Deconstruction of a spino-brain-spinal cord circuit drives chronic mechanical pain

<title>Abstract</title> Inflammation or nerve injury at periphery can cause chronic pain. Although the spinal cord-projecting neurons in the rostral ventromedial medulla (RVMSC neurons) are known can promote pain chronification1-4, the pathway by which peripheral injury signals drive these neurons is poorly understood5,6. Here we report a circuit loop that extends from spinal cord to ventral posterolateral thalamus and posterior complex of the thalamus, proceeds to primary somatosensory cortex; then returns to the spinal cord via lateral superior colliculus, which in turn connects to μ-opioid receptor expressing RVMSC neurons. Silencing any node along this multisynaptic circuit has minimal effect on nociception in healthy mice, but can eliminate mechanical hypersensitization and restore normal nociceptive response thresholds in mouse models of inflammatory and neuropathic pain. Repetitive, but not acute, activation of each node within this circuit in healthy mice is sufficient to cause robust chronic mechanical hypersensitization. Our findings elucidate a spino-brain-spinal circuit loop linking ascending and descending pathways that specifically drives chronic mechanical pain, and identify novel cellular targets for treating chronic pain.