Dr. Nackley Awarded NIH Grant to Study Functional Pain Syndromes

The National Institutes of Health’s National Institute of Neurological Disorders and Stroke has awarded Duke Anesthesiology’s Andrea Nackley, PhD, a $2,623,436, five-year grant for her project, titled “Defining the Role of Peripheral Adrb3 in Chronic Pain and Inflammation.”

Functional pain syndromes affect more than 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to low activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66 percent of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves.

Consistent with clinical syndromes, Nackley’s Translational Pain Research Laboratory has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhances pain following repeated stress. In subsequent studies, they demonstrated that COMT-dependent pain is initiated by peripheral adrenergic receptor beta-3 (Adrb3) through the release of pro-inflammatory cytokines in local tissues. The pain is maintained by subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Together, this data reveals that heightened catecholamine tone leads to chronic pain via peripheral Adrb3 and its downstream effectors. However, the cell types that express Adrb3 and mediate pain still need to be identified and the molecular mechanisms determined.

Defining the Role of Peripheral Adrb3 in Chronic Pain and Inflammation

Nackley hypothesizes that activation of Adrb3 on adipocytes (fat cells that surround peripheral nociceptor and sympathetic nerve terminals) drives chronic COMT-dependent pain via increases in cytokines and MAPKs that promote inflammation and nociceptor activation. Further, she hypothesizes that stress-induced catecholamine release amplifies the effects of Adrb3 signaling on inflammation and pain. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated by Adrb3 located on adipocytes. Additional data reveal that sustained activation of Adrb3 leads to decreased levels of miR-133a, a microRNA expressed in adipocytes that is able to block MAPK signaling. Nackley’s new study will extend this work to directly determine 1) Adrb3 and miR-133a expression patterns in adipose vs other peripheral tissues over time and their relationship to COMT-dependent functional pain, 2) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent inflammation and neuroinflammation, 3) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent increases in the activity of mechosensitive and thermosensitive nociceptors, and 4) how these molecular and behavioral phenotypes are influenced by stress.

“Conventional therapies, such as opioids and antidepressants, have poor efficacy for managing chronic pain as well as adverse central side-effects, including altered mental states, addiction, and life-threatening respiratory depression,” says Nackley, associate professor in anesthesiology and faculty in the department’s Center for Translational Pain Medicine. “Results from this study will advance our knowledge about the mechanisms whereby peripheral Adrb3 drives chronic pain and elucidate new targets for the development of peripherally-restricted therapies with improved specificity and side-effect profiles for the treatment of functional pain syndromes.”

Stacey HiltonDr. Nackley Awarded NIH Grant to Study Functional Pain Syndromes
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Study Suggests URMC-099 as a Therapeutic Option for Perioperative Neurocognitive Disorders

Niccolò Terrando, BSc (hons), DIC, PhD

Niccolò Terrando, BSc (hons), DIC, PhD

A new study published in the Journal of Neuroinflammation found that prophylactic treatment with URMC-099 – a “broad spectrum” mixed-lineage kinase 3 inhibitor – prevents neuroinflammation-associated cognitive impairment in a mouse model of orthopedic surgery-induced perioperative neurocognitive disorders (PND).

PND, a new term that encompasses postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder, is the most common complication after routine surgical procedures, particularly in the elderly. Following surgery, such as hip replacement or fracture repair, up to 50 percent of patients experience cognitive disturbances like anxiety, irritability, hallucinations, or panic attacks, which can lead to more serious complications down the line. Currently, there are no FDA-approved therapies to treat it.

Developed in the laboratory of Harris A. “Handy” Gelbard, M.D., Ph.D., director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, URMC-099 inhibits damaging innate immune responses that lead to inflammation in the brain and accompanying cognitive problems. Using animal models of diseases like HIV-1-associated neurocognitive disorders, Alzheimer’s disease and multiple sclerosis, Gelbard has shown that the compound blocks enzymes called kinases (such as mixed lineage kinase type 3, or MLK3) that respond to inflammatory stressors inside and outside cells.

Gelbard and Niccolò Terrando, Ph.D., director of the Neuroinflammation and Cognitive Outcomes Laboratory in the Department of Anesthesiology at Duke University Medical Center, used an orthopedic surgery mouse model that recapitulates features of clinical procedures such as a fracture repair or hip replacement, which are often associated with PND in frail subjects. In a pilot experiment, they treated one group of these mice with URMC-099 before and after surgery, and another group prior to surgery only. Gelbard and Terrando’s teams, including first author Patrick Miller-Rhodes, a senior pre-doctoral student in the Neuroscience Graduate Program working in the Gelbard lab at URMC, measured the following:

  • How the surgery affected the central nervous system and the immune cells (microglia) that reside there was evaluated using stereology and microscopy.
  • Surgery-induced memory impairment was assessed using the “What-Where-When” and Memory Load Object Discrimination tasks.
  • The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry.
  • Long-term fracture healing was assessed in fracture callouses using micro-computerized tomography and histomorphometry analyses.
  • For additional details see the “Materials and Methods”section of the study

The team found that the surgery disrupted the blood brain barrier and activated microglia (a first line immune responder present in the inflamed brain), which led to impaired object place and identity discrimination when the mice were subject to the “What-Where-When” and Memory Load Object Discrimination tasks. Both URMC-099 dosing methods prevented the surgery-induced microgliosis (increase in the number of activated microglia) and cognitive impairment without affecting fracture healing.

“A major concern regarding the use of anti-inflammatory drugs for PND is whether they will affect fracture healing. We found that our preventive, time-limited treatment with URMC-099 didn’t influence bone healing or long-term bone repair,” said Gelbard and Terrando, professor of Neurology, Neuroscience, Microbiology and Immunology, and Pediatrics at URMC and associate professor of Anesthesiology at Duke University Medical Center, respectively. “These findings of improvement in cognition and normal fracture healing provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.”

“Right now we have nothing to treat this condition,” said Mark A. Oldham, M.D., assistant professor in the department of Psychiatry at URMC who treats patients with PND. “We work hard to provide good medical care, including helping people sleep at night and making sure they are walking, eating and drinking, but it isn’t clear that these efforts have any meaningful long-term impact.”

According to Oldham, recent studies that track patients following an episode of PND show that many of them don’t resolve completely, and that they have a new cognitive baseline after delirium.

“It is increasingly an accepted fact that after delirium, people have suffered some kind of neurological insult, which leaves them cognitively or functionally worse off than before the incident,” he noted.

Next steps for the research include identifying definitive mechanisms for pain modulation, immune cell trafficking and neuro-immune characterization in PND. Gelbard and Terrando are tackling some of these questions with funds from the National Institutes of Health (RO1 AG057525). The current study was also funded by multiple grants from the NIH (P01MH64570, RO1 MH104147, RO1 AG057525 and F31 MH113504). The University of Rochester has four issued U.S. patents and multiple issued patents in foreign countries covering URMC-099.

Source: University of Rochester Medical Center news release (Rochester, NY – November 6, 2019)

Stacey HiltonStudy Suggests URMC-099 as a Therapeutic Option for Perioperative Neurocognitive Disorders
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Dr. Ulloa Appointed Director of CPOP

Ulloa Appointed Director of CPOP

We are pleased to announce that Luis Ulloa, PhD, MS, associate professor in anesthesiology, officially joined Duke Anesthesiology on September 1 as the director of the department’s Center for Perioperative Organ Protection (CPOP), bringing 23 years of experience to his new role.

Dr. Ulloa joins us from Rutgers New Jersey Medical School, where he spent the past 10 years as an associate professor in the Department of Surgery. He received his PhD in neuroscience and cellular biology from the Autonoma University of Madrid, Spain. There, he worked at the laboratories of Dr. Severo Ochoa, who received the Nobel Prize in Medicine in 1959 for his discoveries on the biological synthesis of the RNA and DNA. During his PhD, Dr. Ulloa studied neuronal differentiation during development and neurodegeneration in Alzheimer’s disease. In 1996, Dr. Ulloa moved to New York City with an award from the Human Frontier Organization to complete his formation at the Memorial Sloan Kettering Cancer Center. He studied immunology and the TGFb signaling pathway in oncogenesis and contributed to the discovery of the Smad proteins in the laboratory of Dr. Joan Massague, current director of the Sloan Kettering Institute for Cancer Research. After his training, Dr. Ulloa combined his training and focused on neuro-immune modulation. In 2000, Dr. Ulloa went on to North Shore LIJ Health System in New York to study vagal regulation of the immune system with Dr. Kevin Tracey, current CEO of the Feinstein Institute for Medical Research in New York. In 2007, he was appointed as the director of science research in the Department of Surgery at the University of Medicine and Dentistry of New Jersey.

Dr. Ulloa has published nearly 100 peer-reviewed articles, mostly focused on neuromodulation of the immune system and organ function in infectious and inflammatory disorders such as sepsis, postoperative recovery, arthritis, and asthma. His research has been published in top journals such as Nature, Nature Medicine, Nature Reviews, Journal of Experimental Medicine, and Science Translational Research. His studies have been funded by the American Heart Association, Department of Defense and the National Institutes of Health. Most of Dr. Ulloa’s research centers on studying how the nervous system controls the immune system and organ function at the cellular and molecular levels. From a translational perspective, he focuses on how to stimulate specific neuronal networks both for experimental and clinical research to control organ and immune dysfunction. His studies include noninvasive techniques of transdermal neuronal stimulation such as electroacupuncture for clinical research. These studies allow to determine why nerve stimulation is not effective in some cohorts of patients, and to design alternative therapeutic strategies to control inflammation and organ injury in clinical settings of critical care, infectious, postoperative recovery, and inflammatory disorders.

In his new role with Duke Anesthesiology, Dr. Ulloa aims to advance the CPOP as an integrative center for basic, translational, and clinical research, focused on the development of novel strategies for perioperative organ protection. The mission of this center is to improve the standard of perioperative care. His goals to achieve this mission and advance the center include 1) developing the Laboratory of Neuro-immunomodulation, 2) developing “common scientific backgrounds” to connect and consolidate research within the CPOP, 3) developing reagents and tools to advance research within the CPOP, 4) mentorship and development of junior faculty members for article publication and grant submission, and 5) creating an internal infrastructure for research and funding.

Dr. Ulloa is originally from Granada in southern Spain. He and his partner, Dana, have three young boys. Please join us in welcoming him to Duke Anesthesiology.

Stacey HiltonDr. Ulloa Appointed Director of CPOP
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