Melzack & Katz, Pain. Part 14j: Neurons, calling glia (over; do you read?)

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 headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input 14i: molecular mediators large and small

SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END

Still working our way through the gliopathy paper on our way back to the rest of the Melzack and Katz paper. We're almost to page 8.  

In the section titled "Neuronal-glial and glial-glial interactions in persistent pain," the very first sentence is a great big face-palm: 

"Because pain is conveyed only by neurotransmission in the neural circuits, glia must interact with neurons to modulate pain sensitivity." 

SOURCE

We're still in the dorsal horn, right? It's exactly this idea of pain being a "thing" to be "conveyed" upward, that Melzack has carefully argued against ever since gate theory way back in the sixties. 

Oh well.. 
I will now get over myself, set aside this philosophically untenable yet remarkably persistent idea fueled by historical movement inertia and continually lubricated by pain researchers for the time being: let's ponder the gliopathy paper, yet again, and see what it is they're talking about. 

..........

Neuron to glia communication:

• Convergent current evidence suggests "nerve injury-released signaling molecules from primary afferent central terminals trigger microglial activation." (At least that's the "as-if" story plot that labelled-line researchers have always assumed, used, and tend to reinforce. Which is fine.. if they would only stop calling this "pain"..)
• C-fibre neurons can be made to release the same substances with only brief, low-frequency electrical stim. (..which is good, because it's likely easier on the poor rats). 
• If C-fibre neurons are blocked in a sustained manner by an appropriate nerve block substance, microglia won't smell their problems, and won't respond by expressing CD11b (a cell surface molecule) or letting p38 (a kinase responsive to stress stimuli) be induced. 
• Sometimes just blocking C-fibres isn't enough, because A-fibres might also be involved. Plus, once they get going (stimulated by C-fibres), microglia can be awfully self-stimulating. 
• Nerve injury stimulates chemokines (like CCL2 ,  CCL21 , CX3CL1) in DRG neurons. Microglia smell this at the central terminals, get excited, make a bunch of P2X4 receptors. Activation of P2X4 leads to increased BDNF expression. (Startle the microglia suddenly and they get excited, wet their little cellular pants - then, once they've started, they don't stop.)
• Nerve injury makes DRG neurons upregulate MMP-9 (protease that breaks down extracellular matrices for remodelling), which makes microglia become active through an IL-1 beta pathway
• Cathepsin S (Ah.. we're about to learn what "CatS" is..) is a "lysosomal enzyme"  microglia make, when provoked by nerve injury/stimulated by CX3CL1. 
• NRG1 is Neuregulin 1, a growth factor DRG neurons make and microglia have receptors for that are called erbB2's. If this pesky receptor is blocked, the microglia don't proliferate so easily, their p38 activation is way dampened, and neuropathic pain way reduced. So, that's good. NRG1 also stimulates microglial reproduction through phosphorylation of ERK and AKT (.. Argh!)
• CGRP is a vasodilator secreted by neurons - it can keep microglia going after chronic morphine exposure. Not good news..
• p38 MAPK integrates lots of inputs to microglia. It's activated by lots of kinds of receptors - ATP receptors like P2X4, P2Y12, and chemokine receptors like CCR2 and CX3CL1; also by CGRP after morphine tolerance has set in. Once it gets going it stimulates production/release of inflammatory mediators like TNF-alpha, IL-1Beta, BDNF (seagull diarrhoea..!) Something called minocycline (an antibiotic) seems to cut back on this p38 business, somewhat at least. (But don't get over-enthusiastic the way the researchers in Denmark recently did - see comment by Lorimer Moseley in BMJ). 
• basic fibroblast growth factor (bFGF, FGF-2) expressed by neurons after being injured stimulates spinal cord astrocytes to reproduce. 

OK, I need to take a little break - this stuff tends to make my brain hurt some. Next post is on how glia talk to each other. We're almost to page 10!

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

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