Wednesday, August 6, 2008

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.

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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)


Eric Matheson said...

What effect do you think manual therapy has on the microglia? Based on that wonderful diagram from the textbook of pain you used to illustrate the overlap of neurogenic and neuropathic pain, I'd suggest it might be to reduce the afferent nociceptive barrage arriving at the cord. Would you agree?

dermoneuromodulator "neuroplastician" said...

Hi Eric,
"I'd suggest (effect of manual therapy) might be to reduce the afferent nociceptive barrage arriving at the cord. Would you agree?"

I would: certainly in a neurodynamic model the whole point of the intervention is to help the neurons access their own oxygenation. If they aren't distressed they won't "sweat" fractalkine (as per Watkins 2003), not so much anyway (fractalkine seems to be some sort of microglial attractant).

The part that cannot ever be ruled out (from a manual therapy perspective) (and I don't know why anyone would ever want to) is stimulation of descending modulation from the hind-brain.

Contact with skin will alert all parts of the nervous system at once, but I suspect responses in different regions differ.
1. The S1 cortex will accept the contact as non-threatening (of course context must be managed to make it so)
2. The hindbrain and assorted nuclei, alert centers such as locus ceruleus won't "know" who or what is touching their organism - they will simply sense and respond. If they do their "alerting" as usual but get absolutely no response from S1, because S1 is happily ignoring or else enjoying the contact, all the hindbrain will be able to arouse will be itself. Part of its arousal function is descending modulation of upcoming nociception - we want to stimulate that, and want it to continue, but we definitely don't want S1 to react, either to us or to the alerts from the hindbrain.

It's more complicated than that, of course, and there are lots of cortical regions/pathways that likely do get alerted/stimulated and somehow their reaction is curtailed - context again.

I think however that this is the beginning of a reasonable hypothesis for the descending analgesia/descending modulation part of getting those microglia back into their little cages, in the context of applying manual therapy.

For manual therapy to work on pain perception, the contact has to be non-nociceptive, and your handling/exteroceptive input has to be placed under veto control of the patient, and the patient has to be told that, explicitly.

The patient has to have a chance to learn how to handle "you" and that you will respond to any discomfort they might feel, either verbally or physically expressed. Once the patient feels in complete control, they can trust you and therefore the process, and allow it to occur.

Fortunately most people "get it" right away. Some take longer. That's life. :)

satyajit mohanty said...


all the parts are too terse for me to follow. can you please simplify the entire thing for me in manual therapy prospective. it would of great help for me a practicing physiotherapist.


dermoneuromodulator "neuroplastician" said...

Hello satyajit,
"can you please simplify the entire thing for me in manual therapy prospective."

Really, I think it all boils down to the fact that on some levels a therapist's handling will be interpreted as an added threat by a patient's non-conscious brain, no matter how kind a person we happen to be. It's really important IMO to reduce the threat factor as much as possible, by controlling the context as best you can.

1. Reassure the patient that you will not intentionally cause them any increased discomfort, as that would be counter-productive for the purpose of pain downregulation.

2. Recruit them to help you determine their own comfort level. Make it clear that it's you and them, teamed up to help a non-conscious part of their system learn to reduce the discomfort it has produced. Then you have to fulfill your end of the bargain:

a. Ask the patient to relax and breathe freely;
b. Do not provoke any more pain in your already pain-provoked patient, and;
c. Watch the patient's motor output like a hawk to ensure you do not provoke their pain further with your well-intended efforts. (Watch eyelids, facial muscles etc., tell the patient to let you know about any discomfort they may be experiencing from your grip, or handling.)

Pain is something that must be contained, meticulously and swiftly, by you on the outside, but mostly by the patient's awareness, on the inside, or it can become/remain widespread, severe, and persisting.

The patient's job (whether they realize it or not) is to learn to downregulate their own pain. To do that they have to learn how - this is something completely kinesthetic and non-verbal. You can't teach them exactly how - all you can do is explain to them that they have brain parts whose job is precisely to do that, and that they will need to help those parts do their job again, and that you'll try to help that happen or at least not interfere.

Our manual therapy benefits people more, I think, when we follow a few simple guidelines, such as these:
* Let the patient's brain lead the way during the actual contact, and learn to "feel" when improvements occur in non-conscious output, mostly autonomic
* Lighter is always better than harder
* Slower is better than faster
* Lingering longer is better than jumping around too abruptly
* More time between visits is better than less (optimal physiological changes take at least three days to complete, then it takes time for the system to settle into/"learn" or neuroplasticize a new "normal")
* The patient should report significant improvement each visit
* Most patients will be "better", as in ready to discontinue, within a span of 3 to 5 sessions, for most kinds of "pain," even pain that seems at first to be complex, mysterious (without clear mechanism) and widespread
* Be completely happy for them and let them go off to live their life as a normal person, not as a lifelong "pain patient."