The effect of the glycine/NMDA receptor antagonist, (+)-HA966, on morphinedependence in neuropathic rats

We have previously shown that rats with a painful peripheral neuropathy dev elop dependence without tolerance after repetitive doses [3 mg/kg subcutane ously (s.c.)] of morphine. After injections of a higher dose (10 mg/kg s.c. ) the animals develop tolerance that can be prevented by the glycine/N-meth yl-D-aspartate (NMDA) receptor antagonist, (+)-HA966. This study examined w hether (1) dependence develops also after repetitive doses of 10 mg/kg of m orphine and, if so, (2) whether (+)-HA966 prevents the development of depen dence after both the low and the higher morphine pretreatment doses. A 4 da y pretreatment regimen (postoperative days 12-16) with two daily s.c. injec tions of saline+saline, saline+morphine (3 or 10 mg/kg), (+)-HA966 (2.5 or 5 mg/kg)+morphine or (+)-HA966 (5 mg/kg)+saline was used, and withdrawal wa s precipitated by an injection of naloxone [2 mg/kg intravenously (i.v.)] a t 17 h after the last pretreatment injection. Three signs of withdrawal (ex ploring, writhing, ptosis) appeared after pretreatment with both doses of m orphine alone, while other signs (teeth chattering, pile-erection) develope d only after injections at the 3 mg/kg dose. One sign (penile grooming/erec tion) appeared only after the higher morphine dose. Pretreatment with the c ombination of (+)-HA966 and morphine at 3 mg/kg prevented the development o f all withdrawal signs. By contrast, except for exploring, (+)-HA966 did no t modify the incidence of the withdrawal signs observed after pretreatment with doses of 10 mg/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. (C) 2000 Elsevier Science Ltd . All rights reserved.