Defining the cells, circuits, and phenotypes of odontogenic pain

About This Grant

PROJECT SUMMARY/ABSTRACT Odontogenic pain, also known as toothache, is the most common form of orofacial pain across the world. Most commonly, odontogenic pain stems from inflammation of the tooth pulp following either bacterial infection or iatrogenic damage. While this pain will resolve with clinical intervention that removes the peripheral insult and dental pulp (e.g., root canal or extraction), it may be accompanied by substantial mechanical and thermal allodynia that is not alleviated by local anesthesia. We continue to lack safe approaches to achieve effective, immediate analgesia toward necessary dental treatments to resolve odontogenic pain. To inform the development of non-opioid analgesics we need fundamental knowledge of the neuronal basis and behavioral phenotypes of odontogenic pain. Mammalian teeth are highly innervated by specialized somatosensory neurons, intradental neurons, that detect damaging stimuli and initiate a reflex response to protect the teeth. However, we have yet to define mechanisms by which intradental neurons produce odontogenic pain in the context of damage and inflammation. Here, Dr. Joshua Emrick and his laboratory will investigate the neuronal basis of toothache to provide targets for future development of analgesics. The overall objective of this application is to use mouse models and powerful, cutting-edge approaches to define the neurons, circuits, and phenotypes of odontogenic pain. Aim 1 will reveal peripheral mechanisms whereby intradental trigeminal sensory neurons are activated representing a basis for pulpitis-induced pain. Aim 2 will reveal central mechanisms whereby intradental trigeminal sensory neuron inputs lead to physiological responses. Aim 3 will provide novel preclinical phenotypes of odontogenic pain in mammals to provide objective measures for future evaluation of analgesia. Upon successful completion of this project, we will have a molecularly-defined cellular origin for odontogenic pain from inflammation. Further, we will define the neurons and circuits that relay odontogenic pain in the brainstem. We also will have defined phenotypes for odontogenic pain initiated by the intradental neurons. These outcomes will provide key mechanistic insight into the origin of odontogenic pain toward the long-term development of novel non-opioid analgesics.