To summarize, although there are multiple potential target nuclei for modulating pain transmission and several candidate efferent pathways that exert modulatory control, the most completely described pain modulating circuit includes the amygdala, PAG, DLPT and RVM in the brainstem. Through descending projections, this circuit controls both spinal and trigeminal dorsal horn pain transmission neurons and mediates both opioid and stimulation produced analgesia. Several different neurotransmitters are involved in the modulatory actions of this circuit, which exerts bi-directional control of pain through On cells that facilitate and Off cells that inhibit dorsal horn nociceptive neurons. There is evidence that this circuit contributes to analgesia in humans and may be activated by acute stress or the expectation of relief. Conversely, through the facilitating effect of On cells, this circuit is theoretically capable of generating or enhancing perceived pain intensity. Such an effect could provide a physiological mechanism for the pain enhancing actions of mood, attention and expectation.