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). When activated, these interneurons release either enkephalin or dynorphin (
endogenous opioid peptides), which bind to
mu and
kappa opioid receptors, respectively, 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
ventral posterolateral nucleus (VPL) of the thalamus. The nociceptive signal is thus inhibited before reaching the cortical areas that interpret the signal as pain, such as the
anterior cingulate. 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. Notably, the anterior cingulate cortex is thought to be responsible for emotional responses to pain, including perceived social or emotional pain. Reducing nociceptive signaling to this area not only reduces overall pain signaling, but appears to also reduce sensitivity to pain. Furthermore, activation of mu-opioid receptors has been shown to provide an "analgesic" effect for emotional pain. ==Role in defensive behavior==