Tolerance to morphine analgesia: evidence for stimulus intensity as a key factor and complete reversal by a glycine site-specific NMDA antagonist.
N-methyl-D-aspartate (NMDA) receptors are widely involved in opioid tolerance. However, it is less clear whether NMDA receptor antagonists reverse already-established tolerance and whether the intensity of the nociceptive stimulus influences morphine tolerance. Three days after implantation of morphine or control pellets the effects of i.v. morphine and pre-administration of saline or (+)-HA966 (a glycine site-specific NMDA receptor antagonist), were studied on the C-fibre reflex elicited by a wide range of stimulus intensities. Morphine both increased the threshold and decreased the slope of the recruitment curve in the "non-tolerant" group of animals. In the "morphine-tolerant" group, the threshold did not change but the gain of the stimulus-response curve decreased. The expression of tolerance to morphine depended on the intensity of the stimulus, being maximal when threshold stimulus intensities were used but considerably less with supra-threshold stimulation. As expected, a single treatment with (+)-HA966, potentiated morphine antinociception in "non-tolerant" rats. However, in "morphine-tolerant" rats (+)-HA966 reversed established morphine tolerance and increased the antinociceptive effects of morphine. These results suggest that (+)-HA966 interfered with expression of morphine tolerance, and offered an encouraging therapeutic approach for pain management in opioid abusers.
Adam
Frédéric
F
Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, 75013 Paris, France.
Bonnet
Francis
F
Le Bars
Daniel
D
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004361:Drug Tolerance; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000503:physiopathology; D017288:Pain Threshold; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D013237:Stereoisomerism; D013497:Sural Nerve / Q000187:drug effects / Q000503:physiopathology
D000701:Analgesics, Opioid; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C001369:1-hydroxy-3-amino-2-pyrrolidone