Periaqueductal

Periaqueductal refers to the periaqueductal region of the midbrain that surrounds the cerebral aqueduct (aqueduct of Sylvius). The most studied structure in this region is the periaqueductal gray (PAG), a column of gray matter located in the tegmentum of the midbrain around the aqueduct. The PAG is commonly divided into functional subregions, such as dorsal, dorsolateral, lateral, ventrolateral, and ventral columns, each associated with different behavioral and autonomic responses.

Functions

A primary role of the PAG is in descending pain modulation. It integrates inputs from the cortex, limbic structures (notably the amygdala and hypothalamus), and ascending nociceptive pathways, and exerts analgesia by activating downstream brainstem nuclei—particularly the rostral ventromedial medulla and the nucleus raphe magnus—which project to the spinal cord to dampen nociceptive transmission. The analgesic effect is often opioid-mediated, involving endogenous opioids and receptors; administration of opioids or stimulation of the PAG can produce pain relief, an effect that can be reversed by opioid antagonists such as naloxone.

In addition to pain control, the PAG participates in defensive and autonomic responses. Different PAG columns coordinate coping strategies to threats, including fight, flight, freezing, and vocalization, as well as autonomic adjustments in heart rate and respiration. It also contributes to complex behaviors such as maternal defense.

Clinical relevance

Insights into PAG function have informed approaches to pain management, including research on deep brain stimulation and pharmacologic modulation for chronic pain. Functional imaging has linked PAG activity to placebo analgesia and stress-related analgesic effects.