Duncan Lascelles

In the United States, roughly 68 million veterinary visits are adversely affected by fearful behavior annually with negative consequences for canine welfare. Dog characteristics account for only a small portion (<7%) of the fear experienced in the clinical environment. It is critical that we address this knowledge gap regarding what drives fearful behavior in the clinic. We postulate that pain catastrophizing may be the missing factor. Pain catastrophizing is a cognitive and emotional response toward actual or anticipated pain, often characterized in humans by verbal reports and behavioral changes. People who are high in pain catastrophizing are at higher risk of pain-related interference in activity, development of chronic pain, and have worse health outcomes across a spectrum of diseases. In pediatric medicine, pain catastrophizing occurs in children and results in higher reported pain intensity scores and greater anxiety. Additionally, childrens’ pain experience is affected by caregivers who catastrophize about their child’s pain. Using the pediatric/caregivers model, we hypothesize that pain catastrophizing can be quantified in dogs using our novel experimental paradigm and is positively associated with owner catastrophizing about their dog’s pain. Establishing a measure of pain catastrophizing in dogs and understanding the owner influence on the phenomenon would be a major advance for veterinary medicine – specifically in pain management and behavioral health and welfare. Ultimately, our work will improve health outcomes including surgical recovery and management of chronic pain conditions – both of which have been shown in humans to be negatively affected by pain catastrophizing.

Bedinvetmab is a fully canine monoclonal antibody targeting nerve growth factor, which plays an important role in pain signaling in dogs. It has been approved for osteoarthritis pain management in Europe, Canada, and some other countries. The efficacy of Bedinvetmab has been shown using a subjective measure, however, has not been tested using an objective measure. The gait analysis has been validated as an objective measure of changes in limb use as it relates to joint pain in dogs and has been used to determine the efficacy of an analgesic in dog OA studies. The study will be a prospective, single-center, randomized, double-blinded, noninferiority study. We hypothesized that subcutaneous injection of Bedinvetmab will be non-inferior to an active comparator (grapiprant) based on improvement in limb function. Additionally, it will improve owner assessment scores and activity in dogs with naturally occurring OA.

The National Research Council has documented a dire national need for veterinary specialists trained in biomedical research. Furthermore, veterinary researchers play a key role in comparative and translational research activities since they naturally bridge basic and clinical research. To address this training need, we request continued NIH funding for 7 fellows per year for 3 years. NC State University will provide funding for up to 2 fellows per year and 2 pre-T32 positions. Trainees will be degree-seeking fellows in the Comparative Medicine and Translational Research training program established by the faculty in the College of Veterinary Medicine (CVM) and the Comparative Medicine Institute (CMI) at North Carolina State University. This training program specifically targets individuals with the DVM degree who have completed specialty training and is designed to prepare trainees to compete for an early career development award and a rapid transition to independence as a principal investigator or in another research-intensive career. Trainees complete requirements leading to the PhD degree in Comparative Biomedical Sciences (CBS) in one of 7 areas of concentration: 1) Immunology 2) Cell Biology, 3) Pharmacology, 4) Neurosciences, 5) Infectious Diseases, 6) Population Medicine and Global Health, and 7) Pathology. Training faculty are well-funded productive scientists that have a strong training track-record and diverse research expertise. Training faculty are all members of the CBS graduate program and the CMI and represent 5 departments from 3 Colleges. Research projects emphasize comparative and translational themes fostered by the CVM and CMI in functional tissue engineering, translational pharmacology and physiology, and emerging and infectious diseases. Program requirements include: (1) a capstone comparative animal models course; (2) professional development courses and workshops; (3) courses in research ethics and research rigor and reproducibility; (4) a grant writing course and (5) annual research symposia. These requirements are in addition to those associated with the graduate program. Twenty four fellows have completed training. Twenty hold faculty positions in academia, one is a research pathologist, one is a clinical pathologist in industry, and one is a postdoctoral fellow. Fellows were awarded 18 NIH or other federal grants as PI and more than 50 extramural research grants and published 125 papers (84 first author) arising from their research while in training.

The 2023 Pain in Animals Workshop (PAW) on Sept 26th and 27th is a 2-day workshop that will focus on exploring and discussing three topics: 1. Updates on validated approaches to measuring pain 2. Opportunity areas (biopsychosocial) for additional outcome measure development 3. Analytic approaches in utilizing outcome measures in clinical trials

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."

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.

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.

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.

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.

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.