FIGURE 1.

Study design. The vehicle control, REL-1017, and methadone racemate were administered once daily for 4 days during the study via oral gavage. The dose levels for male rats receiving the REL-1017 were 31.25, 62.5, and 110 mg/kg/day. Female rats received 20, 40, and 80 mg/kg/day. The dose volume for all groups was 5 ml/kg. The groups receiving the vehicle control or methadone racemate were administered in the same manner as the REL-1017 at a dose level of 0 (vehicle control), 31.25 (males), or 20 (females) mg/kg/day. The positive control was administered once on Day 1 via subcutaneous injection at a dose level of 5 (males) or 2 (females) mg/kg at a dose volume of 1 ml/kg. Clinical evaluation was performed daily. The presence of neuronal vacuoles (Olney’s effect) was analyzed by light microscopy in H & E stained brain tissue (2 um thick), on brains obtained 8 h after the administration of the first dose of drugs. Neuronal necrosis and microgliosis were assessed by histological examinations in brains collected 24 h after the administration of the second dose (Day 3 of the study) and 24 h after the administration of the fourth dose (Day 5 of the study).