Project Summary Opioids as a pain medication has been the most preferred pain treatments in order to provide quick relief from severe pain. Decades of opioid abuse have triggered negative impact on pain therapies. Understanding of neural circuits that are actually driving pain is essential in order to develop more effective and safer pain therapies. Neuroanatomical studies have allowed us to define the regions and subsets of neurons that are important for pain. However, there is very limited understanding of neural circuits that are activated by each pain modality; i.e. how all of the pain-dependently activated neuronal subsets communicate to transmit nociceptive signals derived by distinct pain conditions as well as to distinguish the transition of acute and chronic pain. In addition, recent attention has also tuned into mechanisms underlying emotional dimension of pain such as depression, anxiety, and loss of cognition, especially associated with chronic pain. The anterior cingulate cortex (ACC) is a brain structure known to drive aversion associated with chronic pain. The functional changes in the ACC neurons caused by chronic pain have yet to be clearly explained at the molecular and neural circuit levels. Our preliminary studies have demonstrated that a larger number of neurons are pain specifically activated in the ipsilateral side of the spinal cord in SNL mice compared to those of sham. Similarly, neurons in the contralateral side of the ACC are also selectively activated under a chronic pain condition, which is also consistent with the previous studies describing aversive response associated with chronic pain due to the hyperexcitability of ACC neurons. Here, we therefore focus on two representative regions for pain-related behaviors: the ACC as a key brain structure in the affective pain; and the spinal cord for sensory using mouse genetics combined with neuroanatomy, chemogenetics, and neural recording in order to obtain a better understanding of the mechanisms underlying pain-related behaviors by shedding light on active neural circuits under specific pain conditions. In Specific Aim 1, we will identify the neuronal subsets activated by distinct pain stimuli (acute heat and mechanical pain, and chronic pain) in the spinal cord, and chemogenetically manipulate the activity of pain specifically-activated neurons in order to validate that these neurons are directly regulating the specific pain modalities. In Specific Aim 2, we will investigate the role of chronic pain dependently activated ACC neurons in order to obtain a better understanding of the mechanism by which the ACC discriminates the affective and sensory pain behavior associated with chronic pain. We will use neuroanatomical tracing to identify the ACC neuronal subsets and their projection neurons communicating with other pain-related brain regions. Our proposed studies will enable us to collect feasibility data for a future Targeted BRAIN Circuits Projects R01 research proposal, which will help to further understand the active neural circuits regulating the transmission of pain sensory signals elicited by different pain modalities at the spinal cord and also the expression of affective and sensory pain behavior mediated by the ACC circuits in chronic pain.

Project Narrative Due to the misuse of opioid for pain therapies and their severe side effects, we are facing urgency in the needs for the development of alternative novel pain medications. A better understanding of the mechanism underlying active neural ensemble driving distinct pain modalities is essential to develop and identify alternative and safer pain treatments. In this grant proposal, by taking advantage of state-of-the-art technologies including mouse genetics, chemogenetics, and neural recordings, we will identify pain dependently activated neural circuits at the level of the brain and spinal cord in acute and chronic pain.