Earl Carstens, PhD, is a distinguished professor in the Department of Neurobiology, Physiology and Behavior, College of Biological Sciences at University of California, Davis, US, where he studies how itch and pain are encoded and regulated within the nervous system. He recently finished his second term as president of the International Forum for the Study of Itch (IFSI). Following the 10th World Congress on Itch, which took place November 17-19, 2019, in Sydney, Australia, Carstens took time to talk with Tayler Sheahan, a postdoctoral fellow at the University of Pittsburgh, US. In this interview, Carstens discusses his path to somatosensory research, seminal findings of the itch field, and much more. Below is an edited transcript of the conversation.
How did you become interested in itch and somatosensory research?
I went to college at Cornell and actually started out as a psychology major, but I quickly found their excellent curriculum in neurobiology and behavior. I took several courses on topics such as bird behavior and cockroach behavior, and I really got interested in neuroscience that way.
Then, I went to graduate school at University of North Carolina-Chapel Hill. At that time, the graduate program was headed by Ed Perl. In fact, one of the defining events of graduate school for me was when Ed Perl himself held a seminar in which he talked about his early work with nociceptive reflexes and the discovery of nociceptors. I just found that really fascinating and was immediately hooked on pain research.
I did my PhD dissertation with Daniel Trevino, characterizing the anatomy and physiology of the spinothalamic tract. I then went on to postdoc with Manfred Zimmerman in Heidelberg, Germany. Together, we worked on descending pain modulation, looking primarily at the influence of the periaqueductal gray on spinal pain transmission.
I went on to get a faculty job at University of California, Davis, and it wasn’t until my sabbatical in the 1990s with Hermann Handwerker in Erlangen, Germany, that I got interested in itch. I was especially interested in his work with Martin Schmelz, where they proposed the idea of itch-specific receptors based on microneurography recordings from histamine-sensitive C-fibers in humans. That really piqued my interest in itch.
My first foray into the field of itch was on spinal cord dorsal horn neuron responses to cutaneous injections of histamine in rats. In that paper, I actually concluded that the histamine responses were not really itch-related, but that they were more pain-related. This was because the histamine responses were suppressed by morphine, they were suppressed by descending pathways, and they had a lot of characteristics of pain responses, but not itch responses. It turns out that serotonin, rather than histamine, is the main itch mediator in rats. So that was my progress into itch research.
What specific projects is your lab focused on currently?
Right now, we are primarily focused on descending modulation of itch signals within the spinal cord. We used to do mainly electrophysiology, and we still do that a lot. But we’ve modernized, and now we are using optogenetics and chemogenetics to address our questions. In a way, we are circling back to what I did 40 years ago, looking at descending modulation of pain.
Until recently, itch has received relatively little research attention, especially compared to pain. What factors do you think spurred interest in itch research over the past two decades?
I think there are key discoveries that really stimulated the field. One of the first ones, as I mentioned earlier, was the finding by Hermann Handwerker, Martin Schmelz, and colleagues that there are human C-fibers that respond to histamine. They recorded from these C-fibers in conscious humans while they applied histamine, and the response of the C-fibers paralleled the perceived itch sensation of the participants. That was an important discovery around the turn of the century.
The finding from Zhou-Feng Chen’s lab that gastrin-releasing peptide plays an important role in spinal signaling of itch was also an incredibly important discovery in the mid-2000s. Shortly after, Xinzhong Dong’s group discovered that the Mas-related GPCRs [G protein-coupled receptors] are involved in itch, and now the discoveries just keep coming and coming.
Methods like optogenetics and chemogenetics that let us look at the effects of stimulating specific populations of neurons on behavior has given us a new window into itch circuitry. This has really been taken advantage of by labs like Yan-Gang Sun’s in China, who is using these techniques to tease apart itch circuitry in the spinal cord and also up in the brain.
At the recent IFSI World Congress on Itch, you spoke about the challenges of basic itch research. What do you think are the biggest challenges in the field?
In my mind, the most important and the largest challenge in itch research is understanding how the nervous system can discriminate between itch and pain. I think that’s very intriguing.
A lot of the challenges of basic itch research are the same challenges that we face in basic pain research. What are the mechanisms by which pruriceptors, or itch receptors, transduce itchy stimuli into electrical signals? How is that information transmitted through the spinal cord and on to higher brain centers? And how is itch information modulated within the brain? We still don’t quite understand how the responses of individual neurons come together to give rise to the sensation of itch.
For me, some of the biggest challenges of basic itch research also involve understanding the mechanisms of chronic itch. And again, I’m sure there are going to be big parallels with mechanisms of chronic pain.
There are several theories of how pain and itch are differentially encoded within the nervous system. Which theory or combination of theories do you currently find most compelling?
When I think about my own experiences, I can clearly distinguish between itch and pain, and I never confuse them. And so, there has to be a degree of specificity such that the nervous system is able to separate itch and pain, and call those things different sensations.
There’s a lot of overlap in ascending pathways for itch and pain ─ most of the neurons that are involved in coding itch also respond to pain-evoking stimuli. Despite that, the idea that there is a specificity for itch and a specificity for pain still holds a lot of water for me, and maybe the specificity comes in at higher levels of the nervous system.
Of course, other mechanisms may also be involved that discriminate between itch and pain, and I don’t discount them at all. In fact, Martin Schmelz recently suggested that it’s a combination of different types of mechanisms that distinguish itch versus pain, and these different mechanisms play a greater or lesser role under various pathological conditions.
How important do you think it is that pain researchers also consider itch in their studies?
Immensely! At least from the basic science side, it’s absolutely critical that people who study and understand pain also incorporate itch as part of their methodology and their scientific journey.
A lot of pain researchers now recognize that pain and itch go hand in hand. Yes, there are differences, but a lot of the neurons that are involved in signaling pain are also involved in signaling itch. It just seems logical that anybody interested in pain research should also, to some extent, be interested in itch. And those of us who are interested in itch can’t get away from the fact that pain is very important as well, because it’s probably the same neurons that are involved in signaling both sensations.
You recently received a Fulbright Scholarship for your project on "Herbal Remedies for Itch in Romania: Myth or Fact?" What is a Fulbright Scholarship, and can you share a bit about your experience in Bucharest?
The Fulbright Program is an international exchange program for scholars. If selected, researchers get to go to a foreign country where they work on their research project with their collaborator for anywhere from four to nine months. I was very fortunate to have three Fulbrights in my career so far. Two of them were in Germany, in Heidelberg and Erlangen, working on pain and itch. Most recently, I had a Fulbright to Bucharest, Romania, where the topic was mainly related to itch and how itch can be modified by homemade herbal remedies.
There were several goals for this project. One of the goals was to do field research asking native Romanians, especially in rural areas, if they know about any herbal remedies to treat itch. This was heavily aided by my wife, who’s a native Romanian and speaks Romanian. We got a couple of leads, but this part of the project didn’t really reveal too many things that we didn’t already know about itch.
The other half of the project was centered at the University of Bucharest in the lab of Alex Babes, who is an expert on sensory neuron responses to pain and itch mediators. We started looking at whether the responses of dorsal root ganglia [DRG] neurons to various itch mediators, like histamine and chloroquine, could be affected if we pre-applied some of the chemicals from these herbal anti-itch concoctions.
It’s still an ongoing project, but we did see some suppression of DRG neuron responses to itch mediators when we pretreated the cells with caffeic acid, a naturally occurring compound found in coffee, herbs, and vegetables that has anti-inflammatory properties. As it turns out, a good colleague of mine from Korea, Won-Sik Shim, published a paper similarly showing that caffeic acid inhibits calcium responses of DRG neurons as well as mouse behavioral responses to histamine. It’s a very interesting study.
You’re now a distinguished professor at UC Davis. What were some of the greatest challenges that you faced as you advanced along the tenure track?
The first big challenge was getting a job. I was really lucky to get a job in California after having lived in Germany for three years. I was afraid I was going to be stranded in Germany for the rest of my career, which would have been okay, but luckily I was able to get a job here. That’s sort of a warning to postdocs who do a postdoc abroad – if you’re coming from the US, make sure you have a way to get back into the US if that’s your career goal.
The next big challenge for me was getting tenure. As a young faculty member, you’re expected to be productive and produce lots of publications. I was lucky to have several supportive colleagues here at Davis, but also abroad, to collaborate with and who also helped me climb the academic ladder.
This may be interesting to younger people: When I was a young assistant professor 40 years ago, they told me, “Establish your independent lab and get as many publications as you can with you as the first or sole author.” As you know, expectations are very different today. Collaboration is considered great, and it’s okay if you are a senior author on a paper with 20 other authors; this is a dramatic change from when I started my career. It’s good to have both types of papers: sole authorship to show that you’re in command of a topic, and collaborations to show that you’re willing to work with others to try to answer an overarching scientific question.
What career advice do you have for those trying to make it in academia?
I don’t have any magic bullets. Try to improve your teaching if you have an academic position with teaching responsibilities like I do. And collaborate! Be productive, publish in decent journals, if not top journals. Just keep the research going. Don’t stop, don’t pause.
The thing that I really like about my career is that I’ve been very fortunate to be able to take sabbaticals every seven or eight years, and I have really taken advantage of them. The sabbatical is supposed to give you a chance to try some different things, to catch up on work that you’ve been doing, to establish new collaborations, and to come up with new ideas. Take advantage of sabbaticals, if you can.
Thank you so much for sharing your thoughts and experiences with the PRF community.
Thank you.
Tayler Sheahan, PhD, is a postdoctoral scholar at the University of Pittsburgh, US.
Additional Reading
Pradhananga S, Shim WS
Eur J Pharmacol. 2015 Sep 05; 762:313-21.
Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X
Cell. 2009 Dec 24; 139(7):1353-65.
A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
Sun YG, Chen ZF
Nature. 2007 Aug 9; 448(7154):700-3.
Specific C-receptors for itch in human skin.
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE
J Neurosci. 1997 Oct 15; 17(20):8003-8.
Carstens E
J Neurophysiol. 1997 May; 77(5):2499-514.