Inflammation or nerve injury at periphery can cause chronic pain. The spinal cord-projecting neurons in the rostral ventromedial medulla (RVMSC neurons) facilitate pain chronification1-3. However, the neuronal pathway that transmitting information about peripheral injury to these descending RVMSC neurons is unknown. Here we report a closed-loop circuit extending from spinal cord to ventral posterolateral thalamus and posterior complex of the thalamus, proceeding to primary somatosensory cortex; then returning to the spinal cord via lateral superior colliculus, ultimately connecting 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 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.