Neurons in the rostroventromedial medulla (RVM) project to spinal loci where the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. This possibility and the phenotype of RVM cells that might underlie experimental neuropathic pain were investigated. Cells expressing μ-opioid receptors were targeted with a single microinjection of saporin conjugated to the μ-opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin–saporin, but not dermorphin or saporin, significantly decreased cells expressing μ-opioid receptor transcript. RVM dermorphin, saporin, or dermorphin–saporin did not change baseline hindpaw sensitivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) injury in rats pretreated with RVM dermorphin–saporin failed to elicit the expected increase in sensitivity to non-noxious mechanical or noxious thermal stimuli applied to the paw. RVM dermorphin or saporin did not alter SNL-induced experimental pain, and no pretreatment affected the responses of sham-operated groups. This protective effect of dermorphin–saporin against SNL-induced pain was blocked by β-funaltrexamine, a selective μ-opioid receptor antagonist, indicating specific interaction of dermorphin–saporin with the μ-opioid receptor. RVM microinjection of dermorphin–saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM μ receptor-expressing cells both prevents and reverses experimental neuropathic pain. The data support the hypothesis that inappropriate tonic-descending facilitation may underlie some chronic pain states and offer new possibilities for the design of therapeutic strategies.