Central nervous system mechanism of pain modulation

The Pathophysiology of Pain

Central nervous system mechanisms of pain modulation

Brain stem modulatory systems play a major role in pain facilitation. Descending pain modulatory neurons in the rostral ventromedial medulla (RVM) and dorsolateral pontine tegmentum (DLP) inhibit nociceptive transmission by several mechanisms.1


  • Direct inhibition of projection neurons
  • Inhibition of transmitter release from primary afferents
  • Excitation on inhibitory interneurons
  • Inhibition of excitatory interneurons


Functional studies show that these modulatory systems can exert bi-directional control of pain in response to higher order factors such as fear, attention and expectation. Opioid peptide synthesizing cells and opioid receptors are distributed throughout the pain-modulating circuit. The release of endogenous opioid ligands at spinal sites can produce an analgesic effect. These substances function in part by reducing transmitter release from the dorsal horn terminals of primary afferent nociceptors. They also direct post-synaptic inhibition of central neurons that are activated by noxious stimulation. Both mu and delta opioid receptor agonists block excitatory amino acid release from primary afferents. Endogenous opioids also contribute to pain modulation by inhibiting neuropeptide release from primary afferents.2

1Wall and Melzack’s Textbook of Pain, 5th Edition, p130. 2010.
2Wall and Melzack’s Textbook of Pain, 5th Edition, p128-129. 2010.