Reynolds’ 1969 demonstration that PAG stimulation could substitute for chemical anaesthesia during abdominal surgery in rats opened a line of research that would soon converge on the discovery of endogenous opioids. Within five years, enkephalins and endorphins had been identified, the PAG and rostroventromedial medulla had been characterised as opioid-rich, and the descending analgesic system had become one of the best-worked-out neural circuits in pain research.

Bandler and Shipley’s columnar organisation framework is the dominant account of how the PAG integrates descending command signals from amygdala and prefrontal cortex with ascending sensory information about the body. Different columns control different defensive response patterns; integration across columns produces coordinated behavioural, autonomic, and analgesic responses appropriate to a perceived threat.

The PAG is also a target of deep brain stimulation for chronic pain that is refractory to medication. Long-term DBS of the ventral PAG / periventricular grey produces sustained analgesia in some patients, with the effect persistent over years; the therapy is approved in some jurisdictions but remains uncommon due to the technical demands of the implant location and the availability of pharmacological alternatives.