Morphine induction of c-fos expression in the rat forebrain through glutamatergic mechanisms: role of non-n-methyl-D-aspartate receptors

Neuroscience. 2003;119(3):787-94. doi: 10.1016/s0306-4522(02)00975-2.


Acute injection of morphine induces expression of the immediate-early genes c-Fos and JunB in several forebrain regions of the rat, in part through an N-methyl-D-aspartate (NMDA) receptor-dependent mechanism. Because membrane depolarization through (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is believed to be necessary for full activation of NMDA receptors, we determined the role of AMPA receptors in morphine-induced c-Fos expression. Rats were given the AMPA receptor antagonist GYKI-52466 (12.9 mg/kg, i.p.) 15 min before morphine (10 mg/kg, s.c.), or the AMPA receptor enhancer CX516 (30 mg/kg, i.p.) 5 min after morphine. The c-Fos response was attenuated by the antagonist and augmented by the enhancer. Using double immunocytochemistry, we found that morphine induced c-Fos in neurons containing the GluR2/3, but not the GluR1 and rarely the GluR4, subunits of the AMPA receptor. Double immunocytochemistry for mu opioid receptor and c-Fos showed that c-Fos expression was mainly absent in the patch compartment of the striatum, which is enriched in mu opioid receptors. The glutamatergic synapse often contains metabotropic receptors as well as ionotropic receptors. Type I metabotropic glutamate receptors are coupled to activation of protein kinase C, which has also been shown to mediate the immediate-early gene response to morphine. To determine if activation of metabotropic glutamate receptors is involved in rapid effects of morphine on the brain, rats were given the type I metabotropic glutamate receptor antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.2 mg/kg, i.p.) or vehicle 30 min before morphine treatment. Pretreatment with AIDA completely blocked morphine-induced c-Fos expression in the caudate-putamen.Taken together, these results demonstrate involvement of both AMPA and type I metabotropic glutamate receptors in the acute effects of morphine on the forebrain, supporting an important role for glutamatergic neurotransmission mediated by non-NMDA glutamate receptors in morphine's actions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cerebral Cortex / cytology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Immunohistochemistry
  • Male
  • Morphine / pharmacology*
  • Morphine Dependence / metabolism*
  • Morphine Dependence / physiopathology
  • Neostriatum / cytology
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Prosencephalon / cytology
  • Prosencephalon / drug effects*
  • Prosencephalon / metabolism
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / drug effects
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / agonists
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism
  • Receptors, Glutamate / drug effects*
  • Receptors, Glutamate / metabolism
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Synaptic Transmission / drug effects*
  • Synaptic Transmission / physiology


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, AMPA
  • Receptors, Glutamate
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Glutamic Acid
  • Morphine
  • glutamate receptor ionotropic, AMPA 2