Dr. Ji’s Lab Makes Local Headlines for Autism-Pain Discovery

Ru-Rong Ji, PhDAbnormal pain sensitivity is often associated with autism spectrum disorders which can affect the quality of life of those individuals. New research from two Duke University labs, Dr. Ru-Rong Ji’s Pain Signaling and Plasticity Laboratory and Dr. Yong-Hui Jiang’s autism research lab, reveals a potential mechanism underlying pain insensitivity in autism. According to an article published by Duke Today on December 1 titled, “Autism-Linked Protein Crucial for Feeling Pain,” this finding is the first to connect autism to one of the most well-studied pain receptors, TRPV1 (transient receptor potential ion channel subtype V1).

This research was published in the December 2016 issue of the journal, Neuron, in an article titled, “SHANK3 Deficiency Impairs Heat Hyperalgesia and TRPV1 Signaling in Primary Sensory Neurons.” The manuscript describes how SHANK3 (a prominent autism gene), expressed by peripheral primary sensory neurons, regulates TRPV1 function and heat hyperalgesia after inflammation and nerve injury, offering a mechanistic insight into pain dysregulation in autism. The co-first authors of this paper are Qingjian Han, PhD, Yong-Ho Kim, PhD (both with Dr. Ji’s lab), and Xiaoming Wang, PhD. Co-investigators with Duke Anesthesiology include Dr. Ji, Zhi-Jun Zhang, Di Liu, Mark Lay, Wonseok Chang, Temugin Berta and Yan Zhang.

As explained in the Duke Today article, Dr. Ji’s lab put SHANK3-dificient mice through several sensory tests which found that animals had lower sensitivity than normal mice to heat and heat-related pain, similar to that of a sunburn. Their research found 1) that not only is the SHANK3 protein present in the brain, but also in a cluster of pain-sensing neurons called the dorsal root ganglion in mice, 2) SHANK3 in the same types of cells from human donors who did not have autism, 3) that SHANK3 is expressed on the sending sides of the synapse. Dr. Ji was surprised to find that SHANK3 is expressed in the peripheral nervous system and notes that this is the first study where researchers looked for it outside of the brain – a study that could shape how effective treatments for autism are developed.

Co-expression of SHANK3 (red) and TRPV1 (green) in primary sensory neurons in mouse dorsal root ganglion in the peripheral nervous system.

Co-expression of SHANK3 (red) and TRPV1 (green) in primary sensory neurons in mouse dorsal root ganglion in the peripheral nervous system.

Dr. Ji is the chief of pain research at Duke Anesthesiology, a distinguished professor of anesthesiology in the Duke University School of Medicine, a faculty member of Duke Anesthesiology’s Center for Translational Pain Medicine, and a member of the Duke Institute for Brain Sciences. His lab focuses on identifying molecular and cellular mechanisms that underlie the genesis of chronic pain and developing novel pain therapies that can target those mechanisms.

Chris KeithDr. Ji’s Lab Makes Local Headlines for Autism-Pain Discovery
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Dr. Ji Published in Special Issue of Science

Ru-Rong Ji, PhDChronic pain is a rising health issue affecting as many as 30 percent of adults, worldwide, with an annual cost of more than $600 billion in the United States alone. Chronic pain after arthritis, nerve injury, cancer, and chemotherapy is typically associated with chronic neuroinflammation. Dr. Ru-Rong Ji, the chief of pain research at Duke Anesthesiology, is featured in a special “Pain Research” issue of the journal, Science, for his work that investigates the role non-neuronal cells play in pain regulation and inflammation.

Dr. Ji is the senior author of the review article, “Pain regulation by non-neuronal cells and inflammation,” published in the journal’s November 14, 2016 issue. Co-investigators include Alexander Chamessian (staff member of Dr. Ji’s Pain Signaling and Plasticity Laboratory) and Yu-Qiu Zhang.

Science JournalAccording to the authors, accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells, and stem cells play active roles in the pathogenesis and resolution of pain. They studied how non-neuronal cells interact with nociceptive neurons by secreting neuroactive signaling molecules that modulate pain, revealing that “non-neuronal cells can communicate with nociceptive neurons by ‘listening’ and ‘talking’ to neurons.” The authors add that recent studies suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections. Their study also discusses new, therapeutic strategies to control neuroinflammation for the prevention and treatment of chronic pain.

Dr. Ji is a distinguished professor of anesthesiology at Duke University’s School of Medicine and a faculty member of Duke Anesthesiology’s Center for Translational Pain Medicine where he and other researchers are devoted to understanding the epigenetic processes and signatures of what causes acute pain to become chronic, and reducing the burden of chronic pain by developing innovative, non-opioid pain therapies to improve patient care (highlighted in the cover story of Duke Anesthesiology’s 2016 edition of BluePrint magazine).

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Director of Orofacial Pain Published in AJO-DO

Aurelio Alonso, DDS, MS, PhDAccurate upper airway measurements can play a pivotal role in identifying patients with breathing or sleep disorders. Duke Anesthesiology’s Aurelio Alonso, DDS, MS, PhD, is a co-author of a newly published study that investigated the differences between cone-beam computed tomography (CBCT) and acoustic reflection (AR) in calculating airway volumes and areas. The manuscript, titled “When static meets dynamic: Comparing cone-beam computed tomography and acoustic reflection for upper airway analysis,” was published in the October 2016 issue of the American Journal of Orthodontics and Dentofacial Orthopedics.

Subjects with prescribed CBCT images as part of their records were asked to have AR performed. A total of 59 subjects had their five areas of their upper airway measured from CBCT images, acoustic rhinometry and acoustic pharyngometry. Volumes and minimal cross-sectional areas were extracted and compared with software.

According to the authors, results of this study reveal that CBCT is an accurate method for measuring anterior nasal volume, nasal minimal cross-sectional area, pharyngeal volume and pharyngeal minimal cross-sectional area.

Dr. Alonso is the director of orofacial pain for Duke Anesthesiology’s Center for Translational Pain Medicine and notably the first boarded orofacial pain clinician at Duke. This new center further expands the department’s existing clinical and research program in innovative pain therapies by bringing together, under one umbrella, leading basic scientists, clinicians and clinical researchers who have a common core mission of unraveling the causes of painful conditions to better improve patient care. Dr. Alonso is also a pain specialist at Duke Innovative Pain Therapies, a medical pain practice that opened in September of 2016 at Brier Creek in Raleigh. Learn more about this first-of-its-kind pain practice in Duke Anesthesiology’s 2016 edition of BluePrint magazine.

Chris KeithDirector of Orofacial Pain Published in AJO-DO
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Pain Signaling Study Published in PNAS

Drs. Terrando and MathewPostoperative pain is a common complication of surgery that may contribute to delirium and memory dysfunction, especially in the elderly. To better understand the connection between postoperative pain and cognitive dysfunction, Duke Anesthesiology’s Niccolò Terrando, PhD, and his colleagues, studied pain behavior and nerve injury biomarker expression in mice undergoing orthopedic surgery to repair fractured bones.

Professor Tomas Hökfelt

Professor Tomas Hökfelt

Dr. Terrando and Professor Tomas Hökfelt of the Karolinska Institutet are co-senior authors of a manuscript published in the October 2016 issue of Proceedings of the National Academy of Sciences of the United States of America (PNAS), titled “Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels.” This study is also featured on PNAS’ research highlights page.

Using an established mouse bone-fracture model associating with memory deficits, Dr. Terrando and his collaborators (including the chairman of Duke Anesthesiology, Dr. Joseph Mathew, and Dr. Beilei Lei of Duke Anesthesiology’s Neuroinflammation and Cognitive Dysfunction Laboratory) assessed pain behavior and expression of several molecules in sensory neurons, spinal cord and brain. An increase in cold sensitivity and up-regulation of several injury markers, including activating transcription factor 3, the neuropeptide galanin, and growth factor brain-derived neurotrophic factor (BDNF), were observed in sensory ganglia. In the hippocampus, BDNF protein levels were increased in mossy fibers. In contrast, the BDNF transcript was not increased in the parent granule cell bodies, and c-Fos levels were decreased, as was neurogenesis.

Brain BDNF expression in control mouse (Left) and following orthopedic surgery (Right).

Brain BDNF expression in control mouse (Left) and following orthopedic surgery (Right).

According to the authors, results of this study reveal that impaired BDNF signaling and reduced neurogenesis in the hippocampus may contribute to mental deficits observed after surgery.

Drs. Terrando and Mathew are both notably DREAM Innovation Grant (DIG) recipients. DIGs support innovative high-risk and potentially high-reward investigations to accelerate anesthesia and pain management research. Dr. Terrando received the award in 2016 for his project, titled “The Systemic Milieu and its Role in Postoperative Cognitive Dysfunction.” Dr. Mathew received a DIG in 2011 for his project, titled “Functional Neuroimaging to Assess Cognitive Function after Cardiac Surgery.” The DIG awards are made possible by Duke Anesthesiology’s DREAM Campaign which was established in 2007 to support the department’s research programs and initiatives.

Chris KeithPain Signaling Study Published in PNAS
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Study Shows Menthol Makes Nicotine More Palatable

Sven-Eric Jordt, PhDMenthol, the minty and cooling natural product in peppermint, is a highly popular flavor in tobacco products. More than 30 percent of smokers in the United States smoke menthol cigarettes, and most beginning smokers prefer menthols. Chewing tobacco, snuff and snus also come in highly popular mentholated varieties.

A new study from Dr. Sven-Eric Jordt’s Chemical Sensing, Pain and Inflammation Research Laboratory at Duke Anesthesiology reveals that menthol masks the bad taste of nicotine. Tobacco by itself has a rather unpleasant burnt and bitter taste. This is partially due to nicotine in tobacco that is bitter and irritating, causing a burning and pungent sensation. The manuscript titled, “Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism” is published in the October 2016 issue of the journal Tobacco Control.

“Contributing to Duke Anesthesiology’s pain research efforts, our lab has studied the cooling and soothing effects of menthol that is widely used for topical pain treatment in pain creams and patches,” says Dr. Jordt. “We were intrigued whether menthol would also suppress the irritating effects of nicotine.”

To examine menthol’s effects, Dr. Jordt’s lab scientists presented mice with a choice of water with nicotine or water containing both nicotine and menthol. The mice strongly preferred the mentholated nicotine and did so repeatedly over days. Mice share their aversion to nicotine with humans and also perceive menthol as soothing and cooling, sensing menthol with specific temperature-sensing nerves in the mouth.

“Menthol is not only a pleasant flavor, but has potent sensory effects that make it easier to consume nicotine,” says Dr. Jordt, associate professor in anesthesiology and faculty member of Duke Anesthesiology’s Center for Translational Pain Medicine. “We hope our findings will inform regulatory policies to curtail tobacco use and prevent children from becoming new tobacco consumers.” The study was a collaboration with Dr. Marina Picciotto’s laboratory of the Yale Tobacco Center of Regulatory Science in the Department of Psychiatry, funded by the National Institute on Drug Abuse and the Food and Drug Administration.

Chris KeithStudy Shows Menthol Makes Nicotine More Palatable
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CTPM Faculty Published in Pain Journals

Nerve Injury and Pain Mechanism Laboratory MembersDrs. Thomas Buchheit and Thomas Van de Ven with Duke Anesthesiology’s newly established Center for Translational Pain Medicine, along with their colleagues at the department’s Nerve Injury Pain Laboratory, publish manuscripts that could have a significant impact on patients suffering from chronic pain, post-amputation.

The article featured in the journal Pain on September 23, 2016, titled “Differential Expression of Systemic Inflammatory Mediators in Amputees With Chronic Residual Limb Pain,” has implications for biologic targets and future non-opioid therapies. Dr. Van de Ven and Alex Chamessian (of the Duke University School of Medicine) are co-first authors of this paper.

Chronic post-surgical pain impacts the majority of amputees, with more than half experiencing neuralgic residual limb pain. As part of the Veterans Integrated Pain Evaluation Research (VIPER) study, investigators examined links between systemic inflammatory mediator levels and chronic residual limb pain. Study results suggest that chronic post-amputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the post-injury inflammatory state. The impact of pain catastrophizing on residual limb pain may be due in part to common underlying inflammatory mechanisms. Dr. Buchheit, chief of Duke Anesthesiology’s Pain Medicine Division and Dr. Hung-Lun (John) Hsia, co-authored this paper.

The article featured in the journal Pain Medicine on July 8, 2016, titled “Perioperative Pain Management Strategies for Amputation: A Topical Review,” highlights why patient-tailored analgesic regimens utilizing catheter-based techniques are essential in the acute post-amputation phase. Co-authors of this paper include Drs. Buchheit, Van de Ven and Hsia.

Chris KeithCTPM Faculty Published in Pain Journals
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