Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor

Neurons in the rostroventromedial medulla (RVM) project to spinal loci wher e the neurons inhibit or facilitate pain transmission. Abnormal activity of facilitatory processes may thus represent a mechanism of chronic pain. Thi s possibility and the phenotype of RVM cells that might underlie experiment al neuropathic pain were investigated. Cells expressing mu -opioid receptor s were targeted with a single microinjection of saporin conjugated to the m u -opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, signif icantly decreased cells expressing mu -opioid receptor transcript. RVM derm orphin, saporin, or dermorphin-saporin did not change baseline hindpaw sens itivity to non-noxious or noxious stimuli. Spinal nerve ligation (SNL) inju ry in rats pretreated with RVM dermorphin-saporin failed to elicit the expe cted increase in sensitivity to non-noxious mechanical or noxious thermal s timuli applied to the paw. RVM dermorphin or saporin did not alter SNL-indu ced experimental pain, and no pretreatment affected the responses of sham-o perated groups. This protective effect of dermorphin-saporin against SNL-in duced pain was blocked by beta -funaltrexamine, a selective mu -opioid rece ptor antagonist, indicating specific interaction of dermorphin-saporin with the mu -opioid receptor. RVM microinjection of dermorphin-saporin, but not of dermorphin or saporin, in animals previously undergoing SNL showed a ti me-related reversal of the SNL-induced experimental pain to preinjury basel ine levels. Thus, loss of RVM mu receptor-expressing cells both prevents an d reverses experimental neuropathic pain. The data support the hypothesis t hat inappropriate tonic-descending facilitation may underlie some chronic p ain states and offer new possibilities for the design of therapeutic strate gies.