Sunday, 29 November 2015

A way to silence Neuropathic Pain

Laumet G, Garriga J, Chen SR, Zhang Y, Li DP, Smith TM, Dong Y, Jelinek J, Cesaroni M, Issa JP, Pan HL.G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.Nat Neurosci. 2015;18(12):1746-55.

Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K+ channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation (addition of two methyl groups- which is a carbon and three hydrogens) of Lys9 (The nineth amino acid in the protein which is a lysine amino acid) at postion on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 (potassium channels) promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K+ channel expression. Selective knockout of the gene encoding G9a in DRG neurons completely blocked K+ channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced genes associated with K+ channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K+ channels and in acute-to-chronic pain transition after nerve injury.

Neuropathic pain is caused by aberrant nerve signals generated within the nervous system, typically unrelated to any real pain causing sensation. Pain is often treated by using opiates but in neuropathic pain the opioid receptors are down regulated and this is why opioids , like morphine don't do the business when it comes to treating neuropathic pain.

In biochemistry, transferase is the general name for the class of enzymes that enact the transfer of specific functional groups(e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of different biochemical pathways throughout biology, and are integral to some of life’s most important processes. It is interesting that loss of activity of a methyl transferase (removes methyl group from the begining of the protein). The central point is that this effects way some genes are expressed in the dorsal root ganglia, which contain the nerve cell bodies of sensory nerves. In these nerves there is a excessive activity of methyl transferase function that result down regulation of some potassium channels such as the calcium activated potassium channel (Kcnma1) or voltage sensitive channels. These channels serve to limit rate the firing of nerves, so if the nerves are damaged and these channels are down regulated you get more firing of nerves and so things like pain and possibly spasticity can be aberrantly triggered. So this study indicates that therapy of pain may be achieved by upregulating the potassium channel activity and this may be achieved by blockade of of this transferase. So a new target for neuropathic pain 

11 comments:

  1. Very interesting result. How can we reconcile the positive effect of upregulating potassium channels on neuropatic pain with the positive effect of potassium channel blocking by 4-aminopyridine on walking and perhaps other MS symptoms?

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    1. 4-AP works on the shaker channel KNCA3 and its job is to cause repolarising the nerve allowing it to fire again.The calcium activated potassium channels kick in at different voltages or calcium concentrations and can limit the firing of action potentials. There are about 80 potassium channels and not all located in the same place so they will do different things, openers verses blocker: it will be context dependenent

      1. Calcium-activated potassium channel - open in response to the presence of calcium ions or other signalling molecules.
      2. Inwardly rectifying potassium channel - passes current (positive charge) more easily in the inward direction (into the cell).
      3. Tandem pore domain potassium channel - are constitutively open or possess high basal activation, such as the "resting potassium channels" or "leak channels" that set the negative membrane potential of neurons.
      4. Voltage-gated potassium channel - are voltage-gated ion channels that open or close in response to changes in the transmembrane voltage.

      When i have more time I may do some posts on ion channels

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    2. Thank you, I would really enjoy reading your posts on ion channels. I do realize it's a time-consuning task, but your experience with ion channels will certainly provide a unique view.

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  2. Hi Mr Mouse,
    One question,would a MRI scan give a definitive answer to the origin of pain ? and could it determine if the pain was Neuropathic or Nociceptive ?
    okay two questions ;-)

    (still battling constant pain :-( despite trying all the opiates going.)

    Regards as always

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    1. A nociceptor is a sensory neuron (nerve cell) that responds to potentially damaging stimuli by sending signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.

      In answer to your question perhaps and perhaps not. Neuropathic pain is thought to be centrally generated, yet some people call sciatic nerve (peripheral nerve) ligation a neuropathic pain ans so the lesion is outside of the CNS and would be mised by MRI as would many small lesions. However where in the pain pathway is the pain generated?. A scan my be suggestive of where but I doubt they can help prevention. The problem can be from the spinal cord up to structures like the periductal grey in the brain.

      The problem with opiates and neuropathic pain, is that the opoid receptors down regulate themselves and so the opiods stop working, the cannabinoid receptors apparently don't down regulate but some people respond and other don't

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    2. I was diagnosed with MS two years ago and pain has been my primary symptom. First one side of my face was burning then both my legs began to burn badly quite frequently, especially with increased activity. Then it progressed to bad aching in my legs. I always get confused when I read about pain and deciphering which type of pain I have, such as parathesia or dysesthesia or neuropathic pain. What is the difference between these?

      I don't hear a lot about pain and MS but for me it has been quite debilitating. Thankfully I tried 75mg Lyrica and it has been a lifesaver. Do drugs such as Lyrica lose their effectiveness over time? I've only been taking it for two months now.

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    3. Lyrica is pregabalin and is a calcium channel modulator. the causes of the symptoms are not being eliminated and therefore it is possible that your dose may need to be adjusted in time.

      Parathesia is an abnormal sensation, typically tingling or pricking (‘pins and needles’), caused chiefly by pressure on or damage to peripheral nerves.

      Dysesthesia is an abnormal unpleasant sensation felt when touched, caused by damage to peripheral nerves.

      Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia).

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    4. Thanks for the explanation , mouse doc.

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    5. So know I'm thinking the pain is more in the Nociceptive ???

      Pain doesn't seem to be caused by a stimulus ie touch with something hot or cold, never tingling or burning always stabbing and always in the same region.

      Very strange, when pain wasn't constant, there was never any residual effect ie muscle soreness etc or was never painful to the touch when not in pain.

      Always worse at night

      Nothing as ever been revealed on X-Ray and range of movement was always surprisingly good.

      In general and not specific to anyone, what sort of pain is that ? baffling.

      Regards as always

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    6. I think the pain will be centrally generated somewhere in the spinal cord where there has been a damage in the past. The nerves in the pain pathway are bein artifically stimulated.

      I know very little about pain, but have experienced it, Maybe neuros can do a generalised post on this and explain the diuranal pattern

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    7. Thanks, the battle continues.

      Regards as always.

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