BMI Special Seminar // Xiaoke Chen - Circuitry and molecular mechanisms underlying descending pain facilitation

Spinal cord-projecting neurons in the rostral ventromedial medulla (RVM^SC neurons) play active roles in pain facilitation. However, the underlying circuitry and molecular mechanisms remain largely unknown. We show that acute activation of OPRM1⁺ RVM^SC neurons does not facilitate pain in normal mice, but activity of these neurons is required for both initiation and maintenance of chronic mechanical hypersensitivity in mouse models of inflammatory and neuropathic pain. Excitatory collicular inputs are essential for upregulating pseudokinase CaMKv in the OPRM1⁺ RVM^SC neurons after nerve injury and causing mechanical hypersensitivity. Up- or down- regulation of CaMKv is sufficient to drive or reverse mechanical hypersensitivity. Together, our results reveal a collicular-medulla-spinal cord pathway that drives persistent pain and substantiate CaMKv as a key molecular determinant of chronic mechanical hypersensitivity.