Stimulation of the periaqueductal gray matter of the midbrain activates enkephalin-releasing neurons that project to the raphe nuclei in the brainstem. 5-HT 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. When activated, these interneurons release either enkephalin or dynorphin, which bind to mu and kappa opioid receptors on the axons of incoming C and A-delta fibers carrying pain signals from nociceptors activated in the periphery. The activation of the mu-opioid receptor inhibits the release of substance P from these incoming first-order neurons and, in turn, inhibits the activation of the second-order neuron that is responsible for transmitting the pain signal up the spinothalamic tract to the ventroposteriolateral nucleus of the thalamus. The nociceptive signal was inhibited before it was able to reach the cortical areas that interpret the signal as "pain". 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. The periaqueductal gray is also activated by viewing distressing images associated with pain. Three known kinds of opioid receptors have been identified: mu, kappa and delta. Synthetic opioid and opioid-derivative drugs activate these receptors to produce analgesia. These drugs include morphine, heroin, pethidine, hydrocodone, oxycodone, and similar pain-reducing compounds.
Role in defensive behavior
Dorsal PAG neurons are activated during various defensive behaviors. 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, whereas its inhibition leads to increased locomotor activity. Lesions of the caudal ventrolateral PAG can greatly reduce conditioned freezing, whereas lesions of the dorsal aspect can reduce innate defensive behavior, virtually "taming" the animal.
The PAG may be specifically involved in human maternal behavior. The PAG contains a high density of vasopressin and oxytocin receptors, and it has direct connections with the orbitofrontal cortex, which might mediate the role of the PAG in maternal love. The lateral orbitofrontal cortex is activated by pleasant visual, tactile, and olfactory stimuli. Its response depends on pleasantness rather than on intensity of stimulation. Here, its activity is likely to reflect one aspect of the pleasant emotions associated with motherly love.
