The roles of NMDA receptor activation and nucleus reticularis gigantocellularis in the time-dependent changes in descending inhibition after inflammation

Previous studies indicate that descending modulation of nociception is progressively increased following persistent inflammation. The present study was designed to further examine the role of supraspinal neurons in descending modulation following persistent inflammation. Constant levels of paw withdrawal (PW) and tail flick (TF) latencies to noxious heat stimuli were achieved in lightly anesthetized rats (pentobarbital sodium 3-10 mg/kg/h, i.v.). Electrical stimulation (ES, 0.1 ms, 100 Hz, 20-200 LA) was delivered to the rostral ventromedial medulla (RVM), mainly the nucleus raphe magnus (NRM). ES produced intensity-dependent inhibition of PW and TF. Following a unilateral hindpaw inflammation produced by injection of complete Freund's adjuvant (CFA), ES-produced inhibition underwent time-dependent changes. There was an initial decrease at 3 h after inflammation and a subsequent increase after inflammation in the excitability of RVM neurons and the inhibition of nocifensive responses. These changes were most robust after stimulation of the inflamed paw although similar findings were seen on the non-inflamed paw and tail. The inflammation-induced dynamic changes in descending modulation appeared to be correlated with changes in the activation of the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor, Microinjection of an NMDA receptor antagonist, AP5 (1 pmol), resulted in an increase in the current intensity required for inhibition of the PW and TF. The effect of AP5 was less at 3 h after inflammation and significantly greater at 11-24 h after inflammation. In a subsequent experiment, ES-produced inhibition of nocifensive responses after inflammation was examined following selective chemical lesions of the nuclei reticularis gigantocellularis (NGC). Compared to vehicle-injected animals, microinjection of a soma-selective excitotoxin, ibotenic acid, enhanced ES-produced inhibition at 3 h but not at 24 h after inflammation. We propose that these time course changes reflect dynamic alterations in concomitant descending facilitation and inhibition. At early time points, NMDA receptor and NGC activation enhance descending facilitation; as time progresses, the dose-response curve of NMDA shifts to the left and descending inhibition dominates and masks any descending facilitation. (C) 2002 International Association for the study of Pain. Published by Elsevier Science B.V. All rights reserved.