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College of Medicine Alumni Magazine - Fall/Winter 2016 Unlocking the Secrets of Pain

They're on the case: Working collectively on a range of individual projects, College of Medicine scientists and physicians gain valuable information from each other, enhancing their experience as well as their progress. At left (l-r) Drs. Seena Ajit, assistant professor, and Huijuan Hu, associate professor, Pharmacology & Physiology; Ricardo Cruciani, chair of Neurology; and James Barrett, professor, Pharmacology & Physiology.

They're on the case: Working collectively on a range of individual projects, College of Medicine scientists and physicians gain valuable information from each other, enhancing their experience as well as their progress. At left (l-r) Drs. Seena Ajit, assistant professor, and Huijuan Hu, associate professor, Pharmacology & Physiology; Ricardo Cruciani, chair of Neurology; and James Barrett, professor, Pharmacology & Physiology.

Neurologist Ricardo Cruciani, MD, PhD, sees patients dealing with excruciating pain every day, and he believes that there's much more that can — and should — be done to help them. "Pain is part of our survival — you see it across every species. And yet within the body it's a complex and sophisticated problem to solve," he says.

In joining Drexel, Cruciani came to the right place. Here, he is part of a multidisciplinary group of researchers hunting for the intricate and often obscure causes for pain and uncovering novel solutions for treatment.

Persistent pain is more than a symptom — it's a Pandora's box of systemic issues and associated side effects impacting more than 100 million Americans, according to the Institute of Medicine. Yet, despite an aging population that makes this growing problem even more concerning, therapies and treatments for pain are quite limited.

Part of that has to do with the changing and multidimensional nature of pain itself. "You reach a point in certain pain stages where you don't even have a painful stimulus but you are constantly in pain. There are many syndromes like that," Cruciani says. "When that happens, you don't have only one pathway that is involved, or one channel, or one neurotransmitter — you have many. So you target one, but then the other one is active. That's why it gets difficult to find the right treatment."

While pain has always been an exceedingly complicated problem for physicians to treat, very little progress in the discovery of treatments has been made since the early 20th century. "If you look at the history of pain therapeutics, you know morphine was isolated back in the mid-1800s, and aspirin was identified in the early 1900s," says James Barrett, PhD, director of the Clinical & Translational Research Institute and a driving force behind Drexel's pain research initiative. "By and large, we haven't had too much since then in the way of new therapeutics that are truly effective."

When Barrett accepted the position of chair of Drexel's Department of Pharmacology & Physiology in 2009, he did so with the intention of focusing on that "tremendous unmet need," hiring other researchers who specialized in this area, including Drs. Huijuan Hu and Seena Ajit, both of whom came from the pharmaceutical industry. He recognized that it would take a broad scope of approaches and perspectives to tackle the issue, so he put together what he says is "in a sense, a small biotech company within an academic setting."

A veteran of the pharmaceutical industry himself, Barrett has brought his drug development expertise to bear in creating a molecular physiology and pharmacology research corps that spans from the bench to the bedside. "We have embedded within the department a core group of individuals focusing on animal models of pain, molecular mechanisms of pain, biomarkers of pain, and medicinal chemistry," he says. The result, he hopes, will be a set of novel targets that can then be turned into treatment modalities.

A Promising Candidate for Cancer Pain

Barrett's own work has centered on chemotherapy-induced and cancer-related pain. Somewhere between 30 and 50 percent of all cancer patients experience pain, and it's often the first sign of the disease in patients. "Ninety percent of patients have pain at the late stage, and they are often given opioids, but we know that opioids have other debilitating effects and side effects that are not pleasant."

Barrett and his colleagues soon closed in on sigma-1 antagonists. "These drugs were discovered in the 1980s and '90s and classified first as an opioid-like compound, but they didn't show any of the features of any of the opioids, and so they fell into what I call the ‘valley of death' for a long time. Recently, they've been resurrected and people are now looking at a wide variety of indications," he says.

Barrett is interested in how these compounds compare to morphine in the treatment of advanced cancer pain. Using mechanical stimulation in animals, he can measure their degree of discomfort with regard to cancer pain and then compare the effects of the drug compounds to morphine in alleviating it. "What we found is that their effects were quantitatively identical. We did full dose-response curves with the sigma-1 antagonist and compared them with morphine and got the same degree of efficacy. Then we did some chronic administration to see whether or not these drugs lose their ability to attenuate pain, and they don't."

Barrett found that, unlike morphine, sigma-1 compounds did not produce tolerance or related side effects at higher doses, making them less likely to be candidates for abuse. In an era when opioids are widely abused, resulting in addiction and overdose, developing a compound that is non-addictive could be a true game-changer in pain relief medication.

Barrett is currently working with medicinal chemist Joseph Salvino, PhD, in the Department of Pharmacology & Physiology, to synthesize the sigma-1 compounds. In the coming months, he plans to profile the novel chemical entities to understand their efficacy. Equally exciting is the research conducted by Felix Kim, PhD, director of the Pharmacology & Physiology Graduate Program, which suggests that sigma-1 might also be capable of shrinking tumors. "If we can identify a compound that attenuates pain and also inhibits tumor growth — well, what more could you want? We're looking at it, and we will know that answer clearly and unequivocally within the year," Barrett says.

Barrett is currently in the process of pursuing funding for the next phase of his research — determining the ideal compound, conducting follow-up studies and preparing for more drug development work over the coming months.

Exactly how these compounds work is what Barrett calls the "million dollar question. What's known is that this class of drugs are what are called chaperone proteins. In pharmacology, chaperones escort different material to the surface of the receptor, where those proteins interact with other substances, and the traffificking by a chaperone seems to be the mechanism for looking at a pathophysiological state. Under normal conditions, these drugs don't do anything, but when the system is perturbed, the chaperone proteins are activated by the compound, and in some way they appear to interact with ion channels and other receptors that are somehow mediating these effects. What we don't know is exactly how they're doing it."

Finding the Pathways for Inflammatory Pain

Understanding the underpinnings of pain is critical to the drug development process. As Barrett uncovers a potential treatment for cancer pain, Huijuan Hu is starting with the potential cause or progression of inflammatory pain. Hu brought to Drexel an industry-honed expertise in electrophysiology and in vivo ways of assessing pain. At Drexel, her laboratory is zeroing in on the groundbreaking area of calcium channels as a pathway. "Evidence shows that intracellular calcium plays a role in persistent pain," she says.

In particular, she is looking at store-operated calcium (SOC) entry in the central and peripheral nervous system. She has observed that a compound known as a SOC inhibitor can reduce the painful inflammation and swelling that follows the injection of an irritating substance into the hind paw of mice. With the SOC inhibitor, the animals exhibited significantly less spontaneous pain.

These results demonstrate that inhibiting SOC channels can mitigate inflammatory and neuropathic pain. The goal is to understand the molecular and physiological mechanisms in chronic pain, in order to identify new drug targets for treating it. "If things go really well, we'll try to develop a drug targeted to these channels specifically for cancer pain, and maybe also for neuropathic pain."

A leader in this emerging new subject, Hu is now validating her pain targets. "Hu's work has been pioneering in elucidating the role of these channels," Barrett says. "The elegance of her research is that it combines molecular pharmacology, electrophysiology and behavioral pharmacology, using genetic modifications to pull apart the mechanisms of SOC channels. It's very exciting work."

Decoding Pain Mechanisms

Another innovative approach to cracking open the mechanisms underlying pain is through epigenetics, which is the focus of Seena Ajit's work. "Many of the chronic pain conditions are syndromes, and we hope our studies will enable us to put together at least some of the pieces of the pain puzzle," she says.

In Ajit's lab, researchers are examining genetic and epigenetic markers for pain — and ways that new drugs can be developed to target specific populations that don't respond to pain treatments on the market. Specifically, she looks at microRNAs, or naturally occurring noncoding RNA molecules, and their connection to chronic pain for sufferers of complex regional pain syndrome (CRPS).

"A patient's miRNA signature may differ even prior to treatment initiation, and changes in signature may correlate with treatment outcome," Ajit says. "Identifying the potential target genes for individual miRNAs could provide insights into the molecular bases of different types of pain and help identify novel targets for pain therapy."

CRPS is notoriously diffificult to treat, with many sufferers experiencing intense, long-term pain. A proof-of-principle study conducted in Ajit's lab involved examining the use of intravenous ketamine, fifirst to treat pain and then to see if it altered the miRNA expression in chronic pain patients. The results showed that, indeed, miRNAs can be used as biomarkers to predict patients' response to treatment. This finding can help researchers determine, through a personal or precision medicine approach, how and when to prescribe ketamine.

These results have potentially wider implications for pain treatment. "Using the genetic and epigenetic signatures or biomarkers can help us stratify patients to guide treatment strategies. If we can differentiate the CRPS pain state from the cancer pain state on a genetic or epigenetic level and get independent quantififiable assessments — or fifingerprints — associated with that pain, we have much more information to develop and use drugs going forward," Barrett says. "There have been very few instances where people have made signifificant strides in pulling apart these mechanisms."

The next step involves looking at how miRNAs are transported via intracellular communication within a body that's in pain. A team composed of Ajit (principal investigator), Cruciani, and Ahmet Sacan, PhD, a faculty member in the School of Biomedical Engineering, Science and Health Systems, recently received a grant from Drexel's Clinical & Translational Research Institute to conduct this study.

Alternative Forms of Relief

It's one of many studies for Cruciani, who is looking at pain both as a researcher and as a specialist in pain medicine. At the Center for Comprehensive Pain Management & Palliative Care, which he directs, Cruciani offers patients from around the world multiple strategies for feeling better, including psychotherapy, infusions, injections, nerve blocks, and alternative therapies, but he's in search of others, especially those that patients can use at home.

While no one questions the efficacy of opioids, Cruciani is looking for better ways to define and perhaps limit their role in pain treatment. "Opioids are very helpful for certain conditions, like post-operative pain, and I don't think there is any argument about that. The difficult discussions start when you're talking about long-term therapy with opioids and when you have to separate patients who have cancer, or patients who have non-cancer chronic pain."

Developing treatments that don't cause addiction, dependency and negative side effects is the goal. One component of Cruciani's research looks at non-pharmaceutical approaches, in particular repetitive transcranial magnetic stimulation (rTMS), which can decrease the excitability of cells and therefore reduce pain. He is currently looking at its efficacy in treating CRPS. "What we are trying to do is to treat the levels of the brain by manipulating the pain sensations with stimulators, see where everything converges, and determine if we can modulate it that way."

In addition to electrical stimulation, he's also looking at scrambler therapy, a form of peripheral nerve stimulation in which electrical signals simulate non-pain information. "If randomized sham-controlled trials better identify those patients who may benefit from this approach, that would be terrific. We could start using these types of strategies more widely."

Seeing pain patients on the front lines of his medical practice has impassioned Cruciani to continue to push for more answers in the pursuit of what he regards as patients' human right to relief. "It is difficult for any of us to fully understand what it's like for these patients, but we have to do everything that we can to reduce their suffering." His pharmacologist colleagues would agree.

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