Involvement of subtype 1 metabotropic glutamate receptors in apoptosis and caspase-7 over-expression in spinal cord of neuropathic rats

Pharmacol Res. 2008 Mar;57(3):223-33. doi: 10.1016/j.phrs.2008.01.007. Epub 2008 Feb 2.


The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. At 7 days post-CCI, only over-expression of bcl-2, nestin and GFAP mRNA was observed. Administration of AIDA reduced thermal hyperalgesia and mechanical allodynia at 3 and 7 days post-CCI; administration of JNJ16259685 reduced thermal hyperalgesia at 3 and 7 days post-CCI, but not mechanical allodynia. AIDA decreased the mRNA levels of bax, apaf-1, GFAP and caspase-7 genes. JNJ16259685 increased the mRNA levels of bcl-2 and GFAP gene, and decreased APAF-1 and caspases-7 genes. Inhibiting mGlu1 receptors also reduced TUNEL-positive profiles and immunohistochemical reactivity for caspase-7. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect. Moreover, JNJ16259685, but not the non-selective AIDA, increased astrogliosis which may account for its decreased analgesic efficacy. This study provides evidence that the contemporary and partial blockade of group I and likely ionotropic glutamate receptors may be a more suitable therapy than selective blockade of mGlu1 subtype receptors condition to decrease neuropathic pain symptoms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Behavior, Animal / drug effects
  • Caspase 7 / biosynthesis*
  • Constriction, Pathologic
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / genetics
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gliosis / genetics
  • Hyperalgesia / pathology
  • Immunohistochemistry
  • Indans / pharmacology
  • Male
  • Pain / psychology
  • Pain Measurement
  • Posterior Horn Cells / enzymology
  • Posterior Horn Cells / metabolism
  • Posterior Horn Cells / pathology
  • Quinolines / pharmacology
  • RNA / biosynthesis
  • RNA / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / drug effects
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sciatic Neuropathy / enzymology
  • Sciatic Neuropathy / metabolism*
  • Sciatic Neuropathy / pathology
  • Spinal Cord / enzymology
  • Spinal Cord / physiology*


  • (3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone
  • 1-aminoindan-1,5-dicarboxylic acid
  • Apoptosis Regulatory Proteins
  • DNA, Neoplasm
  • Excitatory Amino Acid Antagonists
  • Indans
  • Quinolines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • RNA
  • Caspase 7