Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat

Neuroscience. 2004;128(1):169-76. doi: 10.1016/j.neuroscience.2004.06.040.


We hypothesized that glutamate (Glu) released from the peripheral terminals of primary afferents contributes to the generation of mechanical hyperalgesia following peripheral nerve injury. Nerve injury was performed on rats with a lumbar 5 spinal nerve lesion (L5 SNL), which was preceded by L5 dorsal rhizotomy (L5 DR) to avoid the potential central effects induced by L5 SNL through the L5 dorsal root. Mechanical hyperalgesia, as evidenced by a reduction in paw withdrawal threshold (PWT), was short-lasting (<6 days) after L5 DR, but persistent (>42 days) after L5 SNL preceded by L5 DR. When an intraplantar injection into the affected hind paw was given immediately before L5 SNL, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (20 nmol), group-I metabotropic Glu (mGlu) receptor antagonist DL-amino-3-phosphonopropionic acid (DL-AP3; 70 nmol), and selective group-II mGlu receptor agonist 4-aminopyrrolidine-2,4-dicarboxylate (APDC; 20 nmol) delayed the onset of PWT reduction for 1-4 days. However, this onset was not affected by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4,-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX; 100 nmol). When the same injection was given after L5 SNL-induced mechanical hyperalgesia had been established, MK-801 reversed the PWT reduction for 30-75 min, whereas NBQX, DL-AP3, or APDC had no effect. These results suggest that the manipulation of the peripheral Glu receptors reduces neuropathic pain, by blocking NMDA and group-I mGlu receptors and by stimulating group-II mGlu receptor during the induction phase of neuropathic pain, but only by blocking the NMDA receptor during its maintenance phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology*
  • Male
  • Neuralgia / metabolism*
  • Pain Measurement
  • Pain Threshold / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glutamate / drug effects
  • Receptors, Glutamate / metabolism*
  • Rhizotomy
  • Spinal Nerves / injuries
  • Spinal Nerves / physiopathology


  • Excitatory Amino Acid Antagonists
  • Receptors, Glutamate