e heterozygous (MORCre) or wild-type (MORWT) mice received AAV8-hSyn-DIO-hM4D(Gi)-mCherry in the RVM. After partial sciatic nerve ligation (PSNL), we evaluated pain behaviors and descending control of nociception in response to acute or sustained chemogenetic inhibition of RVM-MOR cells expressing hM4D(Gi). A single systemic administration of hM4D(Gi) agonist clozapine-N-oxide (CNO) reversibly inhibited hind paw tactile allodynia and produced conditioned place preference only in MORCre mice with PSNL. Intrathecal CNO also reversibly inhibited PSNL-induced hind paw allodynia, suggesting that the spinal projections from these RVM-MOR cells are critical for manifestation of pain behaviors. Consistent with enhanced descending facilitation from RVM-MOR cells, MORCre-hM4D(Gi) mice with PSNL showed diminished descending control of nociception that was restored by systemic CNO. Sustained CNO in drinking water before PSNL prevented expression of chronic pain without affecting acute surgical pai