PROJECT SUMMARY Chronic low back pain (LBP) is one of the major contributors to musculoskeletal pain, disability, and lost workdays in the United States. LBP is highly correlated with degeneration of the intervertebral disc. Discogenic pain, specifically, is the leading cause of LBP. Patients with chronic discogenic LBP often exhibit aberrant sensory nerve growth deep within the disc. Once nerves are present in the degenerate disc they can be subjected to a complex milieu of pro-inflammatory mediators and dynamic mechanical loads causing stimulation and therefore pain. Binding of pro-inflammatory mediators to receptors on nociceptors results in lowered stimulation thresholds of ion channels responsible for action potential generation. Whereas mechanical loading of the disc can cause direct stimulation of mechanosensitive ion channels resulting in pain sensation. Previous work has explored the use of local delivery of an anti-inflammatory to the disc, however, incomplete pain resolution was observed. No work has examined targeting mechanoreceptors in the disc to alleviate chronic discogenic LBP. Further, no studies have yet been able to parse out which the role of nerve presence, inflammation, or mechanical loading is the major contributor to emergent pain. This question remains unanswered due to a lack of animal models that accurately mimic human presentation of chronic discogenic LBP. Taken together, these data support our overarching hypothesis that the presence of new nociceptors in the disc combined with inflammation and/or mechanical loading leads to chronic discogenic LBP, and targeted peripheral therapies may alleviate LBP. To test this hypothesis, we have developed an animal model of chronic discogenic LBP that exhibits a robust behavioral pain phenotype and nerve infiltration deep within the disc. By using innovative rodent models and targeted blockade of nerve growth, inflammatory mediators or mechanical sensing we will probe the roles of nerve presence, inflammation, and loading in LBP. We will then use this information to develop novel approaches to alleviate chronic discogenic LBP. Further, findings will be validated in aged animals which are more representative of a human LBP patient. The proposed work will use novel approaches using targeted neuro-inhibition, anti-inflammatories and mechanoreceptor antagonism to decouple the role of nerve presence, inflammation, and mechanical loading in LBP. The outcomes from this work include and better understanding of the specific mechanisms of LBP, laying the foundation to develop peripherally targeted pain for an intractable and widespread condition that is increasing in prevalence.