This is the fifth in a series of Forum interviews with PRF’s eight new science advisors for 2014-2015.
Frank Porreca, PhD, is a professor of pharmacology and anesthesiology at the University of Arizona, Tucson, US. He is interested in approaches that allow measurement and mechanistic evaluation of affective dimensions of pain in animal models. His research focuses on the role of descending modulatory circuits in chronic pain states, the mechanisms by which opioids and stress engage these circuits, and the discovery of molecules that can modulate these circuits through novel mechanisms. Recently, he has worked on understanding intersections between pain and reward pathways. He and his lab are known for developing conditioned place preference methods of behavioral analysis to indicate spontaneous, or ongoing, pain in animal models. Porreca spoke with Neil Andrews, PRF executive editor, to discuss the evolution of his research interests, the use of animal models in pain research, and his advice for young investigators. Below is an edited transcript of their conversation.
Tell me about your early career.
When I started doing work as a graduate student at Temple University in the late 1970s, it was a very exciting time—a time when the endogenous opioid receptors, and the endogenous peptides that interacted with those receptors, were just being discovered. My research was focused on understanding opioid pharmacology, and after I moved to the University of Arizona, I worked on this with Tom Burks and with researchers in the department of chemistry, especially Victor Hruby. We wanted to increase the metabolic stability of endogenous opioids so that they could be studied in vivo and to develop ligands that were highly selective for the different opioid receptors. We thought that these new ligands would be key to understanding the physiological roles of endogenous opioids and to finding out how this system might be exploited to develop new therapies. We were using morphine and other opioids that acted on the mu opioid receptor clinically, but we thought there was therapeutic potential for new molecules that could interact with the delta receptor, or possibly the kappa receptor.
How did your research interests evolve from when you first started out?
Our interest in opioid pharmacology naturally led us to try to understand the circuits in which opioids participated. What really caught my interest was the emerging understanding that descending pain modulatory circuits in the brain are opioid-sensitive circuits. I worked with Michael Ossipov to learn how opioids could produce modulation of nociceptive signaling by engaging these descending pain modulatory circuits in brain regions such as the rostral ventromedial medulla and how these circuits change in the setting of chronic pain. This has been a constant area of interest in my laboratory because these circuits are highly relevant to the human pain experience.
David Yarnitsky and colleagues have been working on understanding and exploiting a phenomenon that, in humans, is called conditioned pain modulation; in animals it’s called diffuse noxious inhibitory controls. David has been showing that patients with less efficient descending modulation seem to have a higher likelihood of developing chronic pain and that drugs that mimic descending modulation may be more effective in those patients. Again, these opioid-sensitive descending pain modulatory circuits are essential in the human pain experience, and that’s why this interests us and why we have been working on it for quite a while.
You are also interested in conditioned place preference as a behavioral measure of pain. What made you go in that direction?
We had been having a series of conversations with individuals in academia, but especially with people in the pharmaceutical industry. The consensus was that even though targets might be very well validated in preclinical studies, when molecules engaging those targets were taken forward into human trials, they did not show efficacy. The criticism was that we really weren’t evaluating pain in the animal models in a way that had translational relevance to humans.
We were thinking a lot about this—about how, exactly, we evaluated pain in animals and in people. The main distinction we wanted to address experimentally was that in people, because of the subjective nature of pain, self-report is how we measure it, while in animals we usually use threshold measurements. That led us to try to work out a procedure where we could essentially obtain a self-report from an animal indicating whether or not an intervention that we would make was meaningful to that animal. Place preference is a learning paradigm that really allows us to do this. We wanted to focus on something that was very fundamental about pain, both in humans and in animals, and pain involves learning. That’s what I worked on with Tamara King to bring into the assessment of pain [see PRF related webinar presented by Porreca].
Many people in the pain field remain critical of animal models of pain. What are your thoughts about that?
I am continuously concerned about the negativity that is sometimes expressed about the so-called failure of our preclinical models and the link that people make between the outcome of a clinical trial and preclinical experimentation. Hopefully, we will move past that negativity because there are so many factors that contribute to clinical trial outcomes that are unrelated to preclinical models. There have been many advances in our understanding of pain, and many of these advances have come from our preclinical studies, so I hope we emphasize the many positive things we have accomplished. Preclinical studies are an essential part of what we do to advance science, and in the end, if we do develop new therapies for pain, these kinds of studies will have a strong role to play.
How should the animal models fit into pain research?
I think the models are, for the most part, very useful in understanding mechanisms that underlie basic translational biology. Each model has its advantages and disadvantages, and they each provide us with specific information. The question is, How do we interpret and use that information for the ultimate goal of understanding the human pain experience and developing new therapies? We have talked about the assessment of ongoing pain and capturing pain-motivated behaviors and affective features of pain, and that is important, but that doesn’t mean that evoked threshold measurements we make in animals to assess pain hypersensitivity are unimportant. In fact, evoked thresholds provide information about a very important clinical issue—allodynia—which is something that really changes a patient’s life. Understanding that the input of a normally innocuous stimulus to a sensitized nervous system is an aversive stimulus and identifying mechanisms that produce amplification of pain signaling are very important, and the animal models help us to study those particular issues, though perhaps not other features of pain that are also important.
We also have models that really begin to approximate disease processes in humans. The cancer chemotherapy models, for example, are extremely valuable in giving us insight into how cancer treatments we use in people may produce negative effects that can limit the use of those treatments. So I think there are tremendous advantages of animal models, and there is too much negativity placed toward them. That being said, it is also important that we don’t overstate what animal models can do. We need to have an understanding of their inherent limitations and use the information that results from these studies appropriately.
What are some of the specific projects your lab is working on now?
We are continuing to study affective dimensions of pain and asking questions that we think will have high relevance across species. In particular, we are working to evaluate pain-motivated behaviors with the concept that relief of pain is a reward. Edita Navratilova, Jennifer Xie, and I have been working with Howard Fields to understand how pain relief is rewarding—how we can assess this neurochemically and identify the underlying brain circuits. We have also been working with David Borsook to use preclinical imaging for this purpose. We are also continuing to explore how we can use the rewarding effect of pain relief as an outcome measure for evaluating the possible efficacy of different treatments working at novel molecular targets.
In addition, we are seeking to understand how the drugs that we currently use to treat pain produce their effects and how they can modulate different aspects of pain. For example, we have been studying systemic administration of opioids to see if we can capture the preferential actions of opioids on affective dimensions of pain and localize the activity to parts of the brain that may be more associated with pain affect and less associated with pain reward. This will help us answer the question of whether or not opioids can preferentially produce pain relief without engaging circuits that may be associated with addiction. We also want to begin to understand the actions of opioids in chronic non-malignant pain, which is something that we really don’t know a lot about. We know that there are a lot of non-addictive pain-relieving drugs, but we don’t know exactly how they work, and they often don’t work very well. The discovery of truly effective analgesics that are non-addictive is really an ultimate goal in pain research.
Another area of focus in the laboratory is exploring mechanisms of migraine pain. We have worked with Milena De Felice and David Dodick to study migraine mechanisms preclinically and have attempted to do so without producing tissue injuries, since migraine pain is pain that occurs in the absence of such injuries. We are looking at adaptations that can enhance sensitivity to triggers that promote migraine. One of our goals is to understand how stress turns into pain biology—into activation of afferents that innervate the dura mater. We really want to understand exactly how those links occur.
Speaking of migraine, what do you think about the anti-CGRP [calcitonin gene-related peptide] antibodies that are being developed for that condition?
The anti-CGRP antibodies are extremely exciting. Targeting CGRP is a mechanism that has been validated both with antibodies and with receptor antagonists. These drugs haven’t yet been introduced to clinical practice, and there are some potential reservations. The body makes CGRP, and it must be important for something, so there is the question of whether blocking CGRP for very long periods of time is going to be safe. It may take some time to find out exactly how to use these treatments safely and in which specific groups of patients. These drugs are going to be extremely important and are likely to be a breakthrough in clinical management of migraine.
Are there any studies from other groups that have recently caught your eye?
There are so many great studies published that it is hard to pick just one. But one that comes to mind is a fantastic paper in Science by Neil Schwartz and Rob Malenka [see PRF related news story]. They were looking at the motivational aspects of chronic pain in animals seeking rewards. They compared food reward in animals with and without pain and showed that, while the intrinsic reward value wasn’t changed, when the food reward became harder to obtain, animals with chronic pain would no longer pursue it. So the issue was motivation. The authors were able to identify a circuit in dopaminergic neurons in the nucleus accumbens underlying this change in behavior and uncovered a role of galanin, a neuropeptide that acts through a specific receptor, the galanin 1 receptor, in this effect. This was a remarkable study that showed the influence of a neuropeptide in pain-induced changes in motivation, with implications for patients with chronic pain.
Any words of wisdom for people just getting into pain research?
There are so many unanswered questions in the pain field that deserve study, so there are plenty of opportunities, along with a tremendous medical need for new pain therapies. That alone should be a motivation for individuals to work on pain. The hope is that society will continue to support research, and this is an issue that will influence the outcome of many careers. That is beyond our control on an individual level, although as a group of scientists we need to continue to emphasize the importance of medical research—for pain as well as for other disease areas. We need to remember that the development of new therapies for patients will ultimately depend on establishing new knowledge that will come from efforts by people entering the pain field.
I hope that people will not be dissuaded from pursuing pain research because of current funding levels. In my experience over several decades, funding goes up and down—that has always been true. What will happen in the future is hard to say, but I think that ultimately the importance of the work will win out, and medical research will continue to be supported. There will be opportunities, especially for individuals who are very creative. I have been lucky to meet many of the young scientists who are getting into the field, and I am always impressed at their extraordinary talent and creativity. That is what will lead to success in understanding biology and in advancing therapies.
Finally, it’s very important to keep patients in mind. Their experience should guide the questions we ask. People starting out in the field should talk with clinicians, ask them what the problems are that patients face, and really try to understand that and allow that information to guide what they do in the laboratory. Understanding how fundamental information coming from the lab may ultimately be relevant to humans will elevate the importance of preclinical work.
Thank you for sharing your thoughts about pain research with the PRF community.
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Navratilova E, Porreca F
Nat Neurosci. 2014 Oct; 17(10):1304-1312.
Borsook D, Hargreaves R, Bountra C, Porreca F
Sci Transl Med. 2014 Aug 13; 6(249):249sr3.
Xie JY, Qu C, Patwardhan A, Ossipov MH, Navratilova E, Becerra L, Borsook D, Porreca F
Pain. 2014 Aug;155(8):1659-66.
Ossipov MH, Morimura K, Porreca F
Curr Opin Support Palliat Care. 2014 Jun; 8(2):143-51.
Felice M D, Eyde N, Dodick D, Dussor GO, Ossipov MH, Fields HL, Porreca F
Ann Neurol. 2013 Aug; 74(2):257-65.
Navratilova E, Xie JY, Okun A, Qu C, Eyde N, Ci S, Ossipov MH, King T, Fields HL, Porreca F
Proc Natl Acad Sci U S A. 2012 Dec 11; 109(50):20709-13.
Felice M D, Sanoja R, Wang R, Vera-Portocarrero L, Oyarzo J, King T, Ossipov MH, Vanderah TW, Lai J, Dussor GO, Fields HL, Price TJ, Porreca F
Pain. 2011 Dec; 152(12):2701-9.
Felice M D, Ossipov MH, Wang R, Dussor G, Lai J, Meng ID, Chichorro J, Andrews JS, Rakhit S, Maddaford S, Dodick D, Porreca F
Brain. 2010 Aug; 133(Pt 8):2475-88.
Felice M D, Ossipov MH, Wang R, Lai J, Chichorro J, Meng I, Dodick DW, Vanderah TW, Dussor G, Porreca F
Ann Neurol. 2010 Mar; 67(3):325-37.
King T, Vera-Portocarrero L, Gutierrez T, Vanderah TW, Dussor G, Lai J, Fields HL, Porreca F
Nat Neurosci. 2009 Nov; 12(11):1364-6.
Other Forum Interviews with PRF’s 2014-2015 Science Advisors: