VIRTUAL SYMPOSIUM ON PAIN

This post is about the up-coming webinar series sponsored by the Canadian Physiotherapy Association and its new Pain Science Division (of which I am a exec. member and one of the founders). An internet approach to current, up-to-the-minute meta-education about pain is being integrated into and embraced by the PT profession in Canada, and I couldn't be more happy about it.

I've had a chance to preview the first webinar, and I can assure you the program will shine in both form and content. The content is not overly difficult - it is easy to follow if you have any medical background. Even if you do not, you can take your time with the material and look up the words you don't know with google. Enter the word "define" (but no quote marks) followed immediately by a colon (like this -> :) and the word you want to look up.

For example, if you wanted to look up the word "nociception" to find out the meaning, you would go to google and enter:

define: nociception

Google will take you to a list of possible meanings.

The technical side of the webinar series is speedy and interactive. You can click on pretty much anything from anywhere, from menus listed on the side or as new menus present themselves. Each module will be accessible for an entire week, can be viewed multiple times, and by more than one individual. A discussion forum will operate, where individuals can log in, ask questions, discuss, and help develop answers for other participants' questions, perhaps from their own specialized level of expertise.

Because this is an internet event and is mostly in virtual time, anyone on the planet can participate (if they use English). Only the last (fourth) session will be in real time, probably sometime during the last week of November.

Every conscious human awareness who is embedded in a physically alive body will have to deal with their own pain circuitry at some time or other during their life span. Pain can be hell, but the more prepared we are, the more we can do about our own response to it at the time. Anyone from any walk of life, therefore, is invited. This is the PT profession, reaching out not only to its own members but to the world, offering everyone some well-organized, coherently-presented and useful basic information on a potentially unpleasant matter that either does or will affect us all.

GO HERE TO REGISTER.

Reframing epidermis as part of the sensing nervous system

Dermatologists are busily investigating that with which they are concerned - skin. The epidermis: a sensory tissue, by Boulais and Misery, is a 2008 paper providing an overview of information that has accumulated to date.

Abstract:
"The skin is an efficient barrier which protects our bodies from the external environment but it is also an important site for the perception of various stimuli. Sensory neurones of the peripheral nervous system send many primary afferent fibres to the skin. They pass through the dermis and penetrate the basement membrane to innervate epidermal cells or remain as free endings. Nerve fibres are clearly involved in somatosensation. However, they are not always so numerous, for example in distal parts of the limbs, and some kinds of sensors can be at a distance of hundreds of micrometers from each other. The skin can detect patterns at a very fine and smaller scale, which suggests that nerve terminals are helped by epidermal sensors. All epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells) express sensor proteins and neuropeptides regulating the neuro-immuno-cutaneous system. Hence, they must play a part in the epidermal sensory system. This review will consider the epidermal components of this forefront sensory system and the stimulations they perceive. The epidermis can be considered a true sensory tissue where sensor proteins and neurone-like properties enable epidermal cells to participate in the skin surface perception through interactions with nerve fibres."

Consider that skin is an organ, a continuous half inch or so thick membrane layer around the entire body, held on by connective tissue filaments, many millions of them, some thick and tubular, through which pass neural fascicles on their way to skin, and others (most) spider web thin. Skin is heavy. The BodyWorlds exhibit states that skin is equal in weight to the skeleton. If you are an obese person, you could well be carrying around skin that weighs as much or more than the rest of you does.

What does it do, other than be a burden? Well, a lot of things, but from a thermodynamic perspective, the skin is there to regulate temperature/promote heat loss. It's useful to remember that life is more a verb than a noun. The human body (any mammal body, but we'll look at our own body) is essentially a 100-trillion cell highly-controlled furnace operation reducing the oxygen gradient of the planet's atmosphere in order to produce carbon dioxide (in more ways than just metabolically.. but they are beyond the scope of this discussion). Plenty of heat is produced in this transformation, and must be eliminated from the multi-cell organism we are. Skin has 10 times the amount of blood flow than it needs to maintain its own existence (Gray's). So, its biggest job is to be a radiator/heat regulator for the entire organism.

It is also useful, I think, to remember (always) that ectoderm builds the body (if "life promotion" is going to be found in anything, it will be in ectoderm- I'm almost sure about that). Ectoderm builds the body in such a way that it kicks off layers, layers that seem to range from least "communicative" to most "communicative." It's first "cells" are germ cells, which lie completely dormant until stimulated. The next layer is mesoderm, which in addition to being the next least communicative, has to grow most of the body, 98% of it - all the bones and muscles and so on we are more familiar with. Next, it builds brain, spinal cord, and PNS- very very communicative. Lastly, what's left of the ectoderm encircles the entire body in a layer of lively communicative non-neural cells, which, even though they are non-"neural," strictly speaking, are still highly communicative, maybe the most communicative of all.

The neuro-immune-cutaneous system (NICS) refers to the communication system skin cells use in their efforts to keep the body as safe as possible through appropriate communication of environmental conditions. Here are some of the points made in the paper:

1. Epidermal cells connect the skin to the mind through a complex communication network, tightly related to the neuroendocrine and the immune systems.

(I would have used the word "perception" instead of "mind," but that's just me being picky, probably.. Had they used the word "perception," it would have been easier to include all the other mammals whose fur rises in fury or fright, reptiles and even invertebrates like cuttlefish and octopuses who can change their color to match their surroundings. I suspect our proclivity to blush or blanch is part of this system rather than primarily something to do with "mind," whatever that is.. all critters can be safely assumed to have perceptual capabilities, but I expect few will be found to be able to deduce meaning from perceptions with something called "mind.")

2. Langerhans cells and mast cells bridge the gap between neuroendocrine and immune systems in the skin. They participate in endocrine function through metabolism of vitamin D, production of neurohormones. They affect the permeability of blood vessels, are implicated in wound healing, pruritus (itching) and other dermatological disorders like psoriasis.

3. Epidermal cells act on the nervous system at local and central levels:
- 30 to 40% of dermatological patients also have psychological problems (understandable if you were being tortured by your own skin...)
- modulate the sensory information of touch or "pain." After ultraviolet (UV) exposure, they lead to a decrease in the pain threshold and immunomodulatory effects through pro-opiomelanocortin (POMC)-peptide release.

4. Brain can act on skin:
- can affect cutaneous functions in an efferent manner to stimulate target tissues; for example during neurogenic inflammation ("pain"-ful).


The authors go on to explain NICS further:

1. NICS consists of a common language shared by sensory neurones, keratinocytes, melanocytes, Langerhans cells and Merkel cells, with the neuromediators as letters. These powerful molecules are widely involved in skin physiology and the response to a stimulus.

2. Skin cells are able to recognize the relevant biological signals transmitted through neuromediators with high specificity because they synthesize the receptors themselves. Such neuroendocrine capabilities are critical for the activity of the NICS.

3. In the NICS, it is currently understood that:
- substance P (SP) plays a key role in pain sensitization and leads to mast cell degranulation
- POMC and derivatives are immunomodulators
- neurotrophines, like the nerve growth factor (NGF), are mitogenic proteins which also stimulate nerve fibre sprouting, regulate neuropeptides synthesis and probably take part in psoriasis
- catecholamine acts as an inflammatory factor

4. Acetylcholine, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) seem to act differentially, depending on the skin environment.

5. Therefore, the NICS acts locally, at the level of the neurogenic inflammation, but it is also considered to affect the whole organism via the endocrine and neurocrine pathways

6. "Until now, the concept of NICS mainly described the effects of the nervous system on skin cells through the presence of synapses, neurotransmitters and specific receptors in the skin. We now know that the epidermis also appears at the forefront of the sensory system, as revealed by new data on the sensory abilities of epidermal cells."

My bold. The authors carefully break down the picture by explaining which sensory proteins are made by which cell and commonly transducted by which size nerve fiber. They discuss the TRP (transient receptor protein) family, in particular TRP vanilloid 1 (TRPV1). It turns out that these receptors function exactly the same no matter which surface of the body they happen to be on - out in the epidermis of the body or that of the tongue - they are the equivalent of what we could perhaps call the nervous system's "weather" channels, sensing temperatures and tastes/ "tasting" temperatures both comfortable and noxious, and their fluctuations.


More about TRPV1:

1. is the most characterized receptor and probably the most expressed within the epidermis

2. TRPV1 is highly expressed in neurones involved in pain transmission and neurogenic inflammation (C and Aδ-fibres)

3. also shows a strong immunoreactivity in keratinocytes from the upper and the basal layers of the epidermis

4. In humans, the temperature responsiveness ranges from – 10 to 60 °C

5. plays a major role in the detection of temperatures over 42 °C and acidic conditions below a pH of 6.6

6. has the ability to bind capsaicin, the molecule which confers spiciness to chili peppers, with high affinity.

7. TRPV1 activation evokes sensations ranging from warmth to burning pain, as well as piquant taste

8. Consequences of its activation vary according to the context.
- once activated by capsaicin, the TRPV1 channel first leads to calcium influx and neuropeptide release.
- the lasting calcium influx, with too high intracellular calcium concentrations, leaves the neurone desensitized, thus it loses its ability to induce the release of neuropeptides such as SP, which is co-localized
- This is responsible for a transient insensitivity, which is exploited by dermatologists to induce analgesia or anti-inflammatory effects.

TRPV2 channel is heat-gated, strongly expressed in Aδ-fibres; it is activated for temperatures above 53 °C, warns of a burn.

TRPV3 channel is camphor sensitive, found in sensory neurones and keratinocytes of the inner boundary of the epidermis, is activated by heat from 31 °C to 39 °C.

TRPV4 channel is present in keratinocytes and Merkel cells, exhibits an apparent threshold of about 27 °C, and reacts to hypo-osmolarity.

TRPM8 (melastin cation channel) is menthol-sensitive and transduces cold; it "gates at temperatures below 30 °C. TRPM8 is expressed almost exclusively in a subpopulation of C-fibres representing 10% of the sensory neurones."

"TRPA1, a member of the TRP ankyrin-repeats family has been reported to be activated below 18 °C, so it may also participate in the cold responsive behaviour."


About touch:

The authors state that there is no firm model yet. They discuss three possible models:

1. high speed channels convert stimuli into an electrical signal (this is what is thought to occur in hair cells of the organ of Corti (hearing) because of their remarkable transduction speed)

2. ion channels are tethered to the cytoskeleton or extracellular matrix

3. a mechanosensory protein initiates a second messenger cascade leading to the opening of the ion channels, thus producing depolarization

Re: the third model, in research done with invertebrates two mechanosensitive proteins have been discovered, MEC-4 and MEC-10. These belong to the Degenerin/Epithelial sodium channel family, or Deg/ENaC. "This family is characterized by common N and C terminals, two membrane-spanning sequences and a large extracellular loop with 14 conserved cysteins. The receptors are organized into homo- or heteromultimers of 4 to 9 subunits, forming nine voltage-insensitive Na+ permeable channels in mammals. Thus the mechanosensitive Deg/ENaC is composed of α, β, γ and δ ENaC, the acid-sensing ion channel (ASIC), the brain Na+ channel 1 (BNC1 or ASIC2), the dorsal root acid-sensing ion channel (DRASIC or ASIC3), the brain-liver-intestine amiloride-sensitive Na+ channel (BLINaC) and the ASIC4, which is not proton-gated despite its name."

Although there is still some conflicting data and gaps, and the work done on invertebrates has yet to be perfectly aligned with mammal models, these proteins are found produced by pacinian and Meissner corpuscles, lanceolate endings of hair follicles and the neurites contacting to Merkel cells, mechanosensory neurones of the dorsal root and trigeminal ganglia and hair cells of the inner ear.

Going back to the TRP family, TRPV4 rescues mechanosensory deficit in C. elegans (worm), TRPC1 are stretch-sensitive ion channels gated by membrane deformation, mutated TRPA1 attenuates mechanical responsiveness, NOMPC (analogue to TRPN1 in Xenopus) is implicated in the somatosensation of Drosophila and is newly found in the vertebrate zebrafish, where it behaves as a mechanically-gated ion channel in sensory hair cells. TRPV4 can do two things: it is expressed in the Merkel cell-neurite complexes, anatomical structures composed of the association of mainly Aβ-fibres and Merkel cells, which play a key role in the slowly adapting type I mechanoreception; furthermore, "TRPV4 is highly expressed in non-sensory tissues too. There, TRPV4 is believed to control the systemic fluid balance by its osmolarity-sensitive capability."

Sensor proteins also include purinergic receptors, thought to participate in many cutaneous phenomena. "They are involved in cell growth, differentiation, neuronal regeneration, wound healing, inflammation, etc." There are two types of these receptors grouped according to the ligand they bind:

1. P1 receptors bind adenosine and are divided into 4 subtypes

2. P2 receptors, which bind ATP, ADP, and UTP, are divided into ionotropic P2X receptors and metabotropic G protein-coupled P2Y receptors.

"Keratinocytes express both the P2Y receptors, implicated in the mobilisation of intracellular calcium stores in response to noxious stimulation, and the P2X ion channel. The latter is involved in the initiation of afferent signals on sensory neurones and plays a key role in sensing tissue-damaging and inflammatory stimuli. Immunohistochemical investigation into Merkel cells has revealed expression of P2Y2 receptors, which could argue for a putative role of this channel in mechanoreception."

The paper goes on to discuss sensory nerve endings. It is worth remembering that single nerve cells span the entire distance between skin and spinal cord. They can be various sizes and have varied degrees of myelination and neuropeptide expression, and convey varied information. Functional properties are not strictly related to morphological aspects. However:

1. "it is currently accepted that cutaneous large myelinated Aβ-fibres of low-threshold are suited to be mechanoreceptors which feel pressure, stretch or hair movement."

2. Unmyelinated C-fibres and lightly myelinated Aδ-fibres are often thermoreceptors which respond to heat and cold with different thresholds of activation.

3. Nociceptors, containing opioid receptors, are mainly high-threshold C-fibres and Aδ-fibres which transduce painful sensations.

4. A pruritus-specific pathway was recently defined - the pathway processing the itch is functionally and anatomically separate from the pain pathway.

"The itch pathway implies its own subgroup of peripheral, mainly mechano-insensitive, C-fibres in the skin. In the central nervous system, histaminergic spinal neurones transduce the itch sensation initiated by dedicated pruriceptors, to the thalamus. The pruriceptors are activated by histamine which consistently provokes pruritus, and rarely pain. However, other inflammatory molecules such as prostaglandin E2, serotonin, acetylcholine, bradykinin or even capsaicin may induce a moderate itching sensation. Thus a complex interaction exists between the pain and the itch pathway. - Scratching that induces pain is well-known to inhibit the pruritus and conversely, the inhibition of pain-processing by µ-opioïd can generate pruritus. Therefore, the distinction between cutaneous fibres is not easy and disrupting criteria are frequently evoked, like nociceptive signalling, normally particular to Aδ and C-fibres, with the conductance speed of Aβ-neurones.
- Further investigations have revealed that Aβ-fibres can phenotypically switch into fibres expressing SP whereas normally, SP is only contained in a subpopulation of small C and Aδ-fibres involved in pain perception. This occurs following nerve injury but also after inflammation. Thus the peripheral endings of primary sensory neurones participate in neurotransmission. But they also participate in the immune response by the release of proinflammatory peptides, from unmyelinated C-fibres or myelinated Aδ-fibres, leading to the set of changes referred to as neurogenic inflammation."

5. Two kinds of nociceptor have been identified based on their ability to bind isolectin B4 (IB4). "Those which bind IB4 are usually small diameter non-peptidergic neurones involved in acute pain." But:
- "only half of them seem to answer to noxious stimuli, with the remainder containing less mechanosensory C-fibres
- Within the epidermis, nerve viability and sensitivity can be modulated by neurotrophic factors secreted by epidermal cells."
- IB4-negative neurones containing SP and CGRP are NGF-responsive, small diameter nociceptors
- IB4-positive neurones, which lack such neuropeptides, respond to glial-derived neurotrophic factor (GDNF)
- NGF (nerve growth factor) produced in large quantities by keratinocytes increases nociceptive-neurone survival while brain-derived neurotrophic factor (BDNF) decreases the activation threshold of mechanosensory Aβ-fibres
- neurotrophin-3 (NT3) enhances the innervation by slow adapting mechanosensory neurones.

6. Cutaneous neurites play a major role in the sensory behaviour, but there is much evidence suggesting a modulation of their sensitivity by epidermal cells:

- stimulated cutaneous sensory neurones induce action potentials, but also the release of neurotransmitters, which modulate inflammation, cell growth or pruritus.

- Such neuronal modulations of cutaneous properties regularly bring heterotrimeric G proteins into play at the beginning of the metabolic cascade, and endopeptidases at the end, for termination of the response degrading the messengers

Fascinating stuff. The paper goes on to discuss each type of skin cell separately in detail, which I won't bring here as I am more interested in the overall picture of touch and what occurs neurologically as a result, which of course involves neurochemistry.

Here are tidbits from the conclusion:

- Ion channels have been discovered on epidermal cells: TRP, purinergic and Deg/ENa channels are putative transducers of touch, thermal sensation and nociception, as shown in invertebrate models and knockout mice. Thus they must start the signalling of the stimulus at the molecular level, based on their thermo-dynamical properties.

- Merkel cells are excitable cells containing the molecular components of synaptic connections so they should transduce the stimuli synaptically.

- "The mechanisms of communication between keratinocytes, Langerhans cells or melanocytes and sensory neurones are more mysterious. They are non-excitable cells with no molecular basis of synaptic connections. Paracrine function is supposed, but the mediator used to transmit rapid stimuli as fast as they occur must exhibit the characteristics of a neurotransmitter. It must be specific enough to carry a unique signal and quickly degraded to transmit a short stimulation. We have started to gain insight into this phenomenon so that some non-peptidic candidates are now being considered, like calcium, which can activate neighbouring cells, once released by keratinocytes."

This is reminiscent of glial communication.

Finally: "Acceptance of the epidermis as a sensory and endocrine tissue as part of the NICS has increased, as some authors define skin as spread brain. However, the relationship between skin and brain, although fascinating, remains poorly understood."

I don't think it is beyond understanding if one considers ectodermal behavior - it is the layer that would seem to be in charge of who knows what and when and how much, like a general manager. It seems to like taking "membran-eity" and playing with it, seeing how small it can fold up a single epithelial membrane (brain) and how much surface area it can cover (skin). Ectoderm is like the protective sensing membrane boundary of single cell creatures that ended up inheriting the job of figuring out how to cover monstrous multi-cell creatures. I think it did a brilliant job of it.

Reference:
Online version of the whole paper (caution: format errors are displayed in table 2).

Related posts:
System Proteomics

Boulais N, Misery L (2008). The epidermis: a sensory tissue Eur J Dermatol , 18, 119-127 DOI: 10.1684/ejd.2008.0348

Smelling someone else's alarm bells

Deric Bownds Mindblog has a post, Do our noses sniff danger in the air? on a recently investigated cluster of cells in the tips of mammalian noses (including humans, it is posited) called the Grueneberg ganglion.
From Science, Aug 2008:

"Grueneberg Ganglion Cells Mediate Alarm Pheromone Detection in Mice
Julien Brechbühl, Magali Klaey, Marie-Christine Broillet*

Alarm pheromones (APs) are widely used throughout the plant and animal kingdoms. Species such as fish, insects, and mammals signal danger to conspecifics by releasing volatile alarm molecules. Thus far, neither the chemicals, their bodily source, nor the sensory system involved in their detection have been isolated or identified in mammals. We found that APs are recognized by the Grueneberg ganglion (GG), a recently discovered olfactory subsystem. We showed with electron microscopy that GG neurons bear primary cilia, with cell bodies ensheathed by glial cells. APs evoked calcium responses in GG neurons in vitro and induced freezing behavior in vivo, which completely disappeared when the GG degenerated after axotomy. We conclude that mice detect APs through the activation of olfactory GG neurons.

Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland."

See also:

Sensing Alarm

Peter Stern

Science, AAAS, Cambridge CB2 1LQ, UK

In 1973, Hans Grueneberg observed the presence of a structure at the tip of the rodent nose that, he thought, belonged to the Nervus terminalis. Recently, using transgenic techniques, several groups reported the rediscovery of this structure. They named this structure the Grueneberg ganglion in memory of the original work. However, the function of these cells remains a matter of controversy. Despite the lack of typical olfactory neuronal features, the ganglion was suggested to have some olfactory function, based on the expression of olfactory marker protein and on its neural connections to the olfactory bulb of the brain. Brechbühl et al. have now identified a function for the Grueneberg ganglion cells. A combination of anatomical, surgical, and behavioral techniques was used to suggest that the Grueneberg ganglion is involved in alarm pheromone detection.

J. Brechbühl, M. Klaey, M.-C. Broillet, Grueneberg ganglion cells mediate alarm pheromone detection in mice. Science 321, 1092-1095 (2008). [Abstract] [Full Text]

Citation: P. Stern, Sensing Alarm. Sci. Signal. 1, ec302 (2008).

It doesn't surprise me anymore that recent neuroscience that I happen to be interested in usually turns out to have come from Lausanne, Switzerland. It does surprise me a little that there have been some papers about this from earlier, so it isn't exactly fresh news.

What's interesting about this is that it used to be thought that there were only two systems, the vomernasal organ (vestigial in humans) and the regular olfactory pathways, or sense of smell. It seems there are actually these three, and that in humans, the Grueneberg ganglion is still with us. It makes sense to me that as humans evolved close social ties and the capacity to relate via language and visual cues, smell (in terms of signaling pheromones) would begin to be less essential to survival. Yet there is this system still existing in humans (it would seem) that can still "smell" and respond to "alarm". I can hardly wait to hear how this turns out, how it might tie in with those whose information base is the pondering of human relations. I can already see applications in my own work - maybe those with persistent pain have alarm bells in a constant uproar - maybe the olfactory bulbs at the other end of their Greuneberg ganglia are dysregulated, or not downregulable by them for some reason. Just a stray thought. In any case it behooves us as therapists to be able to downregulate our own alarm bells, as always, no matter which part of the brain they are to be found or which exteroceptive sense might contribute to them..

Here is some additional information:
1. Mammals emit smell to signal danger. Excerpt: "Cells in the Grueneberg ganglion use their own calcium to transmit the danger warning to the brain... Only warning pheromones could trigger the warning signal."
2. Short video entitled, Smelling Fear
3. Breer H. Fleischer J. Strotmann J; The sense of smell: multiple olfactory subsystems. Cellular & Molecular Life Sciences. 63(13):1465-75, 2006 Jul.

"The mammalian olfactory system is not uniformly organized but consists of several subsystems each of which probably serves distinct functions. Not only are the two major nasal chemosensory systems, the vomeronasal organ and the main olfactory epithelium, structurally and functionally separate entities, but the latter is further subcompartimentalized into overlapping expression zones and projection-related subzones. Moreover, the populations of 'OR37' neurons not only express a unique type of olfactory receptors but also are segregated in a cluster-like manner and generally project to only one receptor-specific glomerulus. The septal organ is an island of sensory epithelium on the nasal septum positioned at the nasoplatine duct; it is considered as a 'mini-nose' with dual function. A specific chemosensory function of the most recently discovered subsystem, the so-called Grueneberg ganglion, is based on the expression of olfactory marker protein and the axonal projections to defined glomeruli within the olfactory bulb. This complexity of distinct olfactory subsystems may be one of the features determining the enormous chemosensory capacity of the sense of smell."

4. Ma M. Encoding olfactory signals via multiple chemosensory systems. Critical Reviews in Biochemistry & Molecular Biology. 42(6):463-80, 2007 Nov-Dec.

"Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world."

Breer, H., Fleischer, J., Strotmann, J. (2006). Signaling in the Chemosensory Systems. Cellular and Molecular Life Sciences, 63(13), 1465-1475. DOI: 10.1007/s00018-006-6108-5

"Dialogues in Clinical Neuroscience" online

A reader, Kent Schnake, sent me a link that looks very good - it's to Dialogues in Clinical Neuroscience, which appears to be open access, for past issues, anyway.

Here is a link to the 2004 issue on neuroplasticity. In it is an article by Fred Gage, downloadable.


Here are some posts that have included discussion of Fred Gage's work:

1. Nervous System Basics VIII: PLASTICITY
2. History of Neuroplasticity

Microglia and Pain: A Manual Therapy Perspective IV

In reference to Microglia and Pain: A Manual Therapy Perspective:
Part I
Part II
Part III

REFERENCES:
1. Rock BR et al; Role of Microglia in Central Nervous System Infections. (open access) Clinical Microbiology Reviews, October 2004, p. 942-964, Vol. 17, No. 4
2. McMahon s and Koltenburg M; Wall and Melzack’s Textbook of Pain 5th Ed. Churchill Livingstone (September 21, 2005)
3. Ramachandran VS (ed); Encyclopedia of the Human Brain. Academic Press; 1st edition (June 2002): Stoll G et al; Microglia Vol. 3. pp 29-41; Angevine JB; Organization of the Nervous System Vol 3 pp 313- 371; Brown AM and Ransom BR; Neuroglia Overview Vol 3 pp 479- 491
4. Verkhratsky A and Butt A; Glial Neurobiology. Wiley 1 edition (Sept. 2007)
5. Kettenmann H; The brain’s garbage men. Nature Vol 446 Apr. 2007
6. . Piao ZG et al; Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. PAIN 121 (2006)
7. Echeverry S et al; Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. PAIN 135 (2008)
8. Coull JAM et al; BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438 (Dec. 2005)
9. Tsuda M et al; P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424 (Aug 2003)
Piao, Z.G. (2006). Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury.. Pain, 121(3), 219-231.

Microglia and Pain: A Manual Therapy Perspective III

In reference to Microglia and Pain: A Manual Therapy Perspective I, and Microglia and Pain: A Manual Therapy Perspective II:


The Dorsal Horn and Microglia

What role do microglia play in pain? Dorsal horns are the laminated posterior areas of the spinal cord where incoming sensory info is handled. Secondary neurons within the cord, actual CNS neurons, deal with it from then on. At the junction between the incoming sensory neurons and the secondary ascending neurons, there are, yes, you guessed it, microglia hanging around, waiting for a chance to “activate” and move along novel chemo-attractive gradients, substances released into the parenchyma by the presence of inflammation(6) and hypoxia(3), among other things(1), including nerve compression.



Once “activated” they “feed,” increase their populations, leave behind chemical “litter.” These chemicals “inhibit” the secondary ascending fibers. Inhibition? That’s good, isn’t it? Well, maybe not - if your job as a secondary ascending neuron is to be a bottle-neck, and your “bottleneck” function becomes inhibited by microglial activation, the brain is more likely to be confronted by too much nociception, too rapidly, and will need to allocate new resources to learn to downregulate it somehow.

What stimulates microglia at a spinal cord level? The Textbook of Pain chapter states, nerve “damage” such as spinal nerve ligation, chronic constriction injury, or rhizotomy. These are factors associated with neuropathic pain definitions, moreso than neurogenic. But remember the overlap. McMahon et al go on to say:
1. “..synaptic connections between neurons are in a continual state of change highly dependent on the activity not only of the pre- and postsynaptic neurons but also of the surrounding glia.
2. ..continual interplay of various modulatory processes serves to produce synaptic modifications (plasticity) that underlie physiological processes such as learning and memory.
3...common molecular pathways that produce these normal forms of plasticity also lead to pathological processes characterized by excessive excitation, including …pain.
4. In the dorsal horn, central sensitization is a form of excessive excitatory synaptic response in nociceptive transmission neurons, which leads to an increased gain of the pain transmission system and pain hypersensitivity.
5. Our knowledge of the molecular mechanisms of pain plasticity in the dorsal horn is rapidly growing.
6. Future advances will provide new insights into the neurobiological basis of pain, and we anticipate that these will provide the basis for novel types of analgesics and of new diagnostic and management strategies beyond what is presently envisaged.”

The story isn’t over yet, but it’s probably safe to say that whatever makes a synapse in the dorsal horn behave in a manner outside the norm is likely to gain the attention of microglia in the cord. They are thought to be responsible for mechanical allodynia that comes along with central sensitization, based on studies that carefully manipulated the P2X4 receptor they express9. Furthermore, whatever helps a synapse in the dorsal horn recover its ability to conduct business as usual, will likely help decrease central sensitization. It may be that the future of pain control will be in the hands of whoever can find the means to keep the microglial population in check and not allow them to gain the upper hand.

<<<<<<<<<<<<<<<<< >>>>>>>>>>>>>>>>>>>>>>

The fourth post will contain references and links to these three content posts.
All pictures/links have been added for the blog and did not appear in the article.
(Picture of dorsal horn was adapted from Nature Neuroscience)

Microglia and Pain: A Manual Therapy Perspective: Part II

In reference to Microglia and Pain: A Manual Therapy Perspective: Part I:


Glial functions

In general, glia keep things running smoothly. Astrocytes make sure the synapses are working properly - duties include the regulation of ions to maintain optimal chemical stability in the extracellular fluid, sopping up and storing excess neurotransmitters such as glutamate, buffering K+, and storing glycogen, feeding the neurons with it when a burst is suddenly needed in a given region. They occupy physical space between neurons and capillaries, keep the blood supply and the neurons apart from each other. Oligodendrocytes in the CNS, and their cousins, the Schwann cells in the periphery, manufacture and maintain myelin coverage of their respective neurons. There are other kinds that do other jobs. (See image below and to right, modified from an article, The Dark Side of Glia (Science May 2005).)


Microglia are the smallest of the glia, and (in my opinion) the most mysterious, not just because of their unconventional origins, but also their behaviour; mostly they just sit there, inactive, sessile, not bothering anything, making up 5-15% of the total glial population. Yet they sense everything, and are capable of “activation,” generating a big response to altered environment, which sometimes works well (to take care of invaders) and sometimes not so well (from a pain point of view). They have many kinds of ion receptors - when their environment provides them with sufficient chemical provocation, they change their morphology and begin to mobilize, amoeba-style, drawn to sites of infection or where damage has occurred, where the blood-brain barrier has been breached by injury or vascular failure.

In the brain they act the way macrophages do in the outer body, absorb invaders and corpses, but there is a not-so-good side to all this: the nervous system is generally not used to having these little creatures moving around in it, and sometimes seems to have trouble adapting when they become active. Why should this be?

It is easier to understand if we consider what happens in an ecosystem when scavengers find sustenance in it:

1. First, they will reproduce rapidly. Think of flies on a carcass - soon there are many more flies buzzing around. In the brain and spinal cord, microglia, like the single-cell “creatures” they are, reproduce enormously when times are good - from their perspective. But the CNS, the spinal cord, is an enclosed space, without a lot of room for a burgeoning population of microglia, no matter how small they may be.

2. Microglia and their population explosion alter the chemical environment the nervous system has been used to. Think of excretion (flyspecks) left in their wake - the nervous system is already injured, and now it must adapt to a new chemical environment (polluted in a sense) on top of everything else. Substances released include cytokines, chemokines, trophic factors etc., some of which the neurons can use like “fertilizer” to grow with, others of which merely irritate them.

3. When this sort of “plasticity” occurs in the spinal cord, nociception becomes upregulated.

4. When the brain is exposed to such upregulation, depending on context, it might not succeed in successfully downregulating it back to normal.

The rest of this piece will concern itself with points 3 and 4.


Neurogenic and Neuropathic Pain

In Wall and Melzack’s Textbook of Pain (5th ed.) is a discussion about defining neuropathic as opposed to neurogenic pain. Microglial activation is associated with neuropathic pain which is in turn associated with neuronal damage. In general, from our perspective, we could consider neurogenic pain as more easily downregulated with manual therapy, because there is no irreversible nerve damage - the neurons and dorsal horn can recover. What we do with our contact, both verbal and manual, likely assists nervous systems to increase descending modulation to help decrease perceived pain. Possibly this is sufficient for a system with mere neurogenic pain to right itself, and microglial populations presumably go back to normal levels eventually.


(Image modified from Textbook of Pain 5th Ed.)

Neuropathic pain, or pain felt in the context of actual neuronal or dorsal horn damage due to injury, infection, or ongoing metabolic insult, is less likely to right itself with manual therapy - in fact, manual therapy may worsen matters instead. Luckily for us, at a glance it would seem that there is more neurogenic pain in the population than there is frank neuropathic pain. In the book, the authors conclude that there is no real dividing line yet - that there is a big area of overlap. This is frontier land. We must learn optimal ways to sort out the two main kinds of pain, in the clinic, based on close listening to a patient’s pain history, or risk adding to pain felt by some.