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

Kenneth E. Miller, E. Matthew Hoffman, Mathura Sutharshan, Ruben Schechter

Research output: Contribution to journalReview articlepeer-review

104 Scopus citations


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.

Original languageEnglish
Pages (from-to)283-309
Number of pages27
JournalPharmacology and Therapeutics
Issue number3
StatePublished - Jun 2011


  • Excitatory amino acid receptors
  • Glutaminase
  • Inflammation
  • Sensory nerves
  • Vesicular glutamate transporters


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