It was suggested that the nucleus submedius (Sm) in the medial thalamus and the ventrolateral orbital cortex (VLO) in the prefrontal cortex were involved not only in nociception, but also in modulation of nociception. The Sm VLO PAG may constitute a pathway responsble for nociceptive modulation. Activation of this pathway depresses the nociceptive inputs at the spinal and trigeminal levels via the brainstem descending inhibitory system. This pathway may play an important role in analgesia produced by acupuncture evoked inputs from the small afferent fibers. For proving this hypothesis, a series of studies were performed in our laboratory.① Results of the present study revealed that bilateral electrolytic lesions of the Sm facilitated the radiant heat evoked tail flick (TF) reflex, with the latency of the TF reflex shortening in the rat lightly anesthetized with pentobarbital. If the Sm is purely a nociceptive center, the contrary result should be obtained. Therefore, this result suggests that Sm may be involved in nociceptive modulation, and may exert a tonic descending inhibitory influence on nociceptive transmission. Further investigations indicated that unilateral electrical stimulation of Sm or microinjection of glutamate into Sm significantly depressed the TF reflex, the jaw opening reflex (JOR), as well as the nociceptive responses of neurons in the spinal cord dorsal horn. All these effects were intensity (or dose) dependent and location specific. Moreover, the Sm evoked antinociception could be markedly reduced or eliminated by electrolytic lesion of ipsilateral VLO or bilateral lesions of ventrolateral or lateral parts of PAG, or by microinjection of GABA into VLO or PAG. Similarly, electrical or chemical activation of VLO also produced antinociception, and this effect was eliminated by lesion or depression of the PAG. These facts suggest that the antinociception produced by activation of Sm is mediated by VLO, leading to activation of the PAG brainstem descending inhibitory system and depression of th