Dissecting Neural Circuits Involved in Musculoskeletal Pain

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There is an unmet need to identify therapeutic approaches to alleviate pain associated with inflammatory and osteoarthritic (OA) joint conditions. Joint pain affects over 50 million adults in the United States which is roughly 25% of the population. Severe arthritis is a leading cause of chronic pain, disability and reduced quality of life. Current treatment strategies for OA focus on improving function through weight loss and exercise and providing symptom relief with pharmacological analgesics such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Disease modifying agents for treating OA are limited so chronic administration of these analgesics is the mainstay for treatment. However, adverse outcomes related to long term use of NSAIDs (gastrointestinal bleeding) and opioids (i.e. abuse liability) increase the need for identification of alternative analgesics and approaches to alleviate joint pain. A critical barrier to progress in the field is lack of knowledge regarding the distribution of subsets of sensory neurons in bone and joints and how this changes under arthritic conditions. This is in part due to difficulty measuring patterns of innervation within thin sections of decalcified skeletal tissue. In recent years, methods have been developed to clear large sections of tissue in the brain to better visualize neural circuits; however, these approaches have not been applied extensively for examining distribution and topography of molecularly defined sensory neuron subsets within skeletal tissue. In the current proposal, we will refine methods for clearing, imaging and 3D analysis of molecularly defined subsets of nerve fibers within mouse bone and joints. We will also develop pharmacological and optogenetic approaches using Flp/Cre driver mice and viral vectors to determine the contribution of 5-HT3R+ afferents to spontaneous and movement evoked pain behaviors associated with inflammatory and post-traumatic osteoarthritis. The proposed studies will provide an unprecedented view of the density, topography and distribution of subsets of sensory neurons within the normal and arthritic knee joint. Importantly, these studies will lay the groundwork for future studies examining the functional contribution of subsets of sensory neurons in driving pain related behaviors and disease pathogenesis in several musculoskeletal pain conditions. 1