The effect of the glycine/NMDA receptor antagonist, (+)-HA966, on morphine dependence in neuropathic rats.
We have previously shown that rats with a painful peripheral neuropathy develop dependence without tolerance after repetitive doses [3mg/kg subcutaneously (s.c.)] of morphine. After injections of a higher dose (10mg/kg s.c.) the animals develop tolerance that can be prevented by the glycine/N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-HA966. This study examined whether (1) dependence develops also after repetitive doses of 10mg/kg of morphine and, if so, (2) whether (+)-HA966 prevents the development of dependence after both the low and the higher morphine pretreatment doses. A 4day pretreatment regimen (post-operative days 12-16) with two daily s.c. injections of saline+saline, saline+morphine (3 or 10mg/kg), (+)-HA966 (2.5 or 5mg/kg)+morphine or (+)-HA966 (5mg/kg)+saline was used, and withdrawal was precipitated by an injection of naloxone [2mg/kg intravenously (i.v.)] at 17h after the last pretreatment injection. Three signs of withdrawal (exploring, writhing, ptosis) appeared after pretreatment with both doses of morphine alone, while other signs (teeth chattering, pilo-erection) developed only after injections at the 3mg/kg dose. One sign (penile grooming/erection) appeared only after the higher morphine dose. Pretreatment with the combination of (+)-HA966 and morphine at 3mg/kg prevented the development of all withdrawal signs. By contrast, except for exploring, (+)-HA966 did not modify the incidence of the withdrawal signs observed after pretreatment with doses of 10mg/kg of morphine. The results suggest that prevention of the development of morphine dependence by glycine/NMDA receptor antagonism depends on the degree of morphine dependence.
Christensen
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Unité de Recherches de Physiopharmacologie du Système Nerveux, INSERM U-161, 2 rue d'Alésia, F-75014, Paris, France. christen@broca.inserm.fr
Guilbaud
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Kayser
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000503:physiopathology / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000009:adverse effects; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D020426:Sciatic Neuropathy; D012965:Sodium Chloride / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control
D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D009294:Narcotics; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D012965:Sodium Chloride; D009020:Morphine; C001369:1-hydroxy-3-amino-2-pyrrolidone