Evidence for glutamic acid as a possible neurotransmitter between the mesencephalic nucleus cuneiformis and the medullary nucleus raphe magnus in the lightly anesthetized rat

Abstract

Previous anatomic and behavioral studies have provided evidence for a strong projection from the mesencephalic nucleus cuneiformis (NCF) to the medullary nucleus raphe magnus (NRM), an area mediating control of a descending pain inhibitory system. Moreover, physiologic experiments in the deeply anesthetized rat have shown that this projection is predominantly excitatory and, at least partially, cholinergic. Recently Fields and coworkers have described 3 physiologically defined classes of neurons in the NRM: the off-, on-, and neutral cells, which exhibit an abrupt pause, increase, or no change in activity, respectively, just prior to the occurrence of the nocifensive tailflick (TF) reflex. The off-cells have been hypothesized as part of a negative feedback system influencing pain transmission at the spinal level. In this study we have examined the interaction between the NCF and neurons in the NRM that were classified as off-, on-, or neutral cells. In addition, since many NCF neurons are glutamatergic, we have examined the possible role of glutamate in the interaction between NCF and NRM. In the lightly anesthetized rat, low-intensity electrical stimulation of NCF excited 53% of NRM neurons at short latencies (mean onset, 3.9 ms), while 20% of NRM neurons were inhibited. Cells of all 3 NRM classes (off-, on-, and neutral) were predominantly excited, an effect which could be blocked by the broad-spectrum excitatory amino acid antagonist kynurenic acid in 36% of cells tested. Pharmacological stimulation of NCF with glutamic acid induced mixed effects, as 34% of NRM cells were excited while 37% were inhibited. Again, there was no significant difference in the response patterns of the three NRM cell classes. Kynurenic acid microinjected into NRM was effective in blocking 50% of the excitatory responses tested. These results indicate that in the lightly anesthetized rat, electrical or pharmacological stimulation of NCF can activate a descending modulatory system of antinociception that includes a glutamatergic projection to NRM, and this interaction appears to operate without differentially activating a particular neuronal subpopulation within the NRM.