The antinociceptive activity of excitatory amino acids in the rat brainstem: an anatomical and pharmacological analysis.

Rats were stereotaxically implanted with microinjection cannulae aimed at sites ranging caudally from the lower medulla and rostrally to the diencephalon and received microinjections of the excitatory amino acid: L-glutamate 30 nmol/0.5 microliters. The subsequent spontaneous behavioral response and the effect on the thermal noxious-evoked tail flick (TF) and hot plate (HP) responses was recorded. From 331 brain sites mapped with glutamate, an elevation of tail flick and hot plate response latencies was observed in 59 cases and in 34 of these sites the antinociceptive activity was preceded by a shortlasting aversion characterized by vocalization and running. The glutamate-sensitive sites at which TF and HP response latencies were elevated were exclusively distributed in the medullary reticular formation (MRF) and the mesencephalic periaqueductal gray matter (PAG). The aversive and antinociceptive activity of glutamate was dose-dependent and mimicked by the excitatory amino acid (EAA) receptor agonists N-methyl-D-aspartate + (NMDA) kainate and less so quisqualate. The EAA receptor antagonists MK-801 and AP-5, but not glutamyl-amino-methyl-sulfonic acid, antagonized in a dose-dependent fashion both the aversive and antinociceptive responses evoked from the PAG. It is suggested that NMDA receptor-linked neurons in the PAG activate both nociceptive and antinociceptive systems.