Periaqueductal Gray - Role in Analgesia

Role in Analgesia

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 neurotransmitters), which bind to mu 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 (VPL) of the thalamus. The nociceptive signal was inhibited before it was able to reach 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.

Three known kinds of opioid receptors have been identified: mu, kappa and delta. Synthetic opioid and opioid-derivative drugs activate these receptors (possibly by acting on the PAG directly, where these receptors are densely expressed) to produce analgesia. These drugs include heroin, morphine, pethidine, hydrocodone, oxycodone, and similar pain-reducing compounds.