Brainstem excitatory amino acid receptors in nociception: microinjection mapping and pharmacological characterization of glutamate-sensitive sites in the brainstem associated with algogenic behavior.

In awake, freely moving rats, the intracerebral administration of the excitatory amino acid L-glutamate (30 nmol/0.5 microliters) into discrete regions of the brainstem resulted in a transient and spontaneous pain-like syndrome characterized by an initial vocalization and vigorous escape behavior. Systematic microinjection mapping studies were carried out at sites distributed caudally from the lower medulla and rostrally into diencephalon. These studies revealed that the spontaneous pain-like behavior was observed to occur after glutamate injection in 13% of 331 microinjected sites, and these sensitive sites were largely limited to the mesencephalic periaqueductal gray matter. The behavioral syndrome was dose-dependent and antagonized in a dose-dependent fashion by the glutamate receptor antagonists MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. The pain-like behavior was also produced by the other excitatory amino acid receptor agonists N-methyl-D-aspartate, quisqualate and to a certain extent by kainate in a dose-dependent manner with the order of potency being N-methyl-D-aspartate = kainate greater than quisqualate greater than D-glutamate. The effects of N-methyl-D-aspartate and quisqualate were antagonized by MK 801 and DL-2-amino-5 phosphonovalerate but not by gamma-D-glutamyl-amino-methylsulfonic acid. It is suggested that the pain-like behavioral syndrome is the result of focal occupation of N-methyl-D-aspartate receptors on neuronal populations in the terminal regions of rostrally projecting spinomesencephalic systems.