Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats

Pharmacol Biochem Behav. 2003 Sep;76(2):285-93. doi: 10.1016/j.pbb.2003.08.007.


The effect of the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan (DEX), ketamine (KET), and MK-801 on morphine (MOR)-induced antinociception has been investigated in male and female rats. DEX (7.5, 15, and 30 mg/kg), KET (0.75, 1.5, and 3 mg/kg), and MK-801 (0.075, 0.15, and 0.3 mg/kg) dose-dependently enhanced MOR-induced (3 mg/kg) analgesia in female rats. DEX and KET enhanced the peak effect, whereas MK-801 increased both magnitude and duration of analgesia. DEX also enhanced MOR-induced analgesia in male rats. However, the interaction was of less magnitude in male compared with female rats. The effects of KET and MK-801 on MOR-induced analgesia were negligible in male rats. A 3-mg/kg dose of MOR given alone produced greater analgesia in male than in female rats, but in the presence of NMDA antagonists, MOR elicited similar analgesic responses in both sexes.

Publication types

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

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Area Under Curve
  • Dextromethorphan / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Ketamine / pharmacology
  • Male
  • Morphine / pharmacology*
  • Pain Measurement / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Sex Characteristics


  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • Dizocilpine Maleate
  • Dextromethorphan
  • Morphine