Opioid circuit opens path to pain relief.

Manipulation of neural circuits targeted by morphine enables pain relief without opioids.

The 'in's and out's' of descending pain modulation from the rostral ventromedial medulla.

The descending-pain modulating circuit controls the experience of pain by modulating transmission of sensory signals through the dorsal horn. This circuit's key output node, the rostral ventromedial medulla (RVM), integrates 'top-down' and 'bottom-up' inputs that regulate functionally defined RVM cell types, 'OFF-cells' and 'ON-cells', which respectively suppress or facilitate pain-related sensory processing. While recent advances have sought molecular definition of RVM cell types, conflicting behavioral findings highlight challenges involved in aligning functional and molecularly defined types.

Direct and Indirect Nociceptive Input from the Trigeminal Dorsal Horn to Pain-Modulating Neurons in the Rostral Ventromedial Medulla.

The brain is able to amplify or suppress nociceptive signals by means of descending projections to the spinal and trigeminal dorsal horns from the rostral ventromedial medulla (RVM). Two physiologically defined cell classes within RVM, "ON-cells" and "OFF-cells," respectively facilitate and inhibit nociceptive transmission. However, sensory pathways through which nociceptive input drives changes in RVM cell activity are only now being defined.

Neurons in the caudal ventrolateral medulla mediate descending pain control.

Supraspinal brain regions modify nociceptive signals in response to various stressors including stimuli that elevate pain thresholds. The medulla oblongata has previously been implicated in this type of pain control, but the neurons and molecular circuits involved have remained elusive. Here we identify catecholaminergic neurons in the caudal ventrolateral medulla that are activated by noxious stimuli in mice.