Involvement of NCAM and FGF receptor signaling in the development of analgesic tolerance to morphine

Eur J Pharmacol. 2011 Dec 15;672(1-3):77-82. doi: 10.1016/j.ejphar.2011.04.029. Epub 2011 Apr 30.


This study examined the involvement of neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, in the development of tolerance to morphine. Furthermore, we focused on fibroblast growth factor (FGF) receptor and protein kinase C (PKC)-α as part of the intracellular signal transduction pathways underlying NCAM stimulation. The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine (10mg/kg, s.c.) for 5 days. Morphine treatment gradually and significantly decreased the NCAM expression levels. However it returned to normal levels immediately after re-treatment of morphine. Treatment of AS-ODN against NCAM completely inhibited analgesic tolerance to morphine. Protein expression levels of PKC-α were significantly increased by repeated morphine treatment in a NCAM-AS-ODN-reversible manner. Interestingly, alterations of protein interactions between NCAM and FGF receptor were observed under repeated morphine treatment. In addition, SU5402 (2 μg/mouse, i.c.v.), an inhibitor of FGF receptor, completely abolished the development of analgesic tolerance to morphine. Furthermore, κ-opioid receptor stimulation using U-50,488H, a κ-opioid receptor agonist, or establishment of formalin-induced chronic pain can completely suppress these changes in protein expression levels of NCAM and PKC-α and inhibit development of analgesic tolerance to morphine. These findings suggest that NCAM and its interaction with FGF receptor in the mechanism of up-regulation of PKC-α may contribute to the development of analgesic tolerance to morphine. Chronic pain or κ-opioid receptor stimulation could modulate these phenomena and suppress the development of analgesic tolerance to morphine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Analgesics / therapeutic use
  • Animals
  • Base Sequence
  • Chronic Pain / drug therapy
  • Chronic Pain / metabolism
  • Drug Tolerance*
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Enzymologic / drug effects
  • Male
  • Mice
  • Morphine / pharmacology*
  • Morphine / therapeutic use
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism*
  • Oligonucleotides, Antisense / genetics
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrroles / pharmacology
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Receptors, Opioid, kappa / metabolism
  • Signal Transduction / drug effects*
  • Time Factors


  • Analgesics
  • Neural Cell Adhesion Molecules
  • Oligonucleotides, Antisense
  • Protein Kinase Inhibitors
  • Pyrroles
  • Receptors, Fibroblast Growth Factor
  • Receptors, Opioid, kappa
  • SU 5402
  • Morphine
  • Protein Kinase C-alpha