This study in lightly anesthetized rats found that unilateral electrical stimulation delivered to the ventral part of the thalamic nucleus submedius (Sm), the thalamic reuniens nucleus (Re) and the hypothalamic dorsal area (DA) markedly depressed the TF reflex, and this inhibitory effect increased following increasing stimulation intensity. Stimulation in the dorsal part of Sm did not produce any or only slight depression of the TF reflex. Furthermore, an ipsilateral electrolytic lesion of the ventrolateral orbital cortex (VLO) eliminated the unilateral Sm-evoked inhibition, but not the inhibition elicited by Re and DA and contralateral Sm stimulation. Finally, after bilateral electrolytic lesions of the ventrolateral periaqueductal gray (PAG) the DA and Re and contralateral Sm-evoked inhibitions were also eliminated. The results suggest that the Sm plays an important role in modulation of nociceptive inputs, and this role of Sm is mediated by the VLO and leads to activation of the PAG descending inhibitory system and depression of the nociceptive inputs at the spinal cord level.