Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization.
Nerve injury can produce hypersensitivity to noxious and normally innocuous stimulation. Injury-induced central (i.e. spinal) sensitization is thought to arise from enhanced afferent input to the spinal cord and to be critical for expression of behavioral hypersensitivity. Descending facilitatory influences from the rostral ventromedial medulla have been suggested to also be critical for the maintenance, though not the initiation, of experimental neuropathic pain. The possibility that descending facilitation from the rostral ventromedial medulla is required for the maintenance of central sensitization was examined by determining whether ablation of mu-opioid receptor-expressing cells within the rostral ventromedial medulla prevented the enhanced expression of repetitive touch-evoked FOS within the spinal cord of animals with spinal nerve ligation injury as well as nerve injury-induced behavioral hypersensitivity. Rats received a single microinjection of vehicle, saporin, dermorphin or dermorphin-saporin into the rostral ventromedial medulla and 28 days later, underwent either sham or spinal nerve ligation procedures. Animals receiving rostral ventromedial medulla pretreatment with vehicle, dermorphin or saporin that were subjected to spinal nerve ligation demonstrated both thermal and tactile hypersensitivity, and showed significantly increased expression of touch-evoked FOS in the dorsal horn ipsilateral to nerve injury compared with sham-operated controls at days 3, 5 or 10 post-spinal nerve ligation. In contrast, nerve-injured animals pretreated with dermorphin-saporin showed enhanced behaviors and touch-evoked FOS expression in the spinal dorsal horn at day 3, but not days 5 and 10, post-spinal nerve ligation when compared with sham-operated controls. These results indicate the presence of nerve injury-induced behavioral hypersensitivity associated with nerve injury-induced central sensitization. Further, the results demonstrate the novel concept that once initiated, maintenance of nerve injury-induced central sensitization in the spinal dorsal horn requires descending pain facilitation mechanisms arising from the rostral ventromedial medulla.
Vera-Portocarrero
L P
LP
Department of Pharmacology, University of Arizona, Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Zhang
E-T
ET
Ossipov
M H
MH
Xie
J Y
JY
King
T
T
Lai
J
J
Porreca
F
F
D000818:Animals; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D010147:Pain Measurement / Q000379:methods*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000502:physiology*; D011712:Pyramidal Tracts / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley