Chronic mechanical pain, whether caused by inflammation or nerve injury, is a debilitating clinical problem. While injury and inflammation typically originate in the periphery, there is growing evidence implicating the central pain modulation systems in the process of pain chronification. Nearly 40 years ago, seminal work from Howard Fields and colleagues established the essential role of the Periaqueductal Gray (PAG)-Rostral Ventromedial Medulla (RVM) system in descending pain modulation. However, the precise mechanism by which injury information is transmitted from the periphery to the PAG-RVM system in the brainstem remains unclear. Moreover, the role of the PAG in pain chronification is still debated, given that PAG electrostimulation tends to suppress rather than promote pain. In this talk, I will discribe a multisynaptic circuit connecting peripheral input from the spinal cord to the OPRM1+ RVM neurons, which, in turn, projecting back to the spinal cord. Interestingly, PAG is not part of this closed-loop circuit. To the best of our knowledge, this is the first study to fully describe a complete circuit, from end to end, that drives a major neurological disorder.