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Antinociceptive tolerance to the mu-opioid agonist DAMGO is dose-dependently reduced by MK-801 in rats

J Mao1, D D Price, J Lu

  • 1Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.

Neuroscience Letters
|August 26, 1998
PubMed

Insights

Spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptor interactions contribute to antinociceptive tolerance. Blocking NMDA receptors with MK-801 prevented tolerance to the mu-opioid agonist DAMGO.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Morphine's interaction with spinal cord mu-opioid and N-methyl-D-aspartate (NMDA) receptors is implicated in antinociceptive tolerance.
  • Morphine acts on mu-receptors but also other opioid receptor subtypes.

Purpose of the Study:

  • To investigate the role of spinal cord mu-opioid and NMDA receptor interactions in antinociceptive tolerance.
  • To test the hypothesis using a selective mu-opioid agonist, D-Ala2-N-Me-Phe4,Gly-ol5-enkephalin (DAMGO).

Main Methods:

  • Repeated intrathecal (i.t.) administration of DAMGO (6 microg, twice daily for 7 days) in rats.
  • Assessment of antinociceptive tolerance using the tail-flick test on Day 8.
  • Co-administration of DAMGO with NMDA receptor antagonist MK-801 to evaluate prevention of tolerance.

Main Results:

  • Repeated DAMGO administration induced a significant rightward shift (approx. 17-fold) in the dose-response curve, indicating antinociceptive tolerance.
  • Co-administration of MK-801 with DAMGO effectively prevented this induced antinociceptive tolerance.
  • A lower dose range of MK-801 also prevented tolerance to a lower dose of DAMGO.

Conclusions:

  • The results support a model of opioid tolerance involving spinal cord interactions between mu-opioid and NMDA receptors.
  • This highlights the cellular and intracellular mechanisms underlying opioid tolerance.

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