Things that make you go hmmm…

Every once in a while a paper comes out that really makes you reconsider what you thought was true about your biological system of interest. For me, one of those papers came out last week in Science. The paper is from John Wood’s lab at UCL and the link is here. Interestingly, there is also a podcast (which I think is free) associated with the paper.

So what did they do and why is this paper so very interesting and possibly paradigm shifting? Many years ago, Armen Akopian, working in Wood’s lab, discovered a special sort of voltage gated sodium channel that is exclusively expressed in pain sensing neurons and is not sensitive to the prototypical sodium channel blocker tetrodotoxin. This sodium channel — now called Nav1.8 — has been widely considered an important target for drug development for pain for many years now but the gene locus has also been an important tool because it allows you to exclusively express certain genes (via a knockin strategy) in pain sensing neurons. Several years ago Wood’s lab created a Nav1.8-CRE expressing mouse that allows for the knockout of floxed genes in pain sensing neurons. In the current paper they have taken advantage of CRE expressed in pain sensing neurons to allow for the expression of a toxin that wipes out this class of neurons. One might imagine that this would eliminate pain in these mice. That would be only half of the story…

So what did they find? Turns out that ablating Nav1.8-expressing neurons wiped out cold pain, pressure pain, pain induced by chemicals such as capsaicin and hyperalgesia and allodynia induced by inflammation. Elimination of these neurons led to a massive decrease in expression for most genes that we normally associate with nociception in the dorsal root ganglion (like TRPV1 and some voltage gated calcium channels) where pain sensing neurons reside. All of this is somewhat expected and while the approach of the study is cool probably not worthy of a Science paper. But that’s not all…

The truly interesting finding (and the one that I think might be the beginning of a paradigm shift) came when the authors started looking at nerve injury models. Neuropathic pain is the primary clinical challenge for pain clinicians and scientists. It is difficult to treat in humans (if not virtually untreatable) and despite thousands of studies conducted in the lab it still seems like we are barely brushing the surface of our understanding of the disease (or continuum of diseases). One would expect that if you ablated nearly all of the pain sensing neurons in an animal that they would have strongly attenuated neuropathic pain after an experimental insult to peripheral nerves. It seems that the real answer is a resounding NO.

In the paper the authors show that despite the absence of other types of pain neuropathic pain is completely preserved in these animals. Hence, it appears that neuropathic pain does not require an intact peripheral nociceptive system. What does this mean for 1) pain biology basic science and 2) for neuropathic pain clinical management? First a caveat, as with any single paper it would be nice to see some independent confirmation of the findings using alternative methods. That confirmation (or lack thereof) will almost certainly come in the near future. Back to the questions at hand.

1) From the basic science perspective this paper clearly illustrates, at least to me, that central sensitization is playing a key role in neuropathic pain. We knew this already but what we may have underestimated is how central sensitization as a consequence of nerve injury can result from activation of peripheral nerves that are not involved in sensing pain. Some labs have already recognized this and have been working on this for years but I have always had the impression that that particular hypothesis was somewhat fringe. Not anymore, I would predict.

2) From the clinical perspective the present data (at least to me) rather clearly indicates that treatments for neuropathic pain that target peripheral mechanisms may be doomed to failure. Moreover, some of the compounds that we thought were working on pain sensing neurons in neuropathic pain (e.g. gabapentin) may not be doing what we thought they were doing. A search for their action in the CNS (aside from an action on pain sensing neuron afferent terminals in the spinal cord) may yield novel targets for neuropathic pain with increased utility. Basically, if I’m trying to create new compounds or identify new targets for neuropathic pain (and I am) I’ll be looking for CNS actions.

So, congrats to John Wood and colleagues for getting us all thinking with these provocative experimental findings… Can’t wait to see what the buzz is on this one at the upcoming International Association for the Study of Pain meeting in Glasgow!!

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21 responses to “Things that make you go hmmm…

  1. It’s possible that killing the NaV1.8-expressing nociceptors causes rewiring such that other peripheral sensory neurons now synapse onto pain relays in the spinal cord. This would be consistent with the usual neuropathic pain scenario being wholly dependent upon NaV1.8-expressing nociceptor activity.

  2. Sure, it is possible; however, nothing of the sort seemed to happen with a long term inflammatory stimulus (e.g. the CFA experiment). Then again this could be because there was no peripheral nerve injury to stimulate rewiring of the dorsal horn. Its a bit unfortunate that they didn’t do some of the electrophys experiments after nerve injury to see if the rewiring was occuring as you suggest (for instance, does the neuropathic surgery reinstate wind-up — if I was a reviewer I certainly would have asked for that sort of experiment). We’ll see what happens as I’m sure they are following up on these experiments now and we will hear about them at IASP in Glasgow in two weeks. I’ll do a followup post if we hear more.

    With respect to the role of Nav1.8 in neuropathic pain idea this has always been somewhat hit or miss. Some groups have seen big effects and others have seen nothing (like in the KOs with the exception of the neuroma models), or minimal effects. I’ve never been really sure of what to make of that whole story. As Wood mentions in the podcast, Abbott and some other BigPharmas are getting close with their Nav1.8 inhibitors for some clinical trials. Those will be the true test I suppose. Personally, I have little confidence that they will work, but I sure hope that they do, those patients really deserve something better and it would be great to finally deliver on one of these targeted drug discovery approaches.

  3. Its a bit unfortunate that they didn’t do some of the electrophys experiments after nerve injury to see if the rewiring was occuring as you suggest (for instance, does the neuropathic surgery reinstate wind-up — if I was a reviewer I certainly would have asked for that sort of experiment).

    You dick! I hope you never review any of my papers!

    LOLZ!!!

  4. One would expect that if you ablated nearly all of the pain sensing neurons in an animal that they would have strongly attenuated neuropathic pain after an experimental insult to peripheral nerves.

    Might the simplest explanation be that the damaged nerve cells themselves are in fact the pain “sensing” neurons that signal neuropathy to the CNS?

  5. BTW Thanks for pointing out the paper and taking the time to translate for us dummies.

  6. Bayman,
    Yes, that would be part of the simplest explanation. However, I think that many (including me) thought that you needed the damaged pain sensing neurons to sensitize the CNS to the nerve injury and to drive the neuropathic pain. In the case of these experiments this does not appear to be the case. There are some other works that may provide some significant insight into what is going on here. If you’re interested check out the work of Mike Salter’s group over at U Toronto. One might be led to conclude that damaged non-pain sensing neurons are capable of stimulating spinal microglial cells (which gets into Salter’s work) to sensitize the dorsal horn after nerve injury.

  7. Ah, ok I think I see what I was missing (not knowing the first thing about neuropathic pain models). The nerve injury in the neuropathy model causes damage to both non-nociceptive and nociceptive neurons…think I got it.

    Science papers…not the easiest to follow when it comes to foreign methodology.

  8. Science papers…not the easiest to follow when it comes to foreign methodology.

    which makes sense and all since it isn’t like it is a general science journal or anything….wait. what?

  9. which makes sense and all since it isn’t like it is a general science journal or anything….wait. what?

    And now you owe me one mouth-full of coffee.

  10. No shit! If I ever have to look at another Science paper I’m going to have a nervous breakdown. Even worse when it’s in your own field because you know what’s missing, it’s just nowhere to be found…

  11. Which reminds me. A couple years back I got scooped by a paper appearing in none other than good old ScienceMag as my paper was in the early stages of submission at an alternative GlamourMag. The only thing worse than watching the promise of an imminent GlamourMagPub vanish before my eyes was spending hours scrutinizing microscopic figure legends trying to figure out if the bastard deserved to beat me to the punch! LOLZ!!

  12. Honestly I swear sometimes I was able to understand more of the articles in Science when I was a wee monk leafing through MonkeyPere’s copy than I am now….

  13. DM–That may be because the articles have gotten more & more difficult to read…more experiments seem to be necessary to get it into said GlamourMag, but the paper length does not appear to have changed, therefore more stuff left out (I think they call it supplementary material…I’m still not sure why it’s called supplementary when it’s almost always necessary for understanding the damn paper)

  14. oh & tiny ephys traces are not impressive (speaking of microscopic figure legends)…in the past year we had a speaker come & present some work that was published in a GlamourMag a few years ago that had tiny example traces…well, it wasn’t until I saw the traces all blown up for the talk that I realized that their slices were unhealthy (or they were recording in the wrong region)!! A few of us gasped slightly when we saw the traces in the talk…
    No wonder some of these labs can get shit out so quickly…you apparently don’t have to have quality recordings if you’re planning to shrink it down to fit into GlamourMag figures!

  15. Say hi to Glasgow for me! That’s where I went to grad school.

    I will be following this story, since as we’ve talked about before I am currently going through the process of dealing with my own neuropathic pain developments. It sucks! Just when you think it might be getting better, something twangs or picnhes again and you’re right back in there.

  16. sometimes I was able to understand more of the articles in Science when I was a wee monk leafing through MonkeyPere’s copy

    What, back in the pre-microscope days? No kidding! Those were simpler times…

  17. jp – Thanks for this post; I starred this article when it came up on my Google Reader, but wasn’t immediately clear on its significance. See, I told you I was a pain poser.

    Honestly I swear sometimes I was able to understand more of the articles in Science when I was a wee monk leafing through MonkeyPere’s copy than I am now….

    I remember being at a grad student lunch at Stanford where Don Kennedy spoke, I think soon after he assumed editorship of Science. He actually read the first couple sentences of two abstracts, to highlight how one was “good” and understandable by all, and the other was “bad” and filled with jargon.

    Looks like he wasn’t able to affect much change in that respect I suppose.

  18. Hello : i came across this site while trying to understand hyperalgesia. I have 20 physical maladies that have caused me chronic acute pain for 28 yrs. Two yrs ago I was in an auto accident amoung the various injuries my L5/S1 disc was herniated. I have been on and off pain medication at a steady rate for about 12 of the 28 yrs. And intermittent medication prior to the last 12 yrs.
    My pain has increased due to the auto accident. I feel the need for a slight increase of my medication. I have not had an increase for about 3 yrs or so. Am I to believe that I am not actually feeling more pain because I am already on pain medication and have been for many years?
    Before the accident I had come to a, let’s say, 90% functioning state and since the accident I have decreased in my ability to function to about a 45% ability to function. As in the ability to drive w/out an increase in pain, sit too long, stand, walk and so on. After sleeping in one position, most of all on my back, I wake up screaming out loud! I am told I cry in my sleep as well as say things like please stop, ouch ouch & call out for help.
    So, in my case, with all of your infinit

  19. … I guess I wrote too much. Please bare w/me. So, in my case with your infinite knowledge of pain am I to assume I will never receive any further relief from an increase of pain medication? Have my receptors been fried and gone and died? Is there no hope?
    Can you tell me if this is the new wave of controlling a patients level/access to medication for doctors so that they may limit their liability?
    Please, I do understand the science. However, are all the eggs ever in one basket? Are all of the apples always good? How can something subjective like pain be reduced to this receptor and that receptor and an automated system that leaves no room for the intellect and person as a whole?? It’s like speaking of an artist like M. Angelo – and saying he used paint, a brush, he applied the paint to the brush and the brush to the canvas. w/out considering his passion, vision and talent. I appreciate your time. Any response at all will be greatly appreciated. Please pardon my spelling and grammer it’s. 3:26 am and I am in a huge amount of pain. It’s difficult to think clearly. Thank you again and I hope I did not intrude. Kara

  20. Kara, I’m not a physician and I don’t know what meds you are on; however, increased pain medication may give you some relief because you may have developed tolerance to the meds you are taking. I would strongly suggest that you seek the help of a pain specialist. If you live in a big/medium sized city there should be a pain clinic somewhere…. I would start at a university hospital, if there is one.

    In terms of treating the person as a whole, I am not sure what you mean but I will take it as therapies in addition to meds. For people with low back pain, which it would appear that you have, physical therapy can be a big help. A pain specialist should be able to refer you to physical therapists who specialize in helping people with pain disorders.

  21. I am not an academic, nor in the medical field, but have been dealing with pain issues for the last 18 months and after many tests, my dr. Feels I may have fibromyalgia, and small fiber painful axonal neuropathy (still waiting on test results). At the worst times, I have difficulty walking due to pain and balance issues, and daily have some variation of pain. Now for the “hmmm”…over the last two days I was miraculously free of pain! I walked the dog, moved about easily, and was elated! And then last night I began seeing prisms and recognized a migraine coming on. I have migraines infrequently…every couple of years. I quickly took my Zomig and went to bed. I awoke this morning free of the migraine but could hardly walk to the bathroom because the body pain was back! My question: did the neurochemical action leading up to the migraine eliminate my body pain? Is there a connection between the pain perception centers? Thoughts are appreciated

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