Project Summary The central goal of this project is to advance the therapeutic applications and the potential for using ionic direct current to interact with the nervous system. Direct current (DC) compared to biphasic charge balanced pulses normally used by neural prostheses to interface to the nervous system, can more naturally control neural activity. Unlike biphasic current pulses used to excite neurons, DC can excite, inhibit, and modulate sensitivity of neurons. While DC can be used for short durations to interact with the nervous system, chronic use of this stimulation paradigm for implantable prosthetic applications has not been possible due to the DC’s inherent violation of the charge injection safety constraints at the metal electrode interfaces. New technology, safe direct current stimulation (SDCS) overcomes these constraints and opens an additional avenue for research into exciting possibilities of using DC to interface to the nervous system. We will optimize the use of ionic DC to improve the performance of chronic pain suppression. Chronic pain suppression requires inhibiting pain carrying neurons from conducting action potentials. We obtained preliminary data in an anesthetized rat model showing that safe DC neural block at the sciatic nerve could suppress pain signals from propagating to the spinal cord, but allow normal propagation of sensation and muscle movement. Here we propose to understand the mechanism behind safe DC modulation of pain signals through anesthetized mouse and rat experiments. We will conduct the behavioral experiments to understand the effectiveness of this technology for addressing chronic pain in an awake animal. We will also conduct histological studies to investigate the biological impact of the therapy. Finally, we will advance the SDCS technology by identifying and solving the key technical challenges with a miniaturized and implantable SDCS. Aim 1. Examine the mechanism of the iDC effect on suppression of nociceptive pain. Aim 2. Examine the effects and underlying mechanisms of iDC on neuropathic pain signals. Aim 3. Behavioral experiments to study iDC for inhibition of neuropathic pain. Aim 4. Implantable SDCS technology development.