Attenuation of Morphine Tolerance, Withdrawal-Induced Hyperalgesia, and Associated Spinal Inflammatory Immune Responses by Propentofylline in Rats

Neuropsychopharmacology. 2004 Feb;29(2):327-34. doi: 10.1038/sj.npp.1300315.


The activation of glial cells and enhanced proinflammatory cytokine expression at the spinal cord has been implicated in the development of morphine tolerance, and morphine withdrawal-induced hyperalgesia. The present study investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced glial activation and enhanced proinflammatory cytokine levels at the lumbar spinal cord. Moreover, glial activation and enhanced proinflammatory cytokine levels exhibited a temporal correlation with the expression of morphine tolerance and hyperalgesia. Consistently, propentofylline attenuated the development of hyperalgesia and the expression of spinal analgesic tolerance to morphine. The administration of propentofylline during the induction of morphine tolerance also attenuated glial activation and proinflammatory cytokines at the L5 lumbar spinal cord. These results further support the hypothesis that spinal glia and proinflammatory cytokines contribute to the mechanisms of morphine tolerance and associated abnormal pain sensitivity.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Cytokines / genetics
  • Drug Interactions
  • Drug Tolerance / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • Hyperalgesia / genetics
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / immunology
  • Macrophage-1 Antigen / genetics
  • Macrophage-1 Antigen / metabolism
  • Male
  • Morphine / pharmacology
  • Morphine Dependence / drug therapy*
  • Morphine Dependence / genetics
  • Neuroprotective Agents / therapeutic use*
  • Pain Measurement
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Substance Withdrawal Syndrome / complications
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / genetics
  • Xanthines / therapeutic use*


  • Cytokines
  • Glial Fibrillary Acidic Protein
  • Macrophage-1 Antigen
  • Neuroprotective Agents
  • RNA, Messenger
  • Xanthines
  • propentofylline
  • Morphine