Monday, July 15, 2013

Melzack & Katz, Pain. Part 14i: molecular mediators large and small

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 headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input


Congratulations to us.. we are to page 7, in the 19-page gliopathy paper! The references start on p. 13, and there are several very large diagrams in future pages, which take up a lot of space, so really, we're going along quite steadily. 

We are still on our fogbound island, are still in the periphery, or almost - actually we're in the dorsal horn (where we left off in the Melzack paper so many days ago), the DREZ (dorsal root entry) zone, the shoreline where the ocean of the PNS meets the beach of the CNS, where PNS glia end and CNS glia begin influencing synapses, where interneurons might slow the crashing of the waves. 

Is the beach wide and sloped? If so, earth will soften ocean breakers. If shoreline is abrupt
and rocky, waves might be high, steep, crashing, spraying way up into the air. We don't know all about it yet, in this particular voyage, or where we are yet. (Still too foggy to see...) It's a zone of possibility where pain is involved. Born out of the interaction of tiny dancing molecules inside and outside many neuronal, interneuronal, glial, and microglial cells, all signalling each other, messages will be built, then rectified. Stepped-up. Transmitted.  

Remember, though, it's good to substitute the term "nociceptive input" for "pain" when talking about spinal cord activity, because the noxious information still has yet to ascend to cognitive-evaluative areas of the brain via second order afferent nociceptive neurons (.. or via glial connections, supposing there were some way that could even happen. Which probably doesn't..) 

This blogpost is about the section to do with mediators. 

[It's basically just my own study notes. Yes, sorry, I'm subjecting you to my study notes. How completely unexciting. I'm trying to understand cellular biochemistry with no background in it at all, so... sorry. It is what it is. This gliopathy paper is a great intro to the topic in my humble opinion - so please bear with me as I crack my own brain open to try to get some of this material into it.] 

"Mediators" are the actual molecules, manufactured and excreted, that affect neurons, synaptic activity, and "pain" sensitivity, as the authors call it. We aren't talking about "kidneys" of cells anymore, rather we're talking about cell "urine." 

So, mediators.
The authors say, p. 7, "A key issue regarding glial control of pain is to understand how glial mediators are produced and released." 

Pro-inflammatory, pro-nociceptive Mediators

These can be

Pro-inflammatory cytokines (small [..according to Wikipedia!] signalling molecules, including proteins, glycoproteins, peptides, e.g., TNF-alpha, IL-1beta, IL-6) become upregulated in spinal cord glia with nerve injury, inflammation, bone cancer, and chronic opioid exposure. This does not sound like a fun party. 
  • TNF-alpha is cranked out by microglia and is associated with peripheral and central sensitization/persisting pain. It induces chemokines.
  • IL-1beta is cranked out by spinal cord astrocytes/microglia/neurons themselves, with nerve injury, inflammation and bone cancer. Inhibit the signalling by this stuff, and pain related to all three can be reduced, and morphine can become more effective. With nerve injury, and "acute morphine" (whatever that means...) SGCs will make it too. 
  • IL-18 is another microglial product associated with nerve injury. 
Chemokines (small [again, acccording to Wikipedia] signalling proteins that induce directed chemotaxis, i.e., chemotactic cytokines) are mainly made by astrocytes in the dorsal horn although neurons can make them too. They contribute to trigeminal neuropathic pain. I guess they would be the equivalent of a drum kit in a band, the instrument that most makes you want to get up and move. 

Growth factors: BDNF:  (makes neuron cells grow)
  • ligating a nerve upregulates (via P2X4 and p38) brain derived neurotrophic factor in microglia; mechanical allodynia results. 
  • Blocking spinal BDNF receptor TrkB suppresses neuropathic pain. 
  • Microglia treated with morphine make more BDNF. 
  • DRG neurons make BDNF and release it into the spinal cord. 
Basic fibroblast growth factor bFGF, FGF-2 (makes non-neuronal cells grow)

  • is induced in spinal cord astrocytes about 3 weeks post nerve injury
  • upregulates P-JNK and GFAP in astrocytes which sustains mechanical allodynia, maintains chronic pain
  • administering bFGF-neutralizing antibody "attenuates neuropathic pain" p. 7
Proteases (these dismantle proteins)
  • MMP-2 is induced in spinal glia by nerve injury, activates IL-1beta, and ERK, maintains neuropathic pain
  • Cathepsin S is induced in spinal microglia by nerve injury, enhances neuropathic pain
  • tPA is induced in spinal astrocytes by nerve injury, enhances neuropathic pain



Small molecule mediators produced by astroctyes:

Anti-inflammatory, anti-nociceptive mediators
These are good guys:


It's a bit disheartening, isn't it? to look at the great long list of items that enhance or contribute to development of pain, compared to the very tiny list of items that diminish it. We need to remember the first list developed first, as pain science was in its infancy, so it looks more impressive and daunting. The second one will grow, in time.

Next, we'll check out how neurons and glia interact. 

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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