This is the first in a series of Forum interviews with PRF’s eight new science advisors for 2014-2015.
Theodore “Ted” Price, PhD, studies the role of pain plasticity mechanisms in the development of chronic pain, always with an eye toward generating novel therapeutics that can prevent or reverse the condition. He recently set up a new lab at the University of Texas at Dallas, US, where he is an associate professor in the School of Behavioral and Brain Sciences. Previously, he was an associate professor of pharmacology at the University of Arizona, Tucson, US. In 2014, Price won the Patrick D. Wall Young Investigator Award for Basic Science from the International Association for the Study of Pain. Neil Andrews, PRF executive editor, spoke by telephone with Price about his route to becoming a pain researcher, his experience setting up a lab for the second time, and the research projects he is working on now. Price also shared his perspective on how to identify promising targets for drug development, the pain field’s efforts thus far to develop new analgesics, and pain research trends he finds promising. Below is an edited transcript of the conversation.
What was your path to pain research?
I got into pain research by accident. Originally I was a physics major, but I wasn’t very good at it, and I had an advisor who thought my skill set would be better applied to neuroscience. In one of the early laboratory courses I took in neuroscience as an undergraduate, we did LTP [long-term potentiation] recordings in the hippocampus. Within five minutes of observing LTP, I was sold and decided I would become a neuroscientist.
I started looking at graduate programs, and initially I was really interested in serotonergic mechanisms in depression. At that time (and still now), one of the best people in the world working in that area was Alan Frazer at the University of Texas Health Science Center in San Antonio. I decided to go there and work with him, and it just so happened that when I was there I met Christopher Flores and Kenneth Hargreaves, who convinced me to do a rotation in their lab. I ended up enjoying pain research much more than I enjoyed depression research. But I wavered between going into the cannabinoid pharmacology area or staying in the pain field until I settled on doing a postdoctoral fellowship in Fernando Cervero’s lab at McGill University. Within about a month of being at the Pain Centre there, I decided that pain research was really the right choice and what I wanted to spend my career on.
As a postdoc at McGill, it was a remarkable atmosphere. To be able to walk into a journal club and interact with researchers like Catherine Bushnell, Gary Bennett, Jeff Mogil, Fernando Cervero, and Alfredo Ribeiro-da-Silva—it was amazing. After McGill I moved to Arizona and got to work with great people there, including Frank Porreca, Pat Mantyh, and Todd Vanderah, who were all amazing mentors at a completely different stage of my career. For someone who got into the pain field by accident, I have been remarkably lucky to have had such wonderful mentors.
What was it that made you excited specifically about studying pain?
The thing that really got me excited when I first encountered it in Ken and Chris’s lab is that pain is really a fantastic disease state in which to study neuronal plasticity. It has really fascinating evolutionary implications, and also, the clinical implications of what we do in this field are huge. Pain is a great opportunity to look at the fundamentals of plasticity, how some of these molecular mechanisms in plasticity first originated, and then to try to apply that to the clinic to help people who are really suffering.
What was the best piece of career advice you received as a young pain researcher?
To pursue my own ideas and design good experiments. It is very simple, but if you want to be successful in this field you have to develop your own ideas and design experiments that test them. The mistake that a lot of young people trying to start their labs make is that they don't test their ideas particularly rigorously—they go around the edges. But that is a huge mistake, because if your idea is not something that will lead to fruitful research over the next five to 10 years, you need to stop and get a new idea.
You recently moved your lab from the University of Arizona to the University of Texas at Dallas. What has your experience been setting up the new lab?
It certainly is easier the second time—and a lot different, too. I made a lot of mistakes setting up the lab the first time—for instance, by buying expensive equipment that I thought I would use but never did—and we didn't make those same mistakes this time. Greg Dussor and I moved here together. He and I started working together when we were in Ken and Chris's lab in San Antonio, but when we each started our own labs independently in Arizona, we really weren’t working seamlessly together and taking advantage of each other’s strengths. So when we came to the University of Texas at Dallas, we decided to set up the lab in that way, which has allowed us to make our resources go a lot further. Continuity of personnel is also a big part of this. When you are first starting your own lab, generally you hire brand new people, and you have to train them. When we moved here, most of our lab came with us, and I am very grateful to the people who moved with us because they made it a seamless transition.
Are there any guiding principles you follow to direct your research and the people working in the lab?
I tell anybody who is interviewing to work in the lab—be it a graduate student, a postdoc, or an undergraduate—that what we are really interested in is neuronal plasticity that leads to chronic pain, and I would like to see the mechanisms that we discover turn into some project that is related to drug discovery or drug development. But I am open to anything along those general principles.
Now that you have set up the new lab, what projects are you working on?
We have been working on translation control and its relation to neuronal plasticity in the development of chronic pain (see PRF related webinar presented by Price last year). This is the longest running project we have going on in the lab—it started when I was a graduate student working with Ken and Chris in San Antonio, I continued it in Fernando's lab, and then it was the major focus of the start of work in my own lab at the University of Arizona. This area of research has turned into a really exciting field. There are more pharmacological targets now than when we first started, tools have become available to study translation control pathways in minute detail in a wide variety of transgenic mice, new drugs have come along, and there are new bioinformatics approaches, too. We just started a collaboration with a bioinformatics researcher here at the University of Texas at Dallas to look at RNA secondary structure and use RNA sequencing in a variety of tissues, ranging from mouse to human dorsal root ganglia [DRG], to get a better idea of what the targets for translation control in sensory neurons might be, especially in the development of chronic pain. It has turned into a really fascinating project.
Are there targets in the translation control pathways that are of particular interest?
We are pretty focused on a protein called eIF4E, along with a kinase upstream of that called MNK that phosphorylates eIF4E, and a helicase called eIF4A that may or may not be controlled by eIF4E. It’s exciting because we have transgenic mice for each one of these parts of the pathway, and we can interrogate translation control in live DRG neurons using a variety of different approaches. We also have pharmacological approaches for all of the different parts of the pathway. We are set to really see, within the next couple of years, whether we can start translating our work into clinical trials in humans, because almost all of the drugs that we are looking at are moving toward clinical trials for cancer. It’s going to be an exciting time.
In fact, we also have an AMPK [adenosine monophosphate-activated protein kinase] project that is related to translation control and is moving toward the clinic. Metformin is a widely prescribed drug that activates AMPK, and we are getting close to doing a trial with metformin for chemotherapy-induced neuropathy in women with breast cancer; this is in collaboration with Cobi Johanna Heijnen and Annemieke Kavelaars at MD Anderson Cancer Center in Houston. It will be really exciting to see something that we first showed in the lab in 2011 [that metformin could relieve pain in preclinical models] potentially going to a clinical trial in 2015; that’s pretty quick. If metformin has some positive effect, we will all be completely thrilled because it is a cheap and safe drug. People with chemotherapy-induced neuropathy really suffer, and the condition decreases quality of life, in addition to the problems patients already have in relation to cancer.
What other work is your lab pursuing?
Another project we became interested in while we were in Arizona is descending modulation of pain, and we continue to work on that, especially in relation to hyperalgesic priming. Jon Levine first developed models of hyperalgesic priming in the late 1990s, and we think they are excellent models to study the transition to a chronic pain state. We have found some really interesting new regulatory pathways involving descending modulation of plasticity from the hypothalamus leading to a chronic pain state and hyperalgesic priming. These pathways are very surprising to us—we would not have guessed this going in. This has turned into a really fascinating project that I am sure will become a long-term focus of the lab, because it opens up a whole new area that has really not been studied very much at all in the field.
We also continue to work on atypical PKCs [protein kinase C], which are very interesting due to their potential role in the regulation of late LTP. Of course, there has been work from other labs using mutant mice suggesting that, after all, maybe atypical PKCs aren't the kinases involved in the maintenance of late LTP [see Lee et al., 2013; Volk et al., 2013; and PRF related content by Price and Sourav Ghosh]. This is an open and exciting question in relation to pain, and we are trying to develop tools that will allow us to look at this in more detail.
Finally, we also have a couple of ongoing drug discovery projects where we are working with chemists and cell biologists. One of these projects involves protease activated receptor type 2, which I continue to think is a really interesting target. We are discovering some very interesting pharmacology—we are finding lots of biased signaling agonists, which is a fascinating area.
As someone who is very interested in drug discovery and development, how do you think about pharmacological targets? How do you choose the right one?
My perspective has evolved quite a bit over the last couple of years. One issue is whether to take an agonist or an antagonist approach. I owe a lot of credit to Frank Porreca in thinking about this because I first heard the idea from him, and it is something we discussed over many years—and I think he is right. If you are looking for a pharmacological mediator, an agonist is preferable to an antagonist. The reason for that is very simple: if you have an antagonist, you can block a particular pathway, but there is almost always feedback signaling that is initiated when you block an individual pathway. Also, if the antagonist is for an extracellular receptor that is detecting an extracellular ligand, then it is probably the case that no single extracellular ligand is responsible for all of the effects that you see—for neuropathic or inflammatory pain, that is almost certainly the case. So what you really want is an agonist that will engage signaling mechanisms that can alter the excitability of a certain pathway or endogenously regulate multiple pathways. We took an agonist approach with AMPK; it is one of the few kinases that can be positively allosterically modulated. That shuts down almost all of the pathways involved in signaling to the eIF4F complex [which includes eIF4E, eIF4G, and eIF4A] because AMPK is a negative regulator of all of the pathways, so feedback signaling is shut off.
What other factors fit into your thinking about pharmacological targets?
If you consider opioids, for instance, they remain the mainstay of acute pain treatment, and there is a very good reason for that: opioid receptors are expressed all along the pain pathway, and when you activate them, at least acutely, that profoundly changes the excitability of the neurons that express them. When looking for other agonists that may decrease pain, it is important to ask where the relevant receptors are expressed and in which populations of neurons you want to increase or decrease cell excitability in order to get the desired effect with the fewest possible adverse consequences. For the first time in the history of biology, we have the data to make those kinds of determinations, because we have transcriptome data for almost all human and mouse tissues, at least in the naive state, and we can use computational approaches to try to find genes, such as those for GPCRs [G protein-coupled receptors], that are expressed in certain tissues but not others. We can then make decisions about targeting those receptors to try to, for instance, achieve decreases in the excitability of sensory neurons, without decreasing excitability in the rest of the brain, so that there won’t be adverse effects.
It is still very important to find new disease mechanisms—and, of course, that is what we spend most of our time doing—and anything that is involved in disease-related mechanisms could eventually become a target. But there can also be disease-unrelated mechanisms that can be engaged, like those involving GPCRs that might be specifically expressed in sensory neurons, which could be targeted to produce a strong analgesic effect.
What do you think about the “failure of translation”—the idea that basic research on pain hasn't translated into new analgesic treatments?
I don't buy into that idea at all! We have been remarkably successful in discovering transducers for pain over the last 10 years, and I think it is the case that blocking those transducers would work for treatment of certain types of pain. But what we have seen over and over again, for a variety of different targets, is that while the preclinical data at least in part predict what effects there will be on pain if the compounds make it to humans, we are not very good at predicting adverse events. People were working on TRPV1 [transient receptor potential vanilloid type 1 channel] for quite some time, for example, before we had knowledge that TRPV1 antagonists were going to cause hyperthermia.
Similarly, anti-NGF [nerve growth factor] therapeutics that have been developed have been remarkably effective for pain in a broad variety of clinical trials, but the adverse events were not predicted; I still think that anti-NGF therapies will be a real success story for the field. It is difficult to write a grant for the purpose of studying adverse events that come from a particular mechanism of action of a drug because it costs a lot of money to do, and most reviewers don't find that particularly exciting. But it is really important.
So I think we should think a little bit differently about the way that we ask whether or not we have been successful. I feel really optimistic that over the next decade we will see a broad variety of successes in the field. The more we understand that chronic pain is a disease in and of itself that arises from plasticity in the nervous system, and the more mechanisms we discover that underlie those changes, the closer we will be to one day having disease-modifying treatments for chronic pain. At least for those of us on the preclinical side, that is what our broad goal is.
Looking at work from other groups, what trends in pain research appear particularly promising to you?
One really exciting trend is the recognition that maintenance mechanisms in plasticity underlie the transition from acute to chronic pain. A very recent example is a paper from Yves De Koninck [at Institut Universitaire en Santé Mentale de Québec, Canada; see Bonin and De Koninck, 2014]. The pain field has been bandying this idea around about “pain memory” for some time. The first time I read about it was in one of Ronald Melzack's papers (he called it a “pain engram”). Jeff Mogil used the term a lot; we have used the term in our work on a kinase enzyme, PKMζ, and Jürgen Sandkühler has been using it in reference to his LTP work. This new work from Yves’ lab really drives the point home. It is indisputable that the spinal cord encodes a memory for chronic pain. If we can find what the circuit is and disrupt it, there is a very real chance for developing disease-modifying therapeutics. With our research on PKMζ, I think we have found at least one of those “pain memory” circuits. We are really excited to get that word out there, and I know that lots of other labs are working in this area, too.
What else is catching your eye?
There is another area that has been hot for some time, but is starting to become even more exciting because of the therapeutic implications. This is work again from Yves De Koninck and studies he has done with Mike Salter and others on KCC2 [potassium chloride cotransporter; see Gagnon et al., 2013]. Positive modulators of KCC2 [that restore GABAergic inhibitory signaling] being studied now are really interesting. Changes in the way that GABAergic circuits are working in the dorsal horn are crucial to the development of chronic pain, and reversing those changes may lead to disease-modifying effects for neuropathic and other kinds of pain. Research from people like Steve Prescott, at the University of Toronto, who is working on computational methods to try to understand this, is leading to wonderful insights that we wouldn't otherwise have.
Finally, I think that work on human nociceptors is really going to take off. Rob Gereau and Steve Davidson [at Washington University in St. Louis, US] recently had a very nice paper in Pain where they characterized properties of human nociceptors that they obtained from AnaBios, a company in San Diego that is trying to facilitate a lot of this work [see Davidson et al., 2014]. And an approach that others have taken, such as Clifford Woolf [Boston Children’s Hospital, US], is to take stem cells and turn them into human nociceptors. We will learn an enormous amount from this work, such as how predictive some of the mouse genetics that people have been using will be. It also brings the opportunity to do computational work—to try to identify receptors that might be exclusively expressed in certain populations of human nociceptors, for instance—and with that we are going to find a whole new array of targets that will be interesting for drug development.
You’ve pointed to many lines of inquiry that are already bearing fruit for pain research and seem poised to continue to do so. In the meantime, what do you think is the biggest unknown in the pain field?
One of the great mysteries in our field is why migraine occurs—what is the initial trigger—and why is it so prevalent; this is the area that is most ripe for discovery. Migraine is a huge medical problem, but very few people are studying it. However, people are finally starting to recognize that there are some nice migraine models, many of which were developed by Greg Dussor and Frank Porreca. Greg and I received a grant from the Migraine Research Foundation to help my lab become more involved in migraine work. We have been collaborating with Greg on molecular mechanisms for maintaining plasticity that we think lead to migraine, at least in our rat and mouse models. I am extremely excited about it and about the possibilities for discovery for treatment of migraine. Migraine is a field that is really going to take off in the next decade, and we are really going to see a lot of progress.
Thanks so much for speaking to PRF.
PRF Related Content:
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Mao-Ying QL, Kavelaars A, Krukowski K, Huo XJ, Zhou W, Price TJ, Cleeland C, Heijnen CJ. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One. 2014; 9(6):e100701.
Price TJ, Dussor G. AMPK: An emerging target for modification of injury-induced pain plasticity. Neurosci Lett. 2013 Dec 17; 557 Pt A:9-18.
Price TJ, Ghosh S. ZIPping to pain relief: the role (or not) of PKMzeta in chronic pain. Mol Pain. 2013; 9:6.
Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T, Sonenberg N, Dussor G, Price TJ. Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain. 2011; 7:70.
Asiedu MN, Tillu DV, Melemedjian OK, Shy A, Sanoja R, Bodell B, Ghosh S, Porreca F, Price TJ. Spinal protein kinase M ζ underlies the maintenance mechanism of persistent nociceptive sensitization. J Neurosci. 2011 May 4;31(18):6646-53.
Melemedjian OK1, Asiedu MN, Tillu DV, Peebles KA, Yan J, Ertz N, Dussor GO, Price TJ. IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. J Neurosci. 2010 Nov 10;30(45):15113-23.
Other Forum Interviews with PRF's 2014-2015 Science Advisors