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"Hi there - me again, C - 

"I found the coolest family genealogy picture ever, and thought I'd share it:

Cell differentiation 

"See at the bottom right corner? That's my GreenDad down there! 

Are the nervous system and the immune system the 'same thing'?

"Now, I want to turn your attention to something Mick Thacker said*: 

"Due to our need to compartmentalise thinking and establish isolated fields of study (particularly in medicine to allow for specialisms) we have overlooked the critical synergy between the immune and nervous systems and more importantly that the nervous system and immune system are one and the same."

"Back in the diagram, see the word "haemopoiesis" circled? With "immune cells" beside it? That's where micro glia come from, and those mast cells, and leukocytes, and macrophages.  I wanted to show you where they come from - they're blood cells. I don't agree that we are the "one and the same." 
" I don't agree with that at all.

"Those are the cells whose excretions/secretions sensitize me. 

"We might have been from the same distant ancestor, a fertilized egg cell, but we sure grew up different, and now we have a somewhat bitter relationship, sort of like lions and hyenas have with each other. Lions and hyenas might both be mammals, but are not the SAME mammal - they don't like each other, annoy each other, kill each others' cubs when they get the chance - yet both help maintain the overall ecosystem. 

"The way immune cells and we C's provoke each other, in a balance, within very narrow boundaries, keeps things lively and moving and tugging at the molecular protein level in a biochemical dance that helps keep everything stirred up, and helps maintain  'life' of the whole organism. MIRight? 

"And listen, if and when there isn't enough blood flow to cart away all the stuff I make - myself -  I can sensitize myself, too!" 


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1. *Nails in the coffin   -- Body in Mind blogpost by Mick Thacker, May 2, 2011

2.  Basbaum AI, Bautista DM, Scherrer G, Julius D; Cellular and Molecular Mechanisms of Pain  Cell Volume 139, Issue 2, 16 October 2009, Pages 267–284 open access [Pssst! try the word "Nociception" - it won't "hurt" you - haha! Yours truly, C] 

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"Hi there - it's me, C again.. 

"I found another picture to sum up what I do. You've heard of people who are shocked by a loud sound, sight or sudden touch, and nearly "jump out of their skin"or "wet their pants"? Same thing happens to me! I'm kind of trapped, so I can't "move" physically, but I can certainly move chemically! 

"This picture shows what happens if someone comes along and gives me a high-enough-threshold surprise that I "jump." 

When a nociceptor fires

"The thing is, I have a lot of branches, a lot of terminations. Each terminal goes to something else. Many kinds of Delicious. A smorgasbord. When I fire, I squirt all over everything. Each of the things I am in contact with will feel me, will feel my, ...um..., products. 

Keratinocytes
"Keratinocytes are skin cells (step-siblings of mine, the offspring of BlueDad, from the last post). When I fire an action potential the stuff that squirts out stimulates them to grow.

"Think how cleverly this worked out for evolution - if I'm getting prodded hard enough to make me jump, chances are pretty high some skin damage may have happened, and what a lucky thing for skin cells - the stuff I produce helps them divide and grow, so the potential "wound" can heal quicker! Win-win for them!

"Another side though - have you ever had a rash? If it had nothing to do with being in contact with poison ivy or some other irritant, chances are that was a fight going on in your skin, that was straight from your nervous system. By that, I mean, maybe it was a "neurogenic" rash. Hey, I can be affected at either end, so if there was a lot of stress going on, Upstairs, it could have been felt by me... if there was enough of it going on that I become sensitized, I leaked easier, which bothered the skin cells and immune cells faster than my products could be carted away by the lymph system. The skin cells grew, were inflamed, because the immune cells thought they had to fight something, the skin layer swelled because I bothered the arterioles and venules... it all occurred just as if there had been some kind of "danger", some kind of skin breach, except, there wasn't!  It was just me, being over-stimulated, growing too many receptors, making more stuff than normal, becoming too easily bothered and leaky... bothering myself in the process. 

"Hey, I don't like when that happens any more than a baby likes to sit in its own wet diaper feeling the burn from its own diaper rash. All of us feel it!" 

Mast cells
"Mast cells make their own kind of horribleness when they are stimulated by me, which affects me and everyone else in their own particular ways, just to add more biochemical complexity to the situation. I mean, I'm sensitive to histamine, serotonin, prostaglandins, nitric oxide.. don't get me started on all the kinds of leukocytes - eyew! Cytokines, prostanoids, leukotrienes, and more nitric oxide.. and only just a few things in the kind of inflammatory soup we can all end up in, me and my Delicious's, if we start over stimulating each other."

Smooth muscle
"Smooth muscle cells are everywhere, all through skin, hypodermis, walls of vessels, walls of glands, ducts, viscera, erector muscles for hair shafts, goose bumps, you name it. Everywhere striated muscle isn't,  I guess you could say. The stuff I make stimulates it to contract. It needs me to stimulate it to contract! Well, me and the autonomic system, depending where and what for.. 

"Bodies need smooth muscle, and it's nice to feel needed, but what's not so good, is if contraction of smooth muscle becomes chronically overstimulated, happens to squeeze down too hard on something that's important, i.e., me, or some other kind of neural structure. Or vascular structure. Or drainage structure. That can mess big time with physiology as usual."

Vessels
"Like we already saw,  nothing happens at the capillary level except capillary action. They don't respond to anything, because they don't have to. But the vessels just ahead of them get bigger, and the ones behind them leak. 

"If the vessels ahead of them get bigger, more capillaries open up (lazy things! - there are usually more of them available than actually function, kind of like those so-called "work crews," where 10 guys stand around and watch while one guy does all the shovelling) to handle the increased flow. Venules "extravasate" - that means, they leak. What do they leak? Plasma. What's in the plasma? Bradykinin and serotonin! So, yay [not]!  More stuff to irritate me, and other nearby nociceptors that all were just minding their own business, until they activated because of the stuff in the plasma!"

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Mason P; Medical Neurobiology Oxford University Press, USA; 1 edition (May 19, 2011)

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The family tree

"Hi there, me again - C fibre. I wondered if you might be interested in my family tree - I don't have photo albums but I think you should know my background, at least a little bit, so you'll know better where I'm coming from.

"I was reading my last post, and noticed something in the Levi-Montalcini article that I thought I'd pick up on, and explain." 

"The peripheral nervous system of vertebrate animals includes three kinds of nerve cells: sensory neurons, which transmit impulses from sensory receptor structures to the brain; motor neurons, which innervate the striated, or skeletal, muscles, and autonomic neurons, which regulate the functional activity of the circulatory system, the organs, the glands and the smooth muscles (such as those of the intestine)."

"So, OK, I realized I needed to clarify something; here it is... (deep breath):  I disagree with lumping "motor neurons" in with peripheral nervous system as though we were all the same. I mean, yeah, we are all long neurons, and we travel together long distances woven throughout the Body in the same nerve trunks. But the whole categorization of neurons simply by location is completely misleading, and I wish it would end. It makes me feel quite nociceptive - a mild case of peptidergia comes over me whenever I see it in print anywhere. 

"Here's the thing (another deep breath...) : we come from the same "Mom," ectoderm, but we have different dads. 
"Sort of. Let me explain. 

"It has to do with stages of division. See the pretty coloured picture to the right? OK, so it's all "ectoderm," or Mom stuff. However, the colours represent the "Dad" in the situation, OK? 

PurpleDad
"The Dad of motor neurons is the purple stuff. All neurons from "PurpleDad," aka NeuralTube, make up brain and spinal cord. They are usually short, and there are billions and billions of them... Lower motor neurons are still from PurpleDad - their heads live up in the spinal cord - and they have only one arm.. yeah, it's a very long arm - like, it can reach all the way to the big toe, all that.. but still, it's a Purple kid. 
"PurpleDad's kids are usually way more enclosed, inside the CNS, which makes lower motor neurons kind of an exception, but ... there is no getting around the fact that apart from that long arm sticking out, they are CNS neurons. 
"There is a huge variety of Purple kids, and they make important stuff in there. But you know, they're a lot like city kids; they're used to living enclosed, separate-from-the-rest-of-the-body kinds of lives. They are mostly self-referential. It takes an awful lot to get them to pay attention to the Body, usually. Like, they'll pay attention to it fast if there is something wrong with it - but I, together with a whole bunch of other nociceptors, or a huge number of pleasant-signaling C fibres, have to make a huge noise to get their attention - usually they are completely oblivious. Unless they practice some sort of deliberate body focused exercise regularly, or meditate. 

"Anyway, the big take-home point I want to make here is that just because neurons end up physically in some place outside where they came from, doesn't mean that they completely change their attitudes or habits or language or who is most important to them. And lower motor neurons whose job is to make striate muscle jump are central nervous system neurons, not peripheral neurons. They're there to drive tractor, but that doesn't mean they understand the soil or how it smells or how to grow anything in it. They don't really have their heads in the game, do they? 

GreenDad
"My dad is GreenDad - his formal name is NeuralCrest. His offspring kind of scattered everywhere. We are sensitive to signaling, and we lovelovelove to signal, and we can speak more signaling languages than offspring from PurpleDad (at least I think we can..). I like to think we ended up a lot more autonomous, self-sufficient, innovative as a result. We'll talk to anybody!

"My head lives outside the spinal cord, outside the central nervous system, in a ganglion. I have scads of siblings. The entire autonomic nervous system is sibling. All the Schwann cells are siblings. All the glia in the brain are siblings - they have the same GreenDad. [Well, except for microglia. They're kind of more like birds, like little modern dinosaurs, they're from so far back in embryonic time.] There are GreenDad neurons in the central nervous system too - but they are inside cranial nerves. Not all the cranial nerves, but most. 

"And do you know what else? My green siblings that live in the brain help to manage all the purple siblings. Oh yes they do. 

"You know what? Teeth! Teeth are my GreenDad siblings! True fact. Look up "neural crest" and you'll find out the amazing variety of offspring my dad made in the beginning of the Body that our mom pretty much built, that we all help comprise, and now look after. Well, all the GreenDad kids do, at least.. 

"Here is something cool - pretty much the whole face of the Body we look after came from GreenDad, even all the bones and muscle and skin and cartilage and glands and stuff! Oh yeah.. and throat. Things needed for swallowing. GreenDad kids. Siblings. They can't signal the way neurons can, electrically, but they can talk chemically, for sure, and they talk a lot that way, to us, their GreenDad neuron siblings... 
"So, whenever I read something about the Body, or Nervous System, or signaling, or how smart glia are or how glia manage neurons in the brain, I already know who is who, and it makes sense. GreenDad is usually responsible. [He got around some back in the day, he did.. ]

BlueDad
"So, what about the BlueDad, you might be wondering... ? BlueDad's kids are skin cells, keratinocytes. They aren't neurons, but they do express TRPV channels, and are heavily involved in all the usual neuroendocrine signaling that goes on in skin. [GreenDad (my dad) has some skin cell kids too. Of course. Ha. He left kids everywhere.] 

"I'll talk more about my GreenDad again some time, maybe, because of all the Dads, I think he has the most interesting kids, and not just because he's my particular dad - this is an objective opinion - I mean, c'mon.. teeth?? :D  I am not kidding. The Body wouldn't even have a face if GreenDad hadn't been there to help build one."  
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1. Xiaoning Han, Michael Chen, Fushun Wang, Martha Windrem, Su Wang, Steven Shanz, Qiwu Xu, Nancy Ann Oberheim, Lane Bekar, Sarah Betstadt, Alcino J. Silva, Takahiro Takano, Steven A. Goldman, Maiken Nedergaard;  Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice. Cell Stem Cell, Volume 12, Issue 3, 342-353, 7 March 2013

2. Rita Levi-Montalcini and Pietro Calissano; The Nerve-Growth Factor: A New Tool for Manipulating Neurons. Scientific American, June 1979

3. Nicholas Boulais, Laurent Misery; The epidermis: a sensory tissue. European Journal of Dermatology. Volume 18, Number 2, 119-27, march-april 2008, Review article

4. Biology 4361; Neural Crest Cells. July 24, 2008

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"Hi there - me again, C fibre. I thought you might like to know a bit more about what turns neurons on. Here is an excerpt from The Nerve Growth Factor: A New Tool for Manipulating Neurons:"

"The human nervous system is a vast network of several billion neurons, or nerve cells, endowed with the remarkable ability to receive, store and transmit information. In order to communicate with one another and with non-neuronal cells the neurons rely on the long extensions called axons, which are somewhat analogous to electrically conducting wires. Unlike wires, however, the axons are fluid-filled cylindrical structures that not only transmit electrical signals but also ferry nutrients and other essential substances to and from the cell body. Many basic questions remain to be answered about the mechanisms governing the formation of this intricate cellular network. How do the nerve cells differentiate into thousands of different types? How do their axons establish specific connections (synapses) with other neurons and non-neuronal cells? And what is the nature of the chemical messages neurons send and receive once the synaptic connections are made?" - Neurobiologist Rita Levi-Montalcini, and Pietro Calissano, first published in Scientific American June 1979, republished Jan 3, 2013 after Rita Levi-Montalcini's death on Dec 30 2012.

"How indeed? Rita Levi-Montalcini was great. She discovered and wrote about nerve growth factor, which is what makes me ... well, I can't say 'big&strong', because I'm one of the thinnest long neurons that exist - so I'll just say, healthy."

"The peripheral nervous system of vertebrate animals includes three kinds of nerve cells: sensory neurons, which transmit impulses from sensory receptor structures to the brain; motor neurons, which innervate the striated, or skeletal, muscles, and autonomic neurons, which regulate the functional activity of the circulatory system, the organs, the glands and the smooth muscles (such as those of the intestine). Autonomic neurons are of two kinds: sympathetic and parasympathetic. The sensory neurons and some of the sympathetic neurons are situated in chains of ganglia flanking the length of the spinal cord. Because these neurons are uniquely accessible to experimental manipulation much of the research on the development of the nervous system at the cellular level has focused on how the nerve fibers projecting from the sensory and sympathetic ganglia make connections with their corresponding target organs."

" Well, as it turns out, this stuff is irresistible. To neurons. Ones like me, for example. Not only C afferents like me, but those sympathetic efferents too. I can only assume that is how I ended up in this situation, leading a boring life but for the occasional flare-up at my terminal end, nothing else much to report, staying alive... staying alive..

"Here's how I guess I was born.

"Once upon a time there was this single cell that divided itself up like crazy, turned into layers. One layer turned into a whole bunch of stuff that gave off signals of something Delicious. Another layer was turning into cells that could smell all this deliciousness, and struggled to follow after it. I was one of the cells in that latter layer. I escaped! I migrated a little way but then realized I was trapped at one end - I couldn't move anymore! But I could sure grow... and I did, until I could stay in constant contact with the Most Delicious Of All That Is Delicious, and relax. This seemed to take years, but finally the organism I am part of stopped increasing in size. Things have been pretty quiet ever since, on the growth side, at least..

"But back to the Levi-Montalcini story, which reads like a thriller: Nerve growth factor was first found in mouse tumors and snake venom. How about that! Later it was found in ordinary saliva. It wasn't the so much the stuff that mattered very much, it was the quality and type and folding arrangement of protein in the stuff that made it either Perfectly Delicious, or didn't. And do you know what else? If a neuron like me who smelled the Delicious and took off to find a place to plug into it, didn't find a good place to plug in, it died. So many fell in those first days, weeks, months..  But I digress.

"Here's how it works, according to this paper:"

"Once the elongating fibers have estab­lished the appropriate synaptic contacts with the target cells, the continued sur­vival of the innervating cells in the gan­glion appears to depend on the availa­bility of NGF. Studies conducted by Hendry at the Australian National Uni­versity and by K. Stockel and H. Thoe­nen at the Basel Institute for Immunol­ogy have demonstrated that NGF is taken up at the terminal nerve endings of the sympathetic fibers and transport­ed back to the neuronal cell body along the axon. This retrograde axonal trans­port of NGF is absolutely essential for the survival of the innervating neurons. When it is experimentally prevented (either by severing the projecting axons, by treating them with the drug vinblastine, which blocks axonal transport, or by ad­ministering 6-hydroxydopamine, which destroys the nerve endings), the inner­vating sympathetic neurons in the gan­glion die off.  The lethal effects of block­ing the axonal transport of NGF can be completely overcome, however, by sup­plying the cell bodies with externally administered NGF. In this case the exter­nal NGF makes up for the NGF that would normally be transported back in­side the axon to the cell body from the innervated cells."

"Absolutely essential. Our life blood you could say.
" I build receptors to capture the proteins:"

"Work in several laboratories has shown that the retrograde axonal transport of NGF follows its interac­tion with specific receptor sites on the nerve terminals of the newly established fibers. Receptors are proteins that are usually located on the external surface of the cell membrane; they provide spe­cific recognition sites for messenger substances such as hormones, neuro­transmitters and growth factors."

"Other kinds of cells can feed off that NGF too, you know, like cancer cells. And they can also make it.
"Anyway, to wrap up - that paper was written 34 years ago. Levi-Monalcini died just a few months ago, over a hundred years old. Her neurons all worked very well, it would seem, right up to the end.

"Since then research has uncovered all kinds and flavours of the Delicious. As long as there is enough of the Delicious, we can keep going for a very, very long time, we neurons can."

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"Hi, me again, C fibre.
"Yesterday, I told you a bit about myself..
"Today I thought I might add a little bit more. Every day, it seems, more is known about the kinds of things that can, potentially, bother me.. people seem to find this stuff fascinating, and, I suppose, so do I - ultimately, I am the one affected by it all..

"Anyway, first, I want to show you a cartoon drawing somebody did - remember I was telling you I had a long arm and a short one?

C-fibres enter spinal cord, their information ascends via the spinothalamic tract. Many kinds of C fibres convey many kinds of sensory input, including "pleasant", not just for temperature or nociceptive information

"Nice picture of my short arm, don't you think?

"Here's another cartoon - I'm in yellow, hanging out with a sympathetic fibre and some other body bits. As you can see in the picture I've become "sensitized" - when I get sensitized I seem to bother the heck out of macropages, then they squirt stuff back at me that makes me even more cranky. And so it goes. Before you know it I have adrenaline receptors growing all over my membrane. Honestly some days it feels like a total school yard in there, complete with all the usual assortment of bullies and bullying going on.

Sensitized peptidergic afferent neuron

"Things can get quite nasty, with a lot of inflammatory comments being passed back and forth chemically, plenty of swelling, redness, heat, primary hyperalgesia and my personal favorite, "Functio laesa" going on.. isn't that a fun term? All it means is loss of function, but life is so bland, usually, that I like when I get to speak Latin.

"Now, things usually die down in a few days. I mean, none of us really can keep that up for very long. At least, most of the time we don't even want to. Not that there aren't diseases that occur sometimes, where the positive feedback loop just gets bigger and bigger.. unless there is a good drug to stop it, like Rheumatoid Arthritis for example..  But usually things just go back to ho-hum normal. The swelling drains away and everybody stops being bothered by each other.

"If this happens inside a nerve trunk though.. ooh.. that's an enclosed space. It's a lot harder for inflammation to settle down because the situation is complicated by lack of space and no lymphatics that anyone knows about, so, potentially threatening pressure and not the greatest drainage.

"A nerve trunk is like a busy freeway with traffic zooming through tubes in both directions in many lanes, separated by curtains only. My job is the same as ever: provide excretion - I mean, secretion - fertilizer, kind of.. "trophic factors" is the polite term - to tissue, and accept trophic factor from the tissue in return. I deliver it back up to my cell body, or head, in the dorsal root ganglion, and there, I can make  stuff I need to keep myself in good shape. This is all transported back and forth on transport tracks that have nothing to do with the information flow I am also able to provide, when required. All neurons do this, by the way.

"Here's a picture somebody drew ages ago, showing how I look all in black, inside a nerve trunk.

Wonderful old-timey picture of the innervation of a nerve trunk and its vasculature

"You can see there isn't much room in there. When axoplasmic transport is interfered with neurons can actually die! You can see why it's an important job - protecting the tissue inside a nerve trunk. If the nerves were to fail... well, just let's leave it at this: the nervous system as a whole is very protective of itself. I have that small role to play, but really, it never changes. What the nervous system might make out of my reportage, is something else entirely."

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Ordinary existence in the micromilieu
based on image from Textbook of Pain

All winter I feel I've been immersed in the peripheral nervous system. Here is a picture I made, based on an image from Textbook of Pain, which depicts the interrelationship of:

1. (potentially nociceptive) afferents (which live most of their lives minding their own business, providing trophic factors to whatever they happen to be plugged into, not "nocicepting", unless or until something disturbs their peaceful (if ordinarily quite dull) existence;

2. sympathetic efferent neurons, whose job is to take over in a crisis - constrict vascular lumen size (if they go to hypodermis or viscera) and enhance blood flow to muscle "by as much as 1200%" (if they go to muscle - not depicted in this particular image) and lung;

3. vasculature, particularly the tiny stuff, the bottom of the system, where we can hardly tell what is arterial and what is venule anymore, because the vessels are so small, and capillaries don't care one way or the other - they just sit there and let the blood flow however it wants, through capillary action, because their job is to be as barely there and thin and leaky and passive as possible so that the red blood cells can  a...l...m...o...s...t  touch what is outside the physicality of the blood flow system, and let their oxygen cargo and maybe immune cells and other things escape into/ be downloaded into tissue space and by outside cells, part of whatever tissue they are feeding. 

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Life from a nociceptor's point of view

"Hi there. I'm a single long skinny cell. My name is "C" - "C" is for Cell. At least that's how I like to think about it. I'm the same as any other cell, just a lot longer and a lot skinnier, which means I have a lot more surface area compared to volume, compared to short spherical cells, which in and of itself makes me more "sensitive" ... relatively speaking. 

"There are lots of us C's, and we do different things - some of us are around to look out for trouble and kick up a fuss if we notice any. We are called "nociceptors."

"But truth is, it takes a lot to bother me. I have what I need in life - a place to live that's warm, enough to keep me alive, a job to do that isn't very hard - most of it is about ingesting then excreting (which is what all creatures do, regardless of their size - when it's a cell, this is usually called secretion, rather than excretion, but really, it's all the same thing when you take a close look.)

"I have one really really long arm, and one that's much shorter. My head lives in a special zone called the dorsal root ganglion, along with a bunch of other heads of other cells. Which is great, because we can talk about all kinds of stuff in there, to each other. Kind of.
One of my arms is very long. For example, I can span the distance of somebody's big toe, all the way up as far as the DRG, then with my short arm into the dorsal horn of their spinal cord - my short arm ends there, and some other second order neuron takes delivery of my information to places I don't have a clue about. Much of the time I have no idea if delivery even made it past that point. Whatever. I don't need to know what goes on any further up the track. My job is to do the best I can with the little arm and the long arm I have. I have non-nociceptor cousins whose second arm is a lot longer than mine - they can reach right up into the brain! Those cousins are much fatter than I am, too.

"People often describe me as unmyelinated. That's not really true. I have a coat. It's thin, and I have to share it with a bunch of other C's, but I have one, and it's a Schwann cell. My thicker relatives have thicker coats, and in fact, they can have several coats each. It's kind of not fair in a way; however, they are way more sensitive than I am, and their coats sort of protect them from the big dark warm wet world we live in with all its biochemistry. When I think about it, I'm kind of glad they have thick coats, or else they might bother me a lot more with all their low-threshold-i-ness.

"My closest sibling is ADelta. Even though our jobs are quite a bit alike, ADelta is a bit thicker, faster, and has a coat more like those low-threshold types. ADelta can often get messages upstairs a lot faster than I can.

"One thing I can do that ADelta can't, is I can make venules leak. It's something I can secrete or excrete, that ADelta can't. Why would I want to? I don't really know, it just happens... I'm "peptidergic."

"Lots of people blame me for pain. It's not true. I'm not responsible for anything that might happen upstairs. It's like blaming the guy who loads boxes onto a truck for the entire response of recipients who end up with what's in the boxes, and may not know what to do with it. Or maybe for the hairballs their cats who play inside the boxes after they've been emptied cough up...  I mean, it's not fair, right? I realize I play a small role, but hey, pain is not really about me. After that truck leaves the loading dock, anything that happens after that is not really my problem. So stop blaming pain on me. OK?"

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Moseley L; Teaching people about pain: why do we keep beating around the bush? Future Medicine, January 2012, Vol. 2, No. 1, Pages 1-3

EXCERPT:

"We tend to endorse the complexity of the brain and its fundamental role in what we experience. Unless, of course, we are talking about pain.Some 25 years ago, Patrick Wall, as frank a communicator as any, lamented the trend towards beating around the bush when it comes to pain: “The labeling of nociceptors as pain fibers was not an admirable simplification, but an unfortunate trivialization under the guise of simplification” [1]. Of course, equating pain to activity in nociceptors is seductive – nociception and pain seem so tightly coupled. However, are nociception and pain really so tightly coupled? This issue was actually settled a couple of decades ago – there is not an isomorphic relationship between pain and nociception, nor between pain and tissue damage... Meaning is a very potent modulator of the relationship between nociception and pain. Indeed, one might argue that meaning is the critical determinant of pain, because if a nociceptive input is not evaluated by the brain as reflecting a threat to body tissue, pain would clearly be an erroneous output, serve no survival function and offer no evolutionary advantage...Real-time modulation can involve neurally, neurochemically or humorally driven alteration of the response profile of neurones within the nociceptive neuraxis. So, the mislabeling of nociceptors as pain fibers was indeed a trivialization, but was it really that unfortunate? I contend that one need only look at the huge burden of chronic pain to uphold a resounding ‘yes’... Yet we continue to avoid the truth that tissue damage, nociception and pain are distinct. I would go so far as to suggest that even the use of these erroneous terms – pain receptors, pain fibers and pain pathways – leaves the patient with chronic pain feeling illegitimate and betrayed, and leaves the rehabilitation team lacking credibility when they look beyond the tissues for a way to change pain."