965)
Ad & C
Ronald Melzack and Patrick Wall came up with this in 1965.
Since they first published idea that there was a gate keeper within the spinal cord this theory ahs been elaborated considerably. If you look at modern view, very very complex view. From a simple sort of way of thinking about gate control, and regulation of nociceptive signals being passed from primary to secondary and ascending to higher centers ,use this drawing. If we look a delta and C fibers, nociceptors, and if I were doing straight pathway, which is tissue damage, causing action potential, will follow this pathway, to the yellow neuron, P, projection neuron, this is the secondary neuron in the pain pathway in the spinal cord or spinal nucleus, activated by glutamate for instance, signals pass to thalamus then up to the cortex and you feel pain. That doesn't always happen, there is a way of preventing that from happening randomly or all the time. One way of having that happen is within the spinal cord there are other kinds of neurons, neuron in green here, I, Is interneuron, in the case of this drawing, its also an inhibitory neuron. When this inhibitory neuron is firing, impinges on projection neuron, if inhibitory is firing, it will inhibit this projection neuron from firing, it turns down the game. If its releasing inhibitory in the case of spinal cord most common are glycine and GABA, basically when those then are released across the synapse, turns down the sensitivity of the yellow neuron, takes more a delta and C fibers to be firing to get this projection neuron to pass a signal up through the spinal cord. That is one part. Question is what sort of works on inhibitory neuron in order to keep it functioning, to hold down sensitivity of projection neuron. For that, come down to the large fibers. A beta fiber, one of those things that is light brushing on the skin, low threshold mechanoreceptor, it sends normally just plain old mechano sensory information into spinal cord and under most circumstances it synapses in different part of spinal cord then nociceptive neuron. Light touch, things like that are separated physically and anatomically from nociception in this case, see that they drew this synapses from the A beta fibers to actually synapsing not only on projection but also on inhibitory neuron. In the case of the large fibers, it is a positive stimulus for inhibitory as well as for the projection neuron. In this case for nociceptive, its inhibitory on the inhibitory neuron but positive on projection neuron. This looks funny till you think about how the pluses and minuses should be drawn in different [proportion. If you look at A delta and C the positive is much larger than negative regulatory influence on inhibitory. In the same way, the large mechano low threshold receptors, the positive ion the inhibitory is much larger then positive on the projection neuron. As a result, what happens is that the a delta fibers and C fibers basically have positive response, or effect, excitatory on projection neuron, A beta have basically an excitatory effect on inhibitory interneuron. Result is that makes this fiber here the gate keeper, the large fibers. General tactile stimulation low level stuff going on because of clothing brushing on your skin etc, is keeping interneuron functioning, as a result because this is having inhibitory effect, takes a larger effect of the nociceptor neurons to get a pain signal passed up.
What happens if you lose that inhibitory interneuron? One is anything that comes through is only excitatory effect, another thing, clinical syndromes, now the few low threshold mechanoreceptors that have excitatory effect on pain pathway will cause pain. Light brushing on skin will cause intense pain. Interneurons basically act to keep the sensitivity down, act because they are under tonic influence from low threshold mechanoreceptors, all keep random information from A delta and C from firing and being passed up was pain. Simple view of the gate, way to monitor and regulate sensitivity of projection neurons.
Gate says that not every signal gets passed up, there is something that controls what does get passed up. Not a perfect system, some of the branches of the large fibers will synapse on the projection neuron, why that is I cannot tell you, generally because of greater influence on inhibitory neuron, it doesn't cause a problem, only if you have the case where you lose the interneuron, and that does occur in chronic pain condition, so simple light brushing might cause pain.
Experience of banging your thumb, rub somewhere else and pain sensation goes down, basically over riding pain signal by closing the gate a little. A beta are mostly cutaneous fibers coming in. Ab

14. Inhibition Facilitation Descending CNS Pathways
That’s just at spinal cord. Know that in fact there are also other influences on that gate. What else is making the difference? Conceptually, gate is there in spinal cord, that is due to inhibitory interneuron, but also know that information is in addition to being passed up, info passed down that affects whether painful sensations are increased or decreased. Descending CNS pathways in pain pathway involved in either inhibition of facilitation. The exact gross anatomy, not worried that you know ,but go from cortex and either through the hypothalamus and this stands for periaquaductal gray matter, impinge on the same area, not only is there cutaneous information coming in, both nociceptive and mechano receptor, tactile if pain is passed, but signals descending will change how active the pathway is. Very complex.

15. PAIN - - Inhibition Facilitation Nx Nx + EXIN ININ + + DRG DRG + + + +
5-HT, NA(a2)
GABA, GLY
ENK, DNY
bEN, ACh
5-HT, NA(a1)
GLUT, SP
ACh (nic)
PAIN +
EXIN
ININ + +
ACh(nic)
CCK
DNY (N)
bEN, GABA GLY, ENK
DNY (k)
DRG
DRG
Not to remember all of this. There is brain, PAIN, projection neuron (PN), on one side, the inhibitory influences that are involved, and on the other side the excitatory influences. Inhibitory interneuron just talking about, cutaneous A beta fibers will impinge on it, get inhibitory interneuron to release GABA and glycine but also beta endorphins, enkephalins etc, negative inhibitory effect on projection neuron. These neurons are coming from higher centers, not A beta these are neurons located in hypothalamus, or in the periaquaductal gray mater, can be inhibitory or faciltory. Can have inhibitory through GABA glycine endorphins, don’t remember all the chemicals, or you can have facilitation of pain pathway. Typically examples that we might think of for this would be to think about how emotions can effect pain. Two typical emotions that affect whether a person experiences greater pain to a noxious stimulus or smaller pain response are fear and anxiety. Anxious person will end up activating facilitation, phobic patient, those will to the same intensity of noxious stimulus will feel or perceive more intense pain than someone who is not anxious. Phobic patients. We talk about fear, fear does the opposite, it has inhibitory effect, fear in terms of psychological aspect, understanding you are in immediate danger, worrying about the future danger is anxiety. Taking an exam that’s fear, worrying about the exam is anxiety. Not going to ask you about these various chemicals. Understand that these projection neurons are being monitored and controlled by both excitatory and inhibitory interneuron and those excitatory and inhibitory interneuron as well as the projection neuron itself is influence by neurons higher up in brain stem, influence of activation of those sensors can be inhibition of facilitation passing the signal up to nociceptive pathway. Now its getting complex SP
GLUT SP
GLUT - - + + Nx + Nx + PN PN

16. & Stress-induced Analgesia
Endogenous Opioids
& Stress-induced Analgesia
Enkephalins – dorsal horn
Dynorphins – hypothalamus, PAG, dorsal horn
-endorphins (involved in stress-induced analgesia) – hypothalamus
Endogenous opioids. Enkephalins , Dynorphins and beta endorphins are endogenous opioids, all inhibitory in terms of pain pathway. Stress induced analgesia, as a grad student I was angry about something, started across the street not looking, look up in time to see green pinto, the only way to survive this is to jump above the bumper, so I time the bumper, jump, hit the car, found myself 15 feet somewhere else still standing Go to the hospital . . .not feeling a thing. Walk into emergency room, then walked home and didn’t feel a thing. Went to sleep, woke up the next day feeling like id been dribbled. For seven hours I felt nothing before that, no bruises, no broken bones, no lacerations. Endogenous opioids they work! These compounds are a large part of response to stress and the fact that you can have true analgesia under stress.

17. (Inflammatory or Post-surgical Pain)
Clinical Pain
(Inflammatory or Post-surgical Pain)
Hyperalgesia
Allodynia
Pain Response
Stimulus
Intensity
An increased response
to a normally painful
stimulus
An painful response
to a normally innocuous
“Pain Threshold”
Now moving on to clinical pain. Clinical pain, talking about inflammatory pain, inflammation, or post surgical pain also involved in inflammation. Definitions here, to understand what’s going on. One is hyperalgesia, and allodynia. Actually on a continuum, not totally separate. Hyperalgesia, if you look on the x axis, this is stimulus intensity, so what is assumed is stimulus is strong enough to be noxious and activate nociceptive receptor, on the y axis, pain response, how intense do you feel the pain? Under normal circumstances the bottom line, as you increase noxious stimulus intensity goes up. In hyperalgesia, what happens is you take the same level of stimulus intensity and perception increases dramatically. For the normal level you get one pain response, for same stimulus, pain perception of intensity is considerably higher. You have all had this experience where if you have banged your thumb and later on you hit it again, it really hurts. That is an example of hyperalgesia. As a result of one of the things it does is it leads to guarding behaviors, when you thin about trying to protect areas that are injured, motivational aspect of pain. That’s hyperalgesia. Distinguish that form allodynia. Which is that if we look here ,the stimulus and you have stimulus that is normally not noxious, would not lead to activation of nociceptor, like the A beta fiber, just tactile, or non noxious heat stimulation. You get a response but no threshold to get pain as perception, but in allodynia, that changes, now a non noxious stim, like light brushing or warm water might lead to painful response. The example of this is when I was kayaking in gulf islands, spent the day on the beach one day, I forgot to put sunscreen on tops of feet, so they were pink that night, the next day we paddled 15 miles up to hot spring, couldn’t get in the water because the water was not that warm, not painful, but I couldn’t get my feet in the water. Cross between the two ,something that would normally not be painful was now intensely painful.
What sort of leads to the hyperalgesia, this is the one that most of the time you run across.

18. “Peripheral Sensitization”
Primary Hyperalgesia
“Peripheral Sensitization”
Na+ Channels
TTx-S/TTx-R
B: Transcription B
VR1, Na+ channels.
Heat  VR1
Glutamate
 SP
H+  ASIC A
ATP  P2X2
Two different types of hyperalgesia, one is primary, and the other is secondary. Primary, what's that? Basically primary hyperalgesia is increase in sensitivity of primary nociceptive neuron, if your have injury on the skin, in receptive field where you have injured neurons, they become more sensitive to further noxious stimulus, injury then pin prick, it seems more painful in small area. That is primary hyperalgesia. What leads to that? Several things, here was that drawing of nociceptor, central process going right, releasing glutamate, and the various channels involved in the pain response , vanilloid for heat, acid sensing and ATP through purinergic. In area of inflammation, one, you have the formation of Bradykinin from kininogens circulating in plasma, tissue creates this, in itself Bradykinin will activate a nociceptor an cause pain, but also increase sensitivity to other noxious stimulus. Other thing is that Bradykinin and cytokines, inflammatory molecules released by a inflammatory cells lead to increase in prostaglandin synthesis, which also increases sensitivity of nociceptive neuron. How you treat pain? Aspirin, something which is cytooxyginase (??) inhibitor, the pathway of prostaglandin. What are these things doing? Just increasing the sensitivity of the channels by causing changes in intracellular calcium, alter the internal environment, making nociceptive neuron more sensitive. The other thing that they do, quite interesting, straight sensitization, making the channels more liable to being opened up and get depolarization and action potential and activation of nociceptive neuron. Other things that this inflammatory soup does is increase transcription of three things. One is increases transcription of NT, substance P, glutamate is the basically the usual NT used by nociceptive neurons, but substance P under inflammation goes way up. Other thing it does is actually leads to insertion of more vanilloid channels, more channels that respond to noxious stimulus in plasma membrane.
Finally last thing, interesting from clinical problems, what happens to sodium channels. Notice that I’ve drawn in sodium channels, those are voltage gated sodium channels involved in propagation of action potential. Certain number of voltage gated sodium channels in plasma membrane of neuron and they are basically this time, TTX S tetrodotoxin sensitive, sodium channels, eaten foogoo? Foogoo, is the puffer fish, and its not common, most states its illegal to prepare it, the thing is eat enough to get lips to tingle but if you cant feel tongue then call ambulance, deadly toxin. When they were characterizing sodium channels in neurons ,they found that tetrodotoxin, the venom of puffer fish, what it does is binds the channels, blocks sodium entry. It is a reversible thing. That is how they characterize these. What's interesting, local anesthetics are based on ability of compounds like lidocaine to block these tetrodotoxin sensitive sodium channels. Interestingly, what happens in this primary hyperalgesia is that the cell starts making another kind of sodium channel, and in this case, tetrodotoxin resistant sodium channel, starts inserting them in membrane, increase in vanilloid channels, increasing sensitivity to thermal stimulation, but increase in intracellular calcium, increasing sensitivity to transduction, also then have a whole bunch more sodium channels placed in membrane. All of these lead to increased sensitivity in the nociceptive neuron. What makes this interesting is that in areas of inflammation ,clinically noted that its hard to get anesthesia. The basic theory is that the reason that is true is local anesthetic are passed on blocking this type of sodium channel but no affect on TTRs channel. In inflammation a lot of those around and you cant block them. Trying to develop new generations of local anesthetic that drop the tetrodotoxin resistant sodium channels and make am ore effective way of anesthetizing in area of acute inflammation.
Secondary hyperalgesia
A: Sensitization 
PG’s 
Bradykinin 
NGF
Cytokines

19. Secondary Hyperalgesia
“Central Sensitization”
Periphery
CNS
Injury
site
DRG/TG
Injury and inflammatory response results in increased nociceptor activation
Not a problem of sensitization of nociceptive receptor in periphery, but problem back in the spinal cord or trigeminal spinal nucleus, in this case what happens is that the injury and inflammatory response causing increased activation of nociceptors. In area of injury barrage of nociceptive information streaming back into CNS. As a result this barrage released to increased instability and decreased ability of interneuron to inhibit their activation. So you have all this stuff coming in and how its wrecking the gate, destroys the gate, breaks it down, how does it do that
Afferent barrage leads to:
Increased excitability
Decreased inhibition

20. (N-methyl-D-aspartate)
NMDA Receptor
(N-methyl-D-aspartate)
Natural agonist is glutamate; usually blocked by Mg2+
Depolarization opens channel by removing block
Channel opening has a long duration (100 ms) permitting summation of inputs (“wind-up”)
Ca++
Mg++
Glu SP
IP3 PN
AMPA
NMDA
What happens here, most common thing, that's coming back to the idea of glutamate and now substance P which is being made in much greater quantities by little C fibers. Remember that normal glutamate activates AMPA receptors, fast on fast off. But here is another type of glutamate receptor NMDA receptor, shown here, under normal conditions, channel, calcium channel blocked by magnesium. Normally blocked, not normally activated, what happens is as substance P is released at this primary afferent neuron it binds to its receptor leading to increase in inositoltriphosphate and increase of Ca from internal stores, internal calcium relieves the magnesium block, Mg goes away, channel is now possible to be activated by glutamate, now you get these channels and these channels are very long in opening , so duration of signal is very long, what does that mean, means that as you have certain frequency coming through so signal normally between each finger click of short opening and off, everything we close down and have to be open again, because of opening of new receptor signals overlap and pile up on one another, greater excitability of projection neuron, causes wind up, phenomena is something that if you want to do, if you start tapping, very small prick of pin will start getting to be very painful. In the case of NMD, now you have this overlap of signal, hyperexcitability of projection neuron, and that is one of the things that leads to this secondary hyperalgesia, in several cases, so much glutamate, things can be dumped into CNS that the glial cells cant handle it and will kill inhibitory interneuron. Now you have a physical change within CNS that can lead to a chronic pain condition, that’s secondary. Primary is the peripheral sensitization of receptor itself, secondary is problem of central sensitization where projection neurons are more sensitive. In normal course, inflammation clears up and everything goes back to normal, that’s what you want. After you have the inflammatory response everything clears up and goes back to equilibrium

21. Analgesics
Chemist figured out to figure out aspirin. Acetylated salicylic acid

22. The Pharmacological Approach
Glutamate SP
Na+ Channels
TTx-S/TTx-R
VR1
ASIC
P2X2 
PG’s
Opioids
Cytokines
Begin to see if you think of pharmacological aspects, to treat pain, in periphery, block prostaglandins for instance with Ibuprophen, aspirin, some of the other compounds out there, then you prevent sensitization. They are now finding opioid receptors on these nociceptive neurons and research is aimed at how to make flavors of opioids that don’t cross blood brain barrier so they only have peripheral action, limit bad side effects of opioids. Blocking cytokines. Other things, if you learn to figure out how to block TTX S channels, better anesthetic, better ways to inhibit channels. All these things in periphery in terms of current pharmacological research, better analgesic with less bad side effects, in terms of CV and GI

23. PAIN - - Inhibition Facilitation Nx Nx + EXIN ININ + + DRG DRG + + + +
5-HT, NA(a2)
GABA, GLY
ENK, DNY
bEN, ACh
5-HT, NA(a1)
GLUT, SP
ACh (nic)
PAIN +
EXIN
ININ + +
ACh(nic)
CCK
DNY (N)
bEN, GABA GLY, ENK
DNY (k)
DRG
DRG
Central suit here. How to selectively activate inhibitory interneurons or some way to block one of these excitatory molecules, then you have a great way of blocking pain. Right now opioids are what we have for doing most of that, but there are other sorts of things out there, like in some chronic pain conditions, antiepileptic medication is used in trigeminal neuralgia, don’t know why they work and control seizures and stop pain. This again is meant to show you that there are many different targets for potential relief of pain that will come on market SP
GLUT SP
GLUT - - + + Nx + Nx + PN PN

24. The Problem of Persistent Pain
Peripheral Processes
Spontaneous activity
Sympathetic activity
Nociceptor sensitization
Central Processes
Central sensitization
Spinal reorganization
Cortical reorganization
Loss of inhibitory pathways
Conceptually, don’t have time to go through this, difficult problem. If you look at the problem of persistent pain, under normal conditions, after surgery or inflammation goes away that everything goes into equilibrium but it doesn't, variety of chronic pain conditions, these can be due to peripheral problems, either because continued spontaneous activity of nociceptive neuron for whatever reason, sometimes sympathetic activity gets involved sympathetic will increase the receptor sensitivity and nociceptor sensitization we've talked about. Also central sensitization, projection neuron excited and never calms down or lose inhibitory neuron. In some conditions, those a beta fibers, will grow into an area normally responsible for pain, spinal reorganization, or even cortical reorganization causing more pain perception, and loss of inhibitory pathways. Leave you with problems of persistent pain, both peripheral and central changes can lead to chronic pain, diagnosing what is happening can be difficult and there are residencies in pain in major medical centers that do nothing but look at patient with chronic pain.