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 [3 mg/kg subcutaneously (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-methyl-D-aspartate (NMDA) receptor antagonist, (+)-HA966. This study examined whether (1) dependence develops also after repetitive doses of 10 mg/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 4 day pretreatment regimen (postoperative days 12-16) with two daily s.c. injections 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 was precipitated by an injection of naloxone [2 mg/kg intravenously (i.v.)] at 17 h 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, pile-erection) developed only after injections at the 3 mg/kg dose. One sign (penile grooming/erection) appeared only after the higher morphine dose. Pretreatment with the combination of (+)-HA966 and morphine at 3 mg/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 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.