Stimulation of the periaqueductal gray matter of the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem.

5-HT (serotonin) released from the raphe nuclei descends to the dorsal horn of the spinal cord where it forms excitatory connections with the inhibitory interneurons located in Laminae II (aka the substantia gelatinosa).

This is sometimes referred to as the gate control theory of pain and is supported by the fact that electrical stimulation of the PAG results in immediate and profound analgesia.

[7] Stimulation of the dorsal and lateral aspects of the PAG can provoke defensive responses characterised by freezing immobility, running, jumping, tachycardia, and increases in blood pressure and muscle tonus.

In contrast, stimulation of the caudal ventrolateral PAG can result in an immobile, relaxed posture known as quiescence, whereas its inhibition leads to increased locomotor activity.