Previous studies have shown that microinjection of morphine into the nucleus submedius (Sm) of the thalamus produces antinociception. The aim of the current study was to examine whether gamma-aminobutyric acid (GABA)ergic terminals in the Sm were involved in this antinociception. Under light anesthesia, the GABA(A) receptor antagonist bicuculline or agonist muscimol was microinjected into the Sm of the thalamus in Sm non-morphine-treated (control) or Sm morphine-treated (microinjection into the Sm in the thalamus) rats. Tail flick latencies (TFL) were measured in each of these groups of rats every 5 min. Bicuculline (100, 200, 500 ng in 0.5 microL) depressed the TF reflex in a dose-dependent fashion, and this effect was blocked by microinjection of the opioid receptor antagonist naloxone (0.5 microg) into the same Sm site. A small dose (100 ng) of bicuculline microinjected into Sm significantly enhanced the morphine-evoked inhibition of TF reflex. In contrast, administration of muscimol (250 ng) did not significantly influence the TF reflex in Sm non-morphine-treated rats, but it significantly attenuated the morphine-induced antinociception in the Sm morphine-treated rats. These results suggest that locally released GABA acting at GABA(A) receptors is involved in the modulation of Sm morphine-induced antinociception, and support the hypothesis that a disinhibitory effect elicited by morphine on GABAergic terminals in Sm may lead to activation of the Sm-ventrolateral orbital cortex (VLO)-perioqueductal gray (PAG) brainstem descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.