OBJECTIVE: Alphadolone is a neuroactive steroid that causes antinociception in rats and analgesia in humans by interaction with spinal cord GABA(A) receptors. This study investigated whether alphadolone could affect morphine tolerance. METHODS: Morphine tolerance was induced in rats with subcutaneous sustained release morphine emulsion (M-SR; 125 mg/kg/day). Tolerance was assessed by a blinded observer using tail flick latency (TFL) response to intraperitoneal (ip) injection of immediate release morphine (M-IR 6.25 mg/kg). Fifty-five rats given M-SR were divided into three groups: group A received 1.0 mL subcutaneous emulsion containing vehicle; groups B and C had emulsions injected subcutaneously at the same time as the M-SR (B-250 mg/kg alphadolone; C-alphaxalone 80 mg/kg). RESULTS: Tail flick latency responses (percentage of maximum possible effect [ MPE]) to M-IR were reduced from 89.6 +/- 2.5 pretreatment to 20.3 +/- 4.8 after M-SR treatment (mean +/- SEM; P <0.001, one-way anova). Coadministration of alphadolone emulsion with the M-SR caused no sedation and prevented the occurrence of morphine tolerance. TFL responses to M-IR (6.25 mg/kg) given to morphine tolerant rats were 29 +/- 8 MPE whereas the TFL was 78.6 +/- 9.8 MPE when immediate release alphadolone (10 mg/kg ip) was injected at the same time as M-IR to tolerant rats (P <0.001 one-way anova). Alphaxalone treatment caused sedation and no effects on morphine tolerance. CONCLUSIONS: We conclude that the alphadolone can prevent morphine tolerance and it also restores normal morphine antinociception in rats with established morphine tolerance. The lack of sedation suggests clinical utility in human pain states requiring morphine.