Melzack & Katz, Pain. Part 14f: gleeful about glia

The paper, Pain

Most recent blogposts:

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14c: PW Nathan was an interesting pain researcher  Part 14d: Brain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our heads

SEE ALL PREVIOUS BLOGPOSTS IN THEIS SERIES LISTED AT THE END

SOURCE
Still on the island, still fogbound. 

Fog is edgeless; edgelessness is exhausting after awhile. One can hardly blame the poor visual cortex, which, bereft of clarity of input, starts "seeing things," making stuff up. I suspect the sensory-motor cortex also does a lot better with clear, defined input - i.e., clear exercise, movement, exertion, then clear rest. 

The task today is to see if the fog lifts, if we can navigate the shoreline, and get the heck off this island, and back to Melzack and Katz. Here is their next paragraph: 

"It is possible that receptive field expansions and spontaneous activity generated in the CNS following peripheral nerve injury are, in part, mediated by alterations in normal inhibitory processes in the dorsal horn. Within four days of a peripheral nerve section there is a reduction in the dorsal root potential, and therefore, in the presynaptic inhibition it represents.40 Nerve section also induces a reduction in the inhibitory effect of A-fiber stimulation on activity in dorsal horn neurons.41 Furthermore, nerve injury affects descending inhibitory controls from brainstem nuclei. In the intact nervous system, stimulation of the locus coeruleus42 or the nucleus raphe magnus43 produces an inhibition of dorsal horn neurons. Following dorsal rhizotomy, however, stimulation of these areas produces excitation, rather than inhibition, in half the cells studied.44"

This paragraph is about dorsal horn! How about that - the shoreline is actually very close - just covered in fog and a bit hard to see, is all. 

Exploring the glia paper

Glia and pain: Is chronic pain a gliopathy? The lead author of this paper is Ru-Rong Ji, Associate Professor of Anesthesiology at Harvard and  chronic pain researcher. The other author, Temugin Berta, is in social media sites but doesn't have a website yet. He does neuron and glia research. Here are papers he has authored.

These are mechanism seekers, so they start off by discussing peripheral sensitization (first order neurons), and central sensitization (changes in cord neurons), disinhibition, facilitation, and long term potentiation, all well described in rodents. Then they introduce glia, 3 kinds in the CNS (astrocytes, microglia, oligodendrocytes) and 2 in the PNS, satellite cells in the DRGs and trigeminal ganglia, and Schwann cells. Their intention is to review microglia, astrocytes, and satellite cells. My comments are in brackets.

Microglia

• monocytic immune cells resident in CNS (i.e., not ectodermal in origin - they migrate into brains from the yolk sac before the brain closes up)
• actively sense their environment (like seagulls, who can see/smell/sense chum from a mile away), "dynamically interact with synapses to modulate their structures and functions in healthy brain"(p. 2) (OK.. brain as ecological niche..)
• proliferate rapidly in peripheral nerve injury, make a whole bunch of various molecules [tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, IL 18, brain derived neurotrophic factor, "CatS"( whatever that is..)] (when food is plentiful they multiply like seagulls and leave guano aka "fertilizer" all over the place)

Astrocytes

• most abundant cells in CNS
• play multiple active roles in acute and chronic disease - e.g., stroke, seizure, ischemia
• form physically coupled networks mediated by gap junctions
• through these gap junctions (predominantly connexin-43 channels) flow cytosolic contents; by them, Ca2+ signalling and oscillations occur
• each one has a huge non-overlapping territory; collectively these resemble a crystalline, lattice framework (which disappears when they react)
• have extensive contact with synapses, blood vessels, control blood flow increases "evoked by synaptic activity" (p. 2) which results in fMRI BOLD signal, regulate the external chemical environment
• just one can wrap 140,000 synapses (in rodent)
• "tripartite synapse theory" > pre-synaptic neuron, post-synaptic neuron, and glial enclosure, with glia actively contributing to synaptic activity
• this theory is disputed - turns out alterations in astrocytic Ca2+ don't modulate synaptic transmission; however, Ca2+ isn't the only kind of signalling astrocytes wrapped around synapses do (They've got that right!) 

.......

Interlude

I want to take a break from the "gliopathy" paper, at this important juncture, to bask in wonder about about the complexity and immense numbers of synapses and glia and so forth. Astrocytes make proteins. Lots and lots and lots of proteins. 

My confirmation bias is wondering why on earth these authors haven't listed Seth Grant's work in their reference list. Either they did, and decided to ignore it because it wasn't about pain specifically, or else, they never came across it. In my opinion it's exciting and foundational. But then, I'm not a pain scientist, I'm just somebody who reads all the time about all kinds of things and when my brain lands on something particularly juicy, it gives me a huge brain buzz. 

Well, I have come across it, and in my humble opinion, it was and still is huge - I understood so much more about the brain after reading Seth Grant's work than I ever could have, if I hadn't. I won't tell you all the minutia about how mind-boggling his research is, here.. but I'll give you this link to a blogpost I wrote after becoming entranced by these star-chasing ideas, Synapse Proteomics, and you can read all about it, there. If you'd rather listen to him, Ginger Campbell interviewed him a few years ago. Go to BrainSciencePodcast #51, Seth Grant. It's well worth your while because you might gain a way to grasp (a little bit, anyway) the immense implications of the creative juices of human astrocytes. You'll never listen to anyone who is more precise and articulate, I'll bet the farm. (Nowadays he is working on cracking the underpinnings of mental illness.)

Also, check out this riveting TEDxCaltalk, Erin Schuman, The Remarkable Neuron, about 15 minutes. (It's worth the time, I swear!)
Find out how astronomical numbers of things are counted up by researchers.  Learn how a 1930's biologist, Zoe Emily Schnabel who figured out how to count fish in a lake without having to drain the lake, helped Erin Schuman figure out how to count proteins in the brain. 

OK, break over. Back to the paper. 

...........

Astrocytes (cont.)

The authors suggest: "It is possible that the concept of receptor-mediated Ca2+ signalling is a key feature defining astrocytic participation in higher neural function will be expanded to include other intracellular signaling pathways." (P 3)
[I should think so.. heck, I should hope so...] 

• astrocytes maintain potassium hemostasis; increases in Ca2+ can modulate neural activity by taking up extracellular K+; K+ helps determine resting membrane potential/neural activity, so...
• experimenting with substances toxic to astrocytes show they are important for inducing and maintaining inflammation and (.... ta da!) neuropathic pain
• rhizotomy and spinal nerve ligation result in astrocyte proliferation
• reducing their proliferation (in the spinal cord) has been shown to reduce neuropathic pain

Satellite glial cells

• are found in both DRG and trigeminal ganglia, and in sympathetic and parasympathetic glia. 
• are from neural crest, just like Schwann cells are (and the actual neurons for that matter..)
• thin cellular sheaths surround individual neurons
• are like astrocytes in certain ways: express GFAP, S100, glutamate synthetase, and they form gap junctions
• way fewer in number than astrocytes, and there is only one per neuron (well, peripheral neurons are a lot longer..)
• very narrow gap between SGC sheath and plasma membrane of the neuron > so, already pretty good communication
• SGCs are activated after painful injury, may contribute to persisting pain, exhibit enhanced coupling in inflammatory and neuropathic pain of the persisting sort 

..........

The paper is 19 pages long, and goes into great detail about all this. 
So.. we might be stuck on this foggy island for the whole weekend, but we can make a fire and sing songs and tell stories to amuse ourselves!

SOURCE

..................

Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7b: Gate control: "The theory was a leap of faith but it was right!"

Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity

Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9c: Neuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics

Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10d: Conclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10e: The neural network that both comprises and moves "Self" is (only)modified by sensory experience
Part 11: We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!

Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12g: The Action-Neuromatrix 

Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity