Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms

Pharmacol Ther. 2011 Jun;130(3):283-309. doi: 10.1016/j.pharmthera.2011.01.005. Epub 2011 Jan 26.


In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Afferent Pathways / drug effects
  • Afferent Pathways / physiology
  • Afferent Pathways / physiopathology
  • Animals
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology*
  • Humans
  • Pain / metabolism
  • Pain / physiopathology
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / physiology*
  • Peripheral Nerves / physiopathology*
  • Receptors, Glutamate / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Receptors, Glutamate
  • Glutamic Acid