Alleviating pain hypersensitivity through activation of type 4 metabotropic glutamate receptor

J Neurosci. 2013 Nov 27;33(48):18951-65. doi: 10.1523/JNEUROSCI.1221-13.2013.


Hyperactivity of the glutamatergic system is involved in the development of central sensitization in the pain neuraxis, associated with allodynia and hyperalgesia observed in patients with chronic pain. Herein we study the ability of type 4 metabotropic glutamate receptors (mGlu4) to regulate spinal glutamate signaling and alleviate chronic pain. We show that mGlu4 are located both on unmyelinated C-fibers and spinal neurons terminals in the inner lamina II of the spinal cord where they inhibit glutamatergic transmission through coupling to Cav2.2 channels. Genetic deletion of mGlu4 in mice alters sensitivity to strong noxious mechanical compression and accelerates the onset of the nociceptive behavior in the inflammatory phase of the formalin test. However, responses to punctate mechanical stimulation and nocifensive responses to thermal noxious stimuli are not modified. Accordingly, pharmacological activation of mGlu4 inhibits mechanical hypersensitivity in animal models of inflammatory or neuropathic pain while leaving acute mechanical perception unchanged in naive animals. Together, these results reveal that mGlu4 is a promising new target for the treatment of chronic pain.

Keywords: GPCR; allodynia; analgesia; hyperalgesia; mGlu; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carrageenan
  • Chronic Disease
  • Constriction, Pathologic / pathology
  • Electrophysiological Phenomena / physiology
  • Excitatory Amino Acid Agonists / therapeutic use*
  • Fluorescent Antibody Technique
  • Hyperalgesia / drug therapy*
  • Immersion / physiopathology
  • Interneurons / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myelin Sheath / physiology
  • Pain Measurement / drug effects
  • Patch-Clamp Techniques
  • Phosphinic Acids / administration & dosage
  • Phosphinic Acids / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / biosynthesis
  • Receptors, Metabotropic Glutamate / genetics
  • Rhizotomy
  • Sensory Receptor Cells / physiology
  • Spinal Cord / cytology
  • Spinal Cord / physiology
  • Synaptic Transmission / physiology


  • Excitatory Amino Acid Agonists
  • LSP4-2022
  • Phosphinic Acids
  • Receptors, Metabotropic Glutamate
  • Carrageenan
  • metabotropic glutamate receptor 4