Saturday, June 15, 2013

Melzack and Katz, Pain. Part 7 b: Gate control: "The theory was a leap of faith but it was right!"

The paper, Pain

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

"The theory was a leap of faith but it was right!" 
-  A. H. Dickenson (2002)

Dickenson adds in his paper (already 11 years old) that Patrick Wall continued to "add to and refine the theory to include changes in afferents, prolonged central excitability, and changes in these systems after nerve damage." 

Here is Dickenson's list of ways the model has expanded since the 60's: 
  • Excitations and inhibitions are independently controlled
  • Different types of convergent afferent activity may be turned on and off
  • There are signs of both short‐ and long‐lasting actions
  • More info exists re: transmitters, receptors and channels involved in the transmission, control of noxious input
  • New targets and rationales for analgesic therapy including opioids (like this study, on mμ opioid receptor, from June 14, 2013)
  • New experimental drugs are available to help in study of transmitters and receptors (same study, on mμ opioid receptor)
  • Numerous animal models for clinical pain states, e.g., inflammation, neuropathies
  • Several transmitter systems with minor action in acute pain play important roles in persistent pain
  • Signalling events are not fixed, are not the same in all situations
  • Less destruction of pathways, more emphasis on modulation - reduce excitation or increase inhibition
  • Both nociceptive and neuropathic signalling create profound changes in spinal cord and brain - allodynia and hyperalgesia result
  • All persisting pains exhibit plasticity
  • Peripheral changes drive central adaptations and compensations - numerous sites are involved
Gate control theory has generated thousands of studies. It provided a framework "for examining the interactions between local and distant excitatory and inhibitory systems in the dorsal horn."

Mechanisms subsequently accepted include:

  • Inflammation produces peripheral sensitization (Millan MJ 1999)  
  • Ectopic activity will occur in damaged peripheral nerves - transmitters will be released continuously into the spinal cord - this will cause subsequent neuronal activity.(Dickenson AH 1995Suzuki R, Dickenson AH 2000Millan MJ 1999) 
  • Increase in Ca channel activity within the spinal cord drives increased presynaptic transmitter release and postsynaptic neuronal excitability
  • N‐type calcium channels, in particular, activate more, contribute to activity evoked by both low‐ and high‐threshold peripheral stimuli
  • Upregulation of the α2δ subunit of calcium channels occurs, greater number of channels can become active at any one time
  • Gabapentin binds to this component of calcium channels, where it can be presumed to act as an antagonist
  • Glutamate and peptides are released by Ca channels into the spinal dorsal horn (Matthews EM, Dickenson AH 2001) - glutamate is the major transmitter in afferent A and C fibres
  • Increased glutamate enhances activation of NMDA receptors which can lead to wind-up and central sensitization (Dickenson AH 1995)
  • Constant C-fibre activity excites spinal neurons; as they become more excitable their receptive fields increase and secondary hyperalgesia results (McMahon SB, Lewin GR, Wall PD. 1993)
  • Glutamate plays pivotal role together with peptides to regulate transmission of nociceptive input; there are 
  1. Metabotropic receptors activate biochemical cascades leading to modification of other proteins [e.g., ion channels]
  2. AMPA [amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid] receptors mediate fast synaptic transmission: they set baseline level 
  3. NMDA receptors help control synaptic plasticitymemory function, responsible for wind-up which enhances/prolongs trasmission implicating it in many states of central hypersensitivity - only activates when intensity/duration of noxious input exceeds certain level and magnesium blocks are removed (Carpenter KJ, Dickenson AH. 2001)
AMPA receptor
mediates fast synaptic transmission
[cool gif eh? I doubt they actually spin like this. But at a molecular level, form = function]

  • Antagonists can prevent some of the reactions at these sites, e.g., ketamine

This paper is from eleven years ago. I have no idea the extent of the range of discoveries made at the cord level of nociceptive input since then. I know a lot of work has been done on what microglia get up to in there (Beggs S et al 2012), and lately I read a paper on how TRPv receptive C-fibres in the periphery can open the spinal cord/blood barrier for a week or so, allowing larger molecules than usual to bother ascending neurons (Beggs S et al 2010). 
(The above paragraph is my pathetic attempt to touch on just a tiny bit of what's out there to examine. There is a huge amount of research available. Go look at it. Even just some of it. Try to make sense out of whatever you can, about how the nervous system works. We all need to get busy on this if we are to have any hope of getting caught up. We need some kind of collective understanding if we HPSGs are going to have any place in society in the future. Remember, all of us are going to have to know how to deal with pain, in our patients and in ourselves. We're human. )

Gate Control Theory might have been "right".. but as we shall see, it wasn't sufficient. The spinal cord is sort of like that crossover place in a mobius strip where everything changes over to being on the other side all by itself. It's a transition zone. And it's the oldest part of the central nervous system. Fishy ancestors invented spinal cords, and the vertebrate nervous system arrangement in general. But brains came along later, it is thought. Brains select what information to pay attention to. Once they select what they want to attend to they inhibit everything else. See Buzsaki's article about this, Neural Inhibition. Remember what Moseley said about the brain: it's easy to recruit neurons into a neurotag, and very hard to inhibit them later, once they are used to activating. 

Melzack moved pain theory right up past the critter brain, up into the human brain. Which is appropriate, considering that it is humans we deal with, most of the time.. humans who can't fathom how to inhibit pain very well. 

1. Jose Manuel Perez-Aguilar, Jin Xi, Felipe Matsunaga, Xu Cui, Bernard Selling, Jeffery G. Saven, Renyu Liu. A Computationally Designed Water-Soluble Variant of a G-Protein-Coupled Receptor: The Human Mu Opioid Receptor. PLoS ONE, 2013; 8 (6): e66009 DOI:10.1371/journal.pone.0066009
2. Simon Beggs, Tuan Trang & Michael W Salter; P2X4R+ microglia drive neuropathic pain. Nature Neuroscience 15,1068–1073 (2012) doi:10.1038/nn.3155 Published online 26 July 2012

3. Simon Beggs, Xue Jun Liu, Chun Kwan and Michael W Salter; Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Molecular Pain 2010, 6:74 (open access)

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