Four experiments examined the role of the nucleus tractus solitarius (NTS) and subjacent nucleus reticularis ventralis (NRV) in the production of antinociception. Experiment 1 showed that microinjection of glutamate (50 nmol) into the caudal NTS resulted in inhibition of the tail-flick reflex, hypotension, and mild bradycardia, whereas microinjection of glutamate into the rostral NTS resulted only in hypotension and mild bradycardia. Microinjections of glutamate into the NRV resulted in inhibition of the tail-flick reflex, hypertension, and mild bradycardia. Experiment 2 demonstrated that the magnitude of the antinociceptive and cardiovascular responses resulting from glutamate microinjections into both the depressor and pressor regions were dose dependent. Experiment 3 showed that the antinociceptive effects resulting from microinjections of glutamate into either the depressor or pressor regions could not be antagonized by phentolamine (30 μg), methysergide (30 μg), or naloxone (30 μg) alone, but the combined intrathecal administration of phentolamine and methysergide (7.5, 15, or 30 μg of each) attenuated the antinociception resulting from microinjection of glutamate into either depessor or pressor regions in a dose-dependent fashion. Experiment 4 showed that systemic administration of hexamethonium blocked the pressor response produced by microinjection of glutamate into the NRV but did not reduce the antinociceptive effect of the microinjection. These findings are consistent with a role for the NTS and NRV in the production of antinociception.