Central Pain Syndrome (CPS) is a chronic debilitating condition that arises in a large number of patients who suffer from a primary lesion of the central nervous system. Like many neuropathic pain conditions, CPS manifests as chronic spontaneous pain, increased pain to noxious stimuli, and increased sensitivity to innocuous stimuli. Unfortunately for the potentially millions who suffer from chronic neuropathic pain conditions, these conditions are largely resistant to conventional treatments. For these patients, motor cortex stimulation (MCS) serves as an alternative and potentially effective treatment for the relief of pain. However, MCS treatment outcomes vary greatly and little can be done to increase efficacy of this potential therapy until the mechanisms by which MCS reduces pain are fully understood. The goal of this application is to elucidate the neurobiological basis of reduced pain following MCS. In order to investigate the neuronal mechanisms by which MCS reduces pain, we use an animal model of CPS. We have recently demonstrated that activity in the GABAergic nucleus zona incerta (ZI) is suppressed in animals with CPS resulting in increased activity in the posterior thalamus (PO) and subsequently in the neocortex. Additionally, we demonstrate that electrical stimulation of ZI mimics the effects of MCS in reducing behaviors consistent with CPS. Based on these findings, and because the motor cortex projects densely upon ZI, we propose that MCS reverses hyperalgesia by activating the incerto-thalamic pathway. We will test this with the following aims: Aim 1: Reduced hyperalgesia after MCS is associated with enhanced activity in ZI and suppressed activity in PO. Aim 2: ZI is an integral link in mediating MCS effects. PUBLIC HEALTH RELEVANCE: Motor cortex stimulation (MCS) was developed almost 20 years ago as a treatment for conditions of intractable pain. While moderately effective as a pain relief therapy, the varied success rate of MCS leaves potentially millions who suffer from chronic pain without hope for treatment. A major impediment to improving the success rate of MCS and implementing it as therapy in the clinical setting is the lack of understanding regarding mechanisms by which MCS relieves pain. Here we take advantage of an animal model of central pain to study the mechanisms by which MCS affects the activity of specific neuronal circuits.