Saturday, July 13, 2013

Melzack & Katz, Pain. Part 14g: ERKs and MAPKs and pain

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 14cPW Nathan was an interesting pain researcher  Part 14dBrain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our heads Part 14f: Gleeful about glia


Quick update: still on the island, still foggy but looks like it could break up - small clear patches sighted once in awhile. Back to that glia paper

Glial reaction to injury
Various changes in various markers are discussed. 

If the CNS was a huge city surrounded by ocean, and the spinal cord was a neighbourhood on a
land spit that extended way out into the ocean, microglia would be its resident seagulls. They react to nerve injury. They quickly learn where to expect the goodies will manifest and they never stop being hungry. "Microglia can be primed by previous insult in adults, leading to enhanced pain intensity and duration of second insult." p 5. 

Astrocytes are activated by injury too. Also by chronic opioid exposure. Also by HIV infection. And cancer of bone and skin, and the chemotherapy used to treat it. Astrocytes stay active way longer than microglia and in places far more rostral, like anterior cingulate. Maybe these would be city planners with a lot invested in developing and maintaining quality of life and traffic flow. 

Satellite cells (the ones in DRGs and trigeminal ganglia) are activated by injury and also by inflammation. Increased coupling is noticed in SGCs. As soon as 4 hours after a nerve injury, or compression of DRG (remember, these are rats, and these injuries are deliberately inflicted), they proliferate - this peaks at about a week - about 3 weeks later, decline is noted. I don't know who these cells would be, in the port city metaphor... maybe fishing boat captains, living out their lives on boats (but clumped up in a marina), long lines jerking at them from way out in the water, boats bumping into each other during storms, so they radio for help.  
If a glial toxin is introduced into the DRG, neuropathic pain reduces (interesting). Morphine keeps them quiet, but when it declines, they activate. Sailors' rum? (metaphorically speaking). 

Inside the glial cells
There follows a whole section on "Phosphorylation of MAPKs and Src in glia." I don't know anything about any of it. Phosphorylation has to do with adding a phosphate molecule. Mitochondria use oxidative phosphorylation to make ATP... but this is not that: Near as I can make out, thanks to wikipedia, there are many kinds of phosphorylation. 

MAPs (microtubule-associated proteins) are proteins that hold stuff together, and are regulated by another protein, MAPK (K=kinase). If MAPK "phosphorylates" MAP, stuff will come apart. I expect this is ordinary business as usual inside any cell, maintaining itself, its structures. There are a whole pile of different MAPs and MAPKs. The MAPKs include kinds called ERKs. ERK means "extracellular signal-regulated kinase."

Don't you just love how dense all of this is? (/sarcasm)
It's easier if I think of cellular city crews out with equipment all day long, using MAPKs and exploiting ERKs to tear up old pavement and find potential sinkholes, so they can be rebuilt. Anyway, in microglia, something called ERK5 is activated. Another called P-p38 gets busy too. In astroglia, P-JNK (which is, I guess, a particular kind of JNK..) is produced. Also P-ERK. In fact P-ERK turns up in all three. That can't be good...  

Anyway, MAPKs and ERKs in glia become upregulated (meaning, the cell nuclei make way more of them, for whatever reason) and their numbers increase sharply. In people with HIV, those with elevated levels of P-ERK, P-p38, and P-JNK in their dorsal horns have more neuropathic pain. Srcs become more phosphorylated, which isn't likely good news.. they are linked to cancer progression, so we'd like those to remain highly suppressed, thank you. 

All these molecules just look like piles of ribbons to me..
but their shapes are hugely important, to cells at least


A moment for appreciation

Thank you for hanging in there with me (all 20 of you, as it turns out) while I struggle through all this. I really do want to get back to Melzack, but here we are, trying to fathom the pain problem via some of the tiny little things that can have so much impact further downstream in time. For people in pain. What a nightmare, really, to have pain for which no one can do anything because nobody understands what's going on at a molecular level. So thank you also to all the hoards of people who are out there in every country trying hard to figure it all out this way, one little molecule at a time, at the cellular level. Because even neurons are, after all, just body cells (very very very l-----o------n-----g ones), and cells are fundamental units of life. Cells are bound to have molecular opinions on things, and can leave molecular traces of having been stressed out of their little no-minds, maybe especially the ones that are supposed to be minding and guarding neurons. 


Next up, regulation of receptors, channels, transporters.. yay, more stuff I know next to nothing about (more sarcasm). More fog closing in. 
But eventually we'll get through this. 


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 7bGate 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 9cNeuromatrix: 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 10dConclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10eThe neural network that both comprises and moves "Self" is (only)modified by sensory experience
Part 11We 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 12gThe Action-Neuromatrix 
Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

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