Pain modulation likely exists in the form of a descending pain
modulatory circuit with inputs that arise in multiple areas,
including the hypothalamus, the amygdala, and the rostral anterior
cingulate cortex (rACC), feeding to the midbrain periaqueductal
gray region (PAG), and with outputs from the PAG to the
medulla.
Neurons within the nucleus raphe magnus and nucleus reticularis
gigantocellularis, which are included within the rostral
ventromedial medulla (RVM), have been shown to project to the
spinal or medullary dorsal horns to directly or indirectly enhance
or diminish nociceptive traffic, changing the experience of
pain.
This descending modulatory circuit is an “opioid-sensitive”
circuit and relevant to human experience in many settings,
including in states of chronic pain, and in the actions of
pain-relieving drugs, including opiates, cannabinoids, NSAIDs, and
serotonin/norepinephrine reuptake blockers that mimic, in part, the
actions of opiates .
This descending PAG-RVM system forms the circuitry that
underlies the physiological phenomenon of stress-induced analgesia
(SIA), which is mediated by parallel opioid and cannabinoid
neurotransmitter systems in the PAG. At the cellular level, opioids
and cannabinoids are hypothesised to activate descending analgesia
through an indirect process of 'GABA disinhibition'-suppression of
inhibitory GABAergic inputs onto output neurons which constitute
the descending analgesic pathway.