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B. Duncan Lascelles

Professor of Comparative and Translational Pain Research & Management

CVM Research Building 208

Bio

After graduating from the veterinary program at the University of Bristol, U.K., with honors, in 1991 Dr. Lascelles completed a PhD in aspects of pre-emptive/perioperative analgesia at the University of Bristol. After an internship there, he completed his surgical residency at the University of Cambridge, U.K. He moved to Colorado for the Fellowship in Oncological Surgery at Colorado State University, then a period of post-doctoral research in feline pain and analgesia at the University of Florida, and is currently Professor in Small Animal Surgery and Pain Management at North Carolina State University. He is board-certified in small animal surgery by the Royal College of Veterinary Surgeons, the European College of Veterinary Surgeons, and the American College of Veterinary Surgeons.

He is director of the Comparative Pain Research and Education Centre (CPREC). His research program (Translational Research in Pain [TRiP]) is dedicated to answering critical questions about pain control and pain mechanisms through high quality, innovative research. His career has been focused on developing algometry methods (methods to measure pain) in spontaneous disease animal models (pets with naturally occurring disease), and probing tissues from well-phenotyped animals with spontaneous disease to understand the neurobiology, with a strong translational focus. The aim of his research is to improve pain control in companion animals, and facilitate analgesic development in human medicine. He has authored over 180 peer reviewed research papers and reviews and 190 research abstracts, as well as over 30 book chapters.

AFFILIATIONS

International Association for the Study of Pain (IASP), member
IASP Special Interest Group on Non-Human Pain
Chair, World Small Animal Veterinary Association Global Pain Council
Thurston Arthritis Center, Medical School, UNC Chapel Hill, member
Center for Translational Pain Medicine, Duke University, member

CERTIFICATIONS

Fellow of the Royal College of Veterinary Surgeons
Diplomate, American College of Veterinary Surgeons
Diplomate, European College of Veterinary Surgeons
Diploma of the Royal College of Veterinary Surgeons, Soft Tissue Surgery

Area(s) of Expertise

NEUROBIOLOGY, PHARMACOLOGY, REGENERATIVE MEDICINE, VETERINARY CANCER CARE
Dr. Lascelles' research is focused on developing algometry methods in spontaneous disease animal models (i.e. developing ways to measure the many dimensions impacted by pain), and probing tissues from well-phenotyped animals with spontaneous disease to understand the neurobiology of that pain. The two fundamental aims of his research are: 1) to improve pain control in companion animals, and 2) to facilitate analgesic development in human medicine though using companion animals with spontaneous (naturally occurring) disease.

Publications

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Grants

Date: 07/01/20 - 12/31/23
Amount: $4,000.00
Funding Agencies: International Sled Dog Veterinary Medical Association

Endurance and marathon sled dog races have an increased risk of orthopedic injuries that are associated with shoulder, carpal, and pelvic limb lameness, swelling, and pain. These injuries are considered the leading cause for dropping (i.e., removing) sled dogs from races (~50.6% of cases) [1, 2]. Further, acute and repetitive traumatic injuries may lead to early removal from a racing event and the development of degenerative joint disease or osteoarthritis (OA) later in life. OA is a major cause of pain and disability in nearly 40% of the canine population and is associated with structural abnormalities and alterations in peripheral and central sensitization. The first case of OA in sled dogs was documented in 1969 based on the British Antarctic Survey findings. No studies since then have investigated the prevalence of OA, potential diagnostic markers, or investigated validated systems for measuring OA associated pain in working sled dogs. We expect the incidence of OA to be quite high due to the physical demands of these canine athletes. Currently, thoracic and pelvic limb joints and muscle groups are evaluated using physical and orthopedic exams and serum biochemical analysis before races and at checkpoints. These exams ensure that the dogs are in good condition but are often subjective and may vary based on the veterinarian’s experience level. Additionally, to avoid suppression of signs of illness or injury, no analgesic oral or topical agents (Eg: NSAID’s-specific doses, opioids, locals, etc.) are approved for the use in sled dogs during races. Failure to identify signs of early joint pain in sled dogs may increase the likelihood of dropping dogs due to orthopedic injuries during the race. Hence, there is an urgent need to develop objective assays to quantify joint pain that would be indicative of OA-associated pain in racing sled dogs. These assays conducted before a race will predict which dogs may be prone to developing orthopedic injuries, will allow the dogs to work longer, will decrease the likelihood of OA pain later in life, and improve the overall quality of life. Currently, no such assays exist that can predict the incidence or outcome of subclinical OA. Thus, the proposed goal of this project is to use an interdisciplinary team science approach to evaluate if artemin (ARTN), a novel neurotrophin, can be used as a potential prognostic biomarker for diagnosing subclinical OA pain.

Date: 05/01/22 - 4/30/23
Amount: $667,895.00
Funding Agencies: National Institutes of Health (NIH)

Osteoarthritis (OA), the most common form of arthritis, affects ~ 27M Americans and is increasing in incidence. It occurs due to degeneration of tissues comprising joints, and is associated with pain. OA pain is a major contributor to the burden of chronic pain in society. Current treatment options are limited to steroid injections, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids and non-pharmacological approaches (exercise, weight loss). Unfortunately, each of these therapeutic approaches are problematic. Exercise, which helps weight management, is difficult for patients due to ongoing pain. NSAIDS can cause gastrointestinal irritation and bleeding and increase risk of heart attack or stroke, and opioids are associated with addiction and abuse (and can actually worsen chronic pain). Clearly, there is a critical need to identify new therapeutic targets and/or treatments for individuals suffering from OA pain. Here, we propose that a heretofore unrecognized neural pathway is a critical component of OA pain. This pathway involves ARTN, its receptor GFRα3, and ‘pain’ channels on nerves (transient receptor potential [TRP] channels). Activation of this pathway initiates and maintains OA pain. The central hypothesis (based on preliminary data in multiple species [mouse, dog, cat, human]) is that ARTN, released from synovium of the OA joint in response to injury, results in de novo increase in its receptor, GFRα3, in local and distant sensory nerves, producing local and widespread pain and hypersensitivity via Proto-oncogene tyrosine-protein kinase receptor (RET)-mediated upregulation of multiple downstream transient receptor potential (TRP) receptors. In this proposal, we will use multiple OA models and clinically relevant outcome measures, and leverage our unique access to dogs with naturally occurring OA, to achieve the following aims: Aim 1: To test the hypothesis that ARTN expression is increased in OA and is responsible for pain. Aim 2: To test the hypothesis that ARTN/GFRα3 signaling is responsible for behaviorally manifested OA pain both in early and late stage disease. Aim 3: To test the hypothesis that RET-dependent ARTN/GFRα3 signaling results in changes in multiple TRP channel expression and activation. Aim 4: To test/validate involvement of the above-described key molecules in a naturally occurring large animal model of OA (dog). Overall, this will be the first work investigating the role and mechanisms of ARTN/GFRα3/TRP channel in OA pain and sensitivity. Based on solid, clinically relevant preliminary data, and leveraging PI expertise from two different and complementary disciplines, successful completion of this proposed work has the potential to identify clinically relevant neural mechanisms leading to the development of novel, effective therapeutics for the treatment of OA-pain in humans."

Date: 04/15/21 - 3/31/23
Amount: $47,083.00
Funding Agencies: National Institutes of Health (NIH)

In this project, I will work closely with Dr. Shyni Varghese and her team to optimize the methodology around the measurement of pain - sensitivity, activity, limb use. I will provide the apparatus to measure pronograde limb use. I will be present, and work ‘hands on’ to help set up and optimize the behavioral pain assay work, assist with data collection and data analysis.

Date: 03/01/21 - 2/28/23
Amount: $708,461.00
Funding Agencies: National Institutes of Health (NIH)

More than 80% of patients undergoing treatment for head and neck cancer are prescribed opioid pain killers for management of radiation-associated pain, and unfortunately, 6 months after finishing radiotherapy, one-third of head and neck cancer patients will still be opioid-dependent. Chronic opioid use is associated with side effects such as constipation and decreased alertness; it can also lead to opioid abuse, misuse, addiction, and eventual overdose. Safer, more effective and less addictive pain relief strategies are desperately needed, and our proposed research addresses that need by investigating a novel radiation-activated pain signaling pathway that might serve as an excellent target that could be inhibited with new pain medications.

Date: 03/01/20 - 2/28/23
Amount: $104,147.00
Funding Agencies: American Kennel Club Canine Health Foundation, Inc.

Our recent survey found that both veterinarians and members of the public believe that dog breeds differ in their sensitivity to pain. However, whether or not breed differences in pain sensitivity actually exist has never been investigated previously. These beliefs could negatively impact the recognition and treatment of pain in the dog population and result in unnecessary suffering, particularly for dog breeds that are viewed as less sensitive to pain. We believe that dogs have similar pain sensitivity thresholds, regardless of what breed they are, but that perceptions about breed-based differences in pain sensitivity affect ratings of pain and the clinical recognition and treatment of pain. To investigate this, we will use a novel and innovative three-pronged approach. First, we will review records from veterinary hospitals to identify differences in pain scores assigned to dogs of different breeds. Second, we will use a survey to evaluate whether conditions are rated as more or less painful, depending on the breed of dog. Third, we will use non-invasive sensory testing to directly measure pain sensitivity across different breeds, to determine whether breed differences in pain sensitivity actually exist. This work is critical because real differences in sensory thresholds between different breeds may exist; if so, this would lay the foundation for further work to understand genetic differences in pain sensitivity and further understanding of pain in dogs. However, if no differences exist, then the impact of the perception of breed differences must be understood so that we can ensure that dogs of every breed are getting appropriate pain management.

Date: 04/01/21 - 9/30/22
Amount: $5,000.00
Funding Agencies: ACVO Vision for Animals Foundation

To use quantitative sensory testing (QST) to compare pain in dogs with chronic glaucoma following pharmacologic ciliary body ablation (CBA) and enucleation

Date: 04/23/20 - 9/30/22
Amount: $1,017,998.00
Funding Agencies: Hill's Pet Nutrition

Over half of dogs in the United States are overweight or obese, and many of these dogs show signs of osteoarthritis that can be corroborated by use of imaging technologies. Overweight dogs, especially those with osteoarthritis are not as likely to walk or run as other dogs, and their sleep may be disturbed by the discomfort they feel in their joints. The purpose of this clinical study is to evaluate the efficacy of an investigational food for aiding in the nutritional management of overweight adult dogs with osteoarthritis. It is expected that at the time of enrollment, all dogs will be overweight and exhibit lameness and pain attributable to chronic osteoarthritis. The study will employ collar-worn activity sensors to generate data that support new, quantitative claims. The primary endpoints of this study are to determine if sensor detected activities (walking, running, resting, sleep quality, and sleep time) are impacted by dietary intervention. The secondary endpoints are the clinical outcomes impacted by dietary intervention and the relationship of those outcomes to the sensor data. The tertiary endpoint of this study is to determine the feasibility of using sensor data to develop algorithms to detect gait changes associated with signs of osteoarthritis.

Date: 09/12/20 - 8/31/22
Amount: $435,518.00
Funding Agencies: National Institutes of Health (NIH)

Osteoarthritis (OA) affects nearly 100 million Americans, with being the most common form of arthritis and a leading cause of pain and disability. Prevalence and incidence of the disorder are predicted to increase as a result of increased lifespan and obesity. Symptomatic treatments are often ineffective, and/or associated with severe side effects and there is over-reliance on opioids. Recent insurance claim data indicate that >50% of OA were treated with opioids for OA pain, and many OA patients on opioids have become opioid-dependent. Despite the fact that OA is a leading cause of disability, and imposes an annual economic burden exceeding $60 billion, there is no way as yet to cure OA or prevent its progression. There is an urgent need to identify and validate therapeutic targets for pain (symptom) management and to decrease disease progression. Results from our group and others found that a striking feature of OA is the dramatic increase in vascular endothelial growth factor (VEGF) expression and in new blood vessel formation in the joints, both of which correlate with the severity of OA joint pain1. Also, genomic studies revealed that vegf, as an OA marker whose expression is strongly associated with symptomatic OA progression in humans. FDA approval of several inhibitors of the VEGF pathway (i.e., for cancer treatment) has enabled significant advances in the therapy of diseases related to pathological angiogenesis. However, there are multiple VEGF ligands with redundant and compensatory roles4 that may contribute to OA progression and pain. Thus, targeting individual ligands may be less efficacious than targeting multiple ligands. Specifically, VEGF ligands signal via two receptors, VEGFR-1 (known as Flt1) and VEGFR-2 (known as Flk1). We hypothesize that VEGFR-2/Flk1 is primarily responsible for cartilage tissue degeneration during OA progression, while activation of VEGFR-1/Flt1 appears to be the major driver of joint pain transmission. Thus, targeting both Flt1 and Flk1 should simultaneously elicit dual function: (i) immediate symptom alleviation and (ii) gradual cartilage tissue regeneration, and restoring joint function.

Date: 08/01/21 - 7/31/22
Amount: $74,186.00
Funding Agencies: National Institutes of Health (NIH)

Globally this year, there will be an estimated 650,000 new human head and neck cancer (HNC) diagnoses.1 Half of those people will be cured with intensive combinations of surgery, radiation therapy and chemotherapy. But along their path towards a cure, essentially all of those patients will experience oral mucositis (OM) and discomfort. Indeed, significant treatment-associated pain is reported by 70% of HNC patients undergoing definitive radiotherapy, and 60% of patients report persistent pain for at least six months following treatment.2,3 OM occurs in nearly all patients who receive radiotherapy, and, in 10-25%, an interruption or modification in treatment is required. These treatment delays worsen local tumor control and overall survival time.4 To improve comfort and avoid treatment delays, effective analgesics are needed. Development of effective and appropriately targeted analgesics will require deep knowledge of the underlying pain signaling mechanisms that are activated by HNC treatment; however, there has been essentially no research in this area. Anecdotally, some HNC patients report cold sensitivity or pain associated with the development of OM. This observation led to our preliminary studies and the discovery that a critical component of acute orofacial radiation-associated pain is a signaling pathway mediated by neurons that express the TRPM8 (transient receptor potential melastatin family member 8) ion channel. Previously, this pathway has been associated with “cold pain.” We have evidence from mouse models that: ● Oral irradiation causes local release of a neurotrophic factor called artemin (ARTN), ● ARTN binds its receptor (GFRα3) on free nerve endings in the mouth, and ● GFRα3 activates TRPM8 in trigeminal sensory neurons, thus resulting in cold sensitivity and pain.

Date: 12/18/18 - 3/31/22
Amount: $81,212.00
Funding Agencies: MAYDAY Fund

Millions of Americans suffer acute pain every year, and in the new era of the opioid epidemic, there is an urgent search for safe, effective, non-opioid analgesics. Studies in animals with naturally occurring pain conditions can contribute to the translational research paradigm, accelerating the discovery of safe and effective novel analgesics. It was this central idea that inspired us to plan, organize and hold a workshop on measuring chronic pain in companion animals in 2017 (www.PAW2017.com). The reason for focusing on measurement and animals with naturally occurring conditions was that, 1) measurement of pain in animals is critical for advancing translational research; and 2) naturally occurring conditions have so much in common with certain human pain conditions that the ‘model’ is as close to the human condition one can get. Additionally, the challenges faced with measuring and alleviating pain in animals are similar to those faced in non-verbal human populations. Our meeting in 2017 was extremely successful, with 300 delegates from academia, veterinary and human health, industry and regulatory authorities discussing and brainstorming about how to foster translational pain research by using a cross-species approach. Our proposed 2019 workshop is the logical next step in our theme of measuring pain - focusing on acute pain across multiple species in the context of improving translational research and improving pain control in animals. Our proposed 2019 workshop reflects the innovative approach the MAYDAY fund takes. This workshop is unique – there is no other forum within the pain field where academia, industry and regulatory authorities on the human and animal side come together to discuss and exchange ideas. Like many, we recognize that translational pain research needs innovation, however our innovative workshop platform will provide a fertile environment for game-changing ideas and approaches that will benefit both humans and animals suffering acute pain.


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