SUMMARY Chronic pain and disability after bone fracture in the aged population are common. Approaches to pain management following orthopaedic surgery often include the use of opioids. The use of non-narcotic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) for fracture pain is of limited use in the United States because of data suggesting that NSAIDs inhibit early fracture healing. Therefore, identifying new analgesics that do not compromise bone healing or contribute to chronic pain conditions is important. Here we will explore the role of the neuropeptide calcitonin gene-related peptide (CGRP), which is widely distributed in sensory nerves that innervate the skeleton, in both the bone healing process and in mediating chronic pain due to bone fracture in mice. Our approach will test the hypothesis that CGRP signaling is beneficial for bone healing following fracture but compromises the return to normal physiological functioning of the individual due to nociceptive neuron sensitization. This hypothesis will be tested in a setting of a murine model of surgically created femoral fracture using male and female mice. These mice will determine the impact of fracture-targeted delivery of CGRP (tCGRP) on bone healing in animals with treatment of a re-purposed anti-CGRP monoclonal antibody to modulate nociceptive pain due to fracture. Successful completion of this application will provide new insights as to how modulation of CGRP regulates bone healing, inflammation, and pain states. This project, testing therapeutic strategies associated with the regulation of CGRP, may ultimately improve fracture healing and reduce the need for opioid usage for post-fracture pain management.