This is the sixth in a series of interviews with PRF science advisors.
Allan Basbaum, PhD, FRS, studies the molecular mechanisms of neuropathic pain in peripheral neurons and in the central nervous system. He advocates for thinking broadly about pain mechanisms, and for grounding research in a firm understanding of the experience of patients. Basbaum is a professor and chair of anatomy at the University of California, San Francisco (UCSF), US, where he holds a joint appointment in physiology and is also a member of the W. M. Keck Foundation Center for Integrative Neuroscience. He is co-editor of the textbook Science of Pain, and for the last decade has served as editor-in-chief of Pain, the journal of the International Association for the Study of Pain (IASP). Megan Talkington spoke with Basbaum by phone about some of the latest findings from his lab, the avenues in pain research that he’s keeping an eye on, and his to-do list for researchers new to the pain field. The following is an edited transcript of their conversation.
What’s going on in your lab right now that you’re most excited about?
I'm excited about everything. Seriously, I'm having a great time. I should be thinking about retiring, but I'm not—I'm having too much fun.
My lab has always been very eclectic. In collaboration with David Julius [UCSF], we are trying to understand how different ion channels in nociceptors contribute to pain processing, and the extent to which there is specificity in the processing. I was brought up to believe that there is no specificity at all—that it's all a patterning system. But we are pretty convinced that, at least at the level of the afferent, and perhaps at the level of some cells in the spinal cord, there is a lot of specificity. This is demonstrated in the circuitry, in the distribution of ion channels among different nociceptors, and most importantly in the functional contributions from different nociceptors. We now have the ability to take out certain populations of nociceptors, either molecularly or using toxins, and we find that there is a very modality-specific loss of function.
Can you tell me about some of your new projects?
One is our foray into studies of pain vs. itch. In the old days one thought of itch as on the same continuum as pain—that you get touch, and then maybe itch, and then maybe, when things become really severe, you get pain. But now that we are getting a handle on the afferents and the circuits, and it looks like there are segregated circuits for itch and pain. The organization and chemistry of the circuitry in the spinal cord, and the populations of cells that are unique to one or the other sensory process, are becoming clearer.
This is interesting because it is very clinically relevant. Itch used to be thought of as not particularly important. But there are enormous numbers of patients who have severe itch conditions—in particular, atopic dermatitis that doesn't respond to antihistamines—and those patients are miserable.
We are looking at this in many ways—molecularly, anatomically, electrophysiologically—trying to dissect the circuits in the spinal cord and afferents that contribute to itch in response to different pruritogens. Just like you have pain from heat, mechanical, and chemical stimuli, different pruritogens produce itch, and they may do so by activating a common central circuit; certainly they activate different populations of afferents. We're talking about things like chloroquine vs. endothelin vs. histamine, and most recently we have been working with Martin Steinhoff [also at UCSF] on interleukins. We have been studying the signaling by which interleukin-31 induces itch, and have found that its action is, to some extent, via direct binding to interleukin receptors on the afferents. So it’s not through release of a more traditional pruritogen.
The other area that is new and exciting for us is the epigenetics of pain. Working with my colleague Stavros Lomvardas, who studies chromatin regulation in the olfactory system, we are looking at how DNA modifications can influence the predisposition to persistent pain. Specifically, in an animal model, we are looking at the consequences of nerve injury on the dorsal root ganglia—at the level of DNA methylation and hydroxymethylation, and histone modifications. The questions we are asking are: What contributes to the persistence of pain in the setting of injury? Why is it that after you induce a nerve injury and the animals develop pain for a period of time, some animals recover, and some don't? Do epigenetic modifications contribute to those differences? This has been a totally new avenue for us. I've learned a lot, and while I've taught Stavros about pain, he’s taught me about chromatin modification.
What other new lines of research are you pursuing?
In the last year and a half, my lab has turned our attention to the possibility of treating neuropathic pain conditions in the mouse by transplantation of mouse embryonic precursor cells from the cortex into the spinal cord. The particular cells are destined to become cortical GABAergic (gamma-aminobutyric acid secreting) interneurons. These cells were initially described by a colleague, John Rubenstein, here at the university. He and his colleagues transplanted the embryonic cells into the cortex of neonatal animals, and found that they integrate and are functional. In fact, when they transplanted the cells into seizure-prone mice with a K+ channel mutation, they were able to reduce the number of seizures. Since one of the major hypotheses as to the etiology of nerve injury-induced neuropathic pain is loss of GABAergic inhibitory control in the spinal cord, we thought that maybe we could transplant these cells into the spinal cord to reverse the mechanical hypersensitivity that is a hallmark of neuropathic pain.
Previous studies had made transplants (e.g. of adrenal chromaffin cells) into cerebrospinal fluid, but this involved directed transplants in spinal cord tissue. The approach was radical, and I had never done any of that kind of work. My colleagues said it was a great idea, but that it likely would not work because these cells are supposed to live in the cortex; they probably would not survive in the spinal cord. They also said the cells have a tendency to migrate, so you wouldn’t be able to target them to the area that you want—you would put them in one place and they would end up somewhere else, which is what happens in the cortex.
But we tried. We made our first transplants in a genetically engineered mouse that we had generated several years ago, a mouse that allowed us to test for integration of the transplant. These are mice in which we can turn on tracer proteins in different populations of neurons, which allows for the analysis of complex CNS circuits. Instead of putting in an exogenous tracer and seeing if it goes from one neuron to the next, we turn the tracer gene on in neuron X, and it makes a protein that will actually jump synapses to neuron Y. The approach has been published [see Bráz et al., 2002 and subsequent papers].
What we did now is we transplanted the embryonic cells into the spinal cord of our adult tracer mice. That allowed us to demonstrate integration of cells in a way that no one has ever been able to do before, because we could show that the tracer in the host ends up in the transplant. Before, people would show the formation of one synapse here or there, by EM [electron microscopy]. But we can show the nature of the connectivity, and demonstrated, for example, that primary afferent fibers engage the transplanted cells. We also showed that the connections are functional, by measuring the induction of Fos protein in target neurons after different types of peripheral stimulation. Then, most importantly, we transplanted the cells into animals that had hypersensitivity from a nerve injury. And within four weeks of the transplant the animals are completely normalized. It's pretty dramatic [see Bráz et al., 2012].
We don't know for sure that GABA is the cause, but we think that's the most likely explanation. It was previously shown that the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is decreased after nerve injury; we confirmed that, and showed that the transplant actually normalizes the animals’ GAD levels. The transplant doesn't move them above normal, so it looks like there’s a kind of homeostatic switch that gets screwed up after injury, and the transplant brings the animal back to a normal level of GABAergic function.
We are also transplanting these cells into the cortex to try to understand some of the cortical areas implicated in the emotional aspects of pain. These are totally new ventures; it’s an exciting time.
Were you surprised by your findings?
Yes. I wasn’t entirely confident that the transplants would work. What is most interesting is that it appears that the cells retain their cortical phenotype. We thought that somehow they would be modified—these are embryonic cells, after all. That was a surprise. At the same time, they are extremely plastic in their ability to adapt to the new environment.
When you look across the pain field, what are some crucial questions that you believe researchers need to address?
Certainly the poor translation of basic research findings into the clinic is a big issue. How good are the preclinical models? Are the hypersensitivity models sufficient? Probably not. Should everyone be moving to conditioned place preference and conditioned place aversion models that bring into play at least inferences of spontaneous pain?
Imaging is another huge issue—are there biomarkers for pain?
There is also the issue of drug targeting, and what the best approach is to developing new drugs. Do you always want to give drugs systemically? Or should you consider targeting as a better approach to avoid adverse side effects?
Our own laboratory is interested in the subtypes of opioid receptors. The question as to how relevant issues of heterodimerization are remains on the table. Also, what is the mechanism of opioid tolerance? We still don't know.
These are important questions. There are a lot of good pain drugs, but the problem is they have lousy side effect profiles. We need to understand why, and try to mitigate the side effects so we don't throw the baby (namely, morphine, which is basically a good pain relieving drug) out with the bathwater. For example, some of the work that I always look forward to reading is from Hanns Ulrich Zeilhofer [at the Swiss Federal Institute of Technology (ETH), Zurich, Switzerland], who is looking at subtypes of GABA receptors and seeing whether some are more relevant to pain relief versus sedation.
Male/female differences are also a key issue: Women by and large have the greatest majority of clinical pain problems. They also have lower pain thresholds, and they tolerate pain more poorly. We have hints as to why that is, but is there a hormonal basis, or a genetic basis, or a cultural basis?
Another area concerns so-called functional pain disorders—some people refer to them as dysfunctional pain disorders. Here we are talking about fibromyalgia, irritable bowel syndrome (IBS), and temporomandibular joint (TMJ) disorders. Are they related? They tend to be co-morbid in a lot of patients. Is there some predisposition to them? They certainly predominate in women. Understanding those things is important, as there are enormous numbers of people with these problems.
Finally, there is so much data saying that microglia are major contributors to injury-induced—particularly nerve injury-induced—pain. There is an enormous effort underway looking at glial-neuronal interactions. But this hasn’t turned into something that is clinically relevant yet. Why is that?
What questions outside of your own research are piquing your interest?
One big area is the notion of persistent pain being a maladaptive memory of an injury that gets established in the spinal cord and in the brain; there is a lot of evidence to suggest that. Thinking in terms of learning, does it makes sense to ask whether we can induce forgetting, rather than just waiting for the memory to run down or trying to find a drug that prevents the learning in the first place? It is unlikely that we will develop prophylactic treatments—you are not going to give people drugs that prevent them from getting pain. But once pain is established, can you then figure out a way to reverse it? If you understand the process by which the engram, if you will, was established, can you reverse that?
A very controversial issue is the matter of volumetric changes in gray matter. This phenomenon was first described in the pain world by Vania Apkarian [at Northwestern University, Chicago, US] in back pain patients. There seem to be huge changes—20 percent—and not always in the same place. Are those changes really related to pain? Are they related to depression? And to what extent are they reversible? Some data from arthritis patients, from Irene Tracey [University of Oxford, UK], suggest that the changes can be reversed. That’s really mind-boggling. Mechanistically, we don’t have a clue as to what’s going on. Is it a question of restructuring of a neuron’s architecture, and if so, can that be controlled?
Are there ways in which the field needs to change course? Or places where it is getting stuck?
A controversial issue is that many people in the pain world are talking about the “disease of pain.” I do it myself. To some extent it’s a more effective way to highlight the problem of chronic pain, because of where pain research funding comes from. It comes from the federal government, and, less and less, from industry. It doesn’t come from pain foundations. And isn’t that interesting, because every other disease—heart disease, multiple sclerosis, muscular dystrophy, you name it—has a foundation, right? But not pain. Why? Because people don’t die of pain. They die in pain. So people donate money to a cancer society when someone dies of cancer, even though the person may have experienced terrible pain before they died. Everyone sees chronic pain, understandably, as a symptom of an underlying condition.
I would argue that certainly in the case of certain neuropathic pain conditions and central pain, that damage to the nervous system causes changes—reorganization, structural changes, genetic changes—and those changes are what cause the pain. So the pain is a symptom of those changes, but those changes are effectively the disease of pain. When we transplant those GABAergic cells that I talked about earlier, we are actually trying to treat the disease—it’s disease modifying, it’s not symptom management. If you put a GABA pump in the spinal cord, you will block all kinds of pain. The GABAergic precursor cells only reversed the pain/mechanical hypersensitivity that followed nerve injury, i.e., by treating the disease. By contrast, there was no effect in an inflammatory pain model.
I think that’s a very controversial and provocative perspective. Neurologists don’t like it, because it’s hard to fit this into the normal definitions of disease. But the notion that there are abnormalities in nervous system function that need to be addressed—that’s important.
Also, it’s not news, but it’s becoming increasingly recognized from clinical work that without emotion there isn’t pain; all you have is sensation. How do emotion and sensation interact to create pain?
To try to capture aspects of emotion in animal models, some people are using the conditioned place preference and conditioned aversion models. An animal withdrawing its paw from a stimulus just reflects hypersensitivity, but when an animal actually avoids a condition where there was pain, it’s telling you, “I don’t like that” or, “I prefer the box where you gave me a drug that made me feel better.” So there’s this aversive component that is the essence of pain. Understanding that, and perhaps being able to treat it coincidentally or concurrently with traditional analgesics, is important.
One of the most provocative and puzzling things is that in the old days, Henry Beecher spoke about the reactive and the sensory components of pain. By “reactive,” he meant the emotional element. And he said morphine blocked the reactive component. But now everyone focuses on morphine blocking the sensory component at the level of the spinal cord—and I’ve worked on that. But it’s almost like we’ve forgotten that morphine given systemically acts on the whole system. How is it doing that? The more we understand about the pathophysiology that occurs in emotional circuits, the more we get a handle on the pain experience rather than the sensory experience—and there’s a big difference.
You’ve mentioned the work of many different researchers, and some really central concepts in pain. For someone just starting out in pain research, what would you tell them to read?
I could say: “Read the textbook that I edited with Catherine Bushnell. If you read all of that, you’ll know more than enough to get started.” But that won’t necessarily tell you about pain. I happen to believe in the importance of an historical perspective. So I argue that people should be grounded in some classic papers—whether it’s early work of Henry Head or even going way back to Brown-Séquard’s descriptions of patients, Ed Perl’s studies of nociceptors or Melzack and Wall’s early work that was the basis for the gate control theory. Of particular interest is Melzack and Wall’s 1962 paper on cutaneous sensation that talked about the complexity of pain. These are important conceptual papers. It’s fine to keep up with the day-to-day stuff, but if you really want to understand pain, you should read some of the classics.
But if I had to make one suggestion to new basic scientists interested in pain, it would be that they should go to the pain clinic and see the patients. I did that for three years, and that’s what had the biggest influence on my career. I went to the pain clinic at the National Hospital [in London, UK] once a week when I was a postdoctoral fellow in Pat Wall’s laboratory. Most importantly, I learned that a patient with neuropathic pain is not the same as a rat with partial nerve injury.
The experience turned me into a basic scientist who understands a lot about the clinical pain condition. Now I encourage everyone in my lab—preclinical people, basic scientists—to see patients, and they do. They do this with an anesthesiologist, Zhonghui Guan, in the lab who sees patients at the pain clinic. My students and postdoctoral fellows see the interviews with patients, they see procedures, and they hear the patients describe their conditions. They see which approaches work, and which ones do not. The fact is there are very limited approaches to treatment. So in a relatively short period of time, you can run the gamut—learn all the treatments, and see how patients respond.
A patient may come in and say, “Well, I feel a lot better but my pain is still there.” Wow, I never had a rat tell me that! What does that mean? For a preclinical researcher, it teaches that there could be a whole different set of targets.
The most important thing is that you don’t realize how much pain these patients have until they start talking. They walk in, they look pretty good, and then they start telling you what’s going on. There are a lot of fascinating things we don’t know anything about, but I think empathy with the patient, and understanding the patient, will really make a difference when you’re doing preclinical work.
Thanks so much for talking with me.
Thank you. This was fun.
PRF Related Content:
News: Lone Star Snakes Reveal Unexpected Role for Acid-Sensing Channels in Pain (18 Nov 2011)
News: TRPs Through Time and Space (2 Aug 2011)
Forum Discussion: Specificity Versus Patterning Theory: Continuing the Debate (initiated by Allan Basbaum 24 June 2011)
News: Taking Aim at Pain in the Brain (31 Mar 2011)
View Allan Basbaum’s profile on Pain Research Forum (requires member log in)
Basbaum AI, Bráz JM. Transgenic Mouse Models for the Tracing of “Pain” Pathways. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press; 2010. Chapter 7.
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009 Oct 16; 139(2):267-84.
Allan I Basbaum and M Catherine Bushnell, Editors. The Science of Pain. Oxford, UK: Academic Press, 2008.
Christensen BN, Perl ER. Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. J Neurophysiol. 1970 Mar; 33(2):293-307.
Bessou P, Perl ER. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli.J Neurophysiol. 1969 Nov; 32(6):1025-43.
Melzack R, Wall PD. On the nature of cutaneous sensory mechanisms. Brain. 1962 Jun; 85:331-56.
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