Tissue inflammation or nerve injury at the periphery can cause chronic pain. Although the spinal-cord-projecting neurons in the rostral ventromedial medulla (RVMSC neurons) can promote pain chronification1–4, the pathway by which peripheral injury signals drive these neurons is poorly understood1–3,5. Here we report a circuit loop that extends from the spinal cord to the ventral posterolateral thalamus and posterior complex of the thalamus, proceeds to the primary somatosensory cortex and returns to the spinal cord via the lateral superior colliculus, which in turn connects to μ-opioid-receptor-expressing RVMSC neurons. Silencing any node along this multisynaptic circuit has minimal effects on nociception in healthy mice, but can eliminate mechanical hypersensitization and restore normal nociceptive response thresholds in mouse models of inflammatory and neuropathic pain. In healthy mice, repetitive—but not acute—activation of each node in this circuit is sufficient to cause robust chronic mechanical hypersensitization. Our findings reveal a spino-brain–spinal cord circuit loop that links ascending and descending pathways and specifically drives chronic mechanical pain. This could enable the identification of cellular targets for treating chronic pain.
