Glutamate modulation of antinociception, but not tolerance, produced by morphine microinjection into the periaqueductal gray of the rat

Brain Res. 2009 Oct 27;1295:59-66. doi: 10.1016/j.brainres.2009.07.100. Epub 2009 Aug 5.


The periaqueductal gray (PAG) plays an important role in morphine antinociception and tolerance. Co-localization of mu-opioid and NMDA receptors on dendrites in the PAG suggests that glutamate may modulate morphine antinociception. Moreover, the involvement of glutamate in spinally mediated tolerance to morphine suggests that glutamate receptors may contribute to PAG mediated tolerance. These hypotheses were tested by microinjecting glutamate receptor antagonists and morphine into the ventrolateral PAG (vPAG) of the rat. Microinjection of the non-specific glutamate receptor antagonist kynurenic acid or the NMDA receptor antagonist MK-801 into the vPAG did not affect nociception. However, co-administration of these antagonists with morphine into the vPAG enhanced the acute antinociceptive effects of morphine as measured by a leftward shift in the morphine dose-response curves. Repeated microinjections of morphine into the vPAG caused a rightward shift in the dose-response curve for antinociception whether the glutamate receptor antagonists kynurenic acid or MK-801 were co-administered or not. The lack of effect of microinjecting glutamate receptor antagonists into the vPAG indicates that tonic glutamate release in the PAG does not contribute to nociceptive tone. That these antagonists enhance morphine antinociception indicates that endogenous glutamate counteracts the antinociceptive effect of morphine in the vPAG. However, this compensatory glutamate release does not contribute to tolerance to the antinociceptive effects of microinjecting morphine into the vPAG. Previous research showing that glutamate contributes to spinal mechanisms of tolerance indicate that different tolerance mechanisms are engaged in the vPAG and spinal cord.

Publication types

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

MeSH terms

  • Analgesia
  • Analgesics, Opioid / pharmacology
  • Analysis of Variance
  • Animals
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Tolerance*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Hot Temperature
  • Kynurenic Acid / pharmacology
  • Male
  • Microinjections
  • Morphine / pharmacology*
  • Pain / drug therapy
  • Pain Measurement / drug effects
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glutamate / metabolism*
  • Receptors, Opioid, mu / metabolism
  • Staining and Labeling


  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Receptors, Glutamate
  • Receptors, Opioid, mu
  • Glutamic Acid
  • Dizocilpine Maleate
  • Morphine
  • Kynurenic Acid