ABSTRACT Pain hypersensitivity is an early symptom of viral infections. While pain usually subsides with the progression of most infections, in some cases viral infection and antiviral drugs cause painful peripheral neuropathies. Peripheral sensory neurons are often the first target of viruses and are increasingly recognized as active components in pathogen detection and defense. As such it should not be surprising to known that sensory neurons express several singling proteins associated with pathogen recognition, yet very little is known about the neuronal functions of these proteins. The main goal of this application is to determine if the viral signaling adaptor protein known as stimulator of interferon genes (STING) in peripheral sensory neurons is mechanistically linked to pain hypersensitivity and painful peripheral neuropathies. STING is ideally positioned to underly both symptoms because it has been involved in the detection of abnormal cytosolic DNA delivered by viral pathogens or leaked from damaged mitochondria, a hallmark of various peripheral neuropathies. Our preliminary studies demonstrate that STING is express in peripheral nociceptive neurons and its peripheral engagement with specific agonists induces pain hypersensitivity. Therefore, we hypothesize that STING expression in sensory neurons drives unconventional neuronal functions leading to pain hypersensitivity, and in maladaptive conditions to painful peripheral neuropathies. We will test this hypothesis with multiple and unique approaches including the use of a conditional knockout mouse line with specific suppression of STING in sensory neurons. Aim 1 will establish the neuronal role of STING in driving pain hypersensitivity as well as changes in neuronal activity, transcription and release of immune modulators. Aim 2 will explore the role of STING in the development of peripheral neuropathies and evaluate various STING inhibitors as novel therapeutic approaches. Given that STING is pivotal to respond to viral infection, detection of mitochondrial dysfunction, and our testing of multiple drugs with FDA approval or in clinical trials, we expect that this research holds great promise for the adoption and development of new therapies for pain and potentially viral infection.