The development of morphine tolerance and dependence is associated with translocation of protein kinase C

Pain. 1995 Jun;61(3):365-374. doi: 10.1016/0304-3959(95)00023-L.


The development of tolerance to the analgesic effects of morphine as well as morphine dependence were greatly reduced by co-administration with morphine of GM1 ganglioside, a substance reported to block the translocation of protein kinase C (PKC) from cytosol to membrane of neurons. Rats made tolerant to intrathecal administration of morphine showed increased membrane-bound PKC in the superficial layers (laminae I and II) of the spinal cord dorsal horn but not in deeper layers. This increase was prevented by co-administration with morphine of GM1 ganglioside. These results indicate that the translocation and activation of PKC may be a critical step in the development of opiate tolerance and dependence. Modulation of PKC translocation and activation may prove useful for the management of pain and opiate addiction.

Publication types

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

MeSH terms

  • Animals
  • Biological Transport
  • Cell Membrane / drug effects
  • Cell Membrane / enzymology
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Drug Therapy, Combination
  • Drug Tolerance
  • G(M1) Ganglioside / pharmacology*
  • Injections, Spinal
  • Male
  • Morphine / pharmacology*
  • Morphine Dependence / enzymology*
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Spinal Cord / enzymology


  • G(M1) Ganglioside
  • Morphine
  • Protein Kinase C