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!!