title: Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the mu-opioid receptor.
abstract: 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 mu-opioid receptors were targeted with a single microinjection of saporin conjugated to the mu-opioid agonist dermorphin; unconjugated saporin and dermorphin were used as controls. RVM dermorphin-saporin, but not dermorphin or saporin, significantly decreased cells expressing mu-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 beta-funaltrexamine, a selective mu-opioid receptor 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 time-related reversal of the SNL-induced experimental pain to preinjury baseline levels. Thus, loss of RVM mu 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.
authors: Departments of Pharmacology and Anesthesiology, University of Arizona, Tucson, Arizona 85724, USA. frankp@u.arizona.edu
authors: F
authors: F
authors: Porreca
authors: S E
authors: SE
authors: Burgess
authors: L R
authors: LR
authors: Gardell
authors: T W
authors: TW
authors: Vanderah
authors: T P
authors: TP
authors: Malan
authors: M H
authors: MH
authors: Ossipov
authors: D A
authors: DA
authors: Lappi
authors: J
authors: J
authors: Lai
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D000922:Immunotoxins; D008026:Ligation; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008845:Microinjections; D009699:N-Glycosyl Hydrolases; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage; D018847:Opioid Peptides; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D010940:Plant Proteins / Q000008:administration & dosage; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000737:chemistry; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013127:Spinal Nerves / Q000293:injuries / Q000503:physiopathology
chemical_list: D000922:Immunotoxins; D009842:Oligopeptides; D018847:Opioid Peptides; D010940:Plant Proteins; D017450:Receptors, Opioid, mu; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C431163:dermorphin-saporin; C030058:dermorphin; D009271:Naltrexone; C024524:beta-funaltrexamine; D009699:N-Glycosyl Hydrolases; D000076985:Saporins