title: Time-dependent descending facilitation from the rostral ventromedial medulla maintains, but does not initiate, neuropathic pain.
abstract: Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. Tactile and thermal hypersensitivity were induced in rats by spinal nerve ligation (SNL). RVM lidocaine blocked SNL-induced tactile and thermal hypersensitivity on post-SNL days 6-12 but not on post-SNL day 3. Lesion of RVM cells expressing mu-opioid receptors with dermorphin-saporin did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Similarly, lesions of the dorsolateral funiculus (DLF) did not prevent the onset of SNL-induced tactile and thermal hypersensitivity, but these signs reversed to baseline levels beginning on post-SNL day 4. Lesions of the DLF also blocked the SNL-induced increase in spinal dynorphin content, which has been suggested to promote neuropathic pain. These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states.
authors.affiliation: Departments of Pharmacology and Anesthesiology, University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Burgess
authors.forename: Luis R
authors.initials: LR
authors.lastname: Gardell
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: T Philip
authors.initials: TP
authors.lastname: Malan
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003714:Denervation; D004399:Dynorphins / Q000032:analysis; D000922:Immunotoxins; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology; D008026:Ligation; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000503:physiopathology*; D008845:Microinjections; D009699:N-Glycosyl Hydrolases; D009842:Oligopeptides / Q000008:administration & dosage / Q000633:toxicity; D018847:Opioid Peptides; D010146:Pain / Q000209:etiology* / Q000503:physiopathology; D010940:Plant Proteins / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013116:Spinal Cord / Q000737:chemistry; D013127:Spinal Nerves
chemical_list: D000922:Immunotoxins; D009842:Oligopeptides; D018847:Opioid Peptides; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C030058:dermorphin; D004399:Dynorphins; D008012:Lidocaine; D009699:N-Glycosyl Hydrolases; D000076985:Saporins