Antinociceptive properties of neurosteroids: a comparison of alphadolone and alphaxalone in potentiation of opioid antinociception.

In this study, we investigated the antinociceptive and sedative effects of the opioids fentanyl, morphine, and oxycodone given alone and in combination with two neurosteroids: alphadolone and alphaxalone. An open-field activity monitor and rotarod apparatus were used to define the sedative effects caused by opioid and neurosteroid compounds given alone intraperitoneally to male Wistar rats. Dose-response curves for antinociception were constructed using only nonsedative doses of these drugs. At nonsedating doses, fentanyl, morphine, and oxycodone all caused dose-dependent tail flick latency (TFL) antinociceptive effects. Because neither neurosteroid altered TFL, electrical current was used as the test to determine doses of neurosteroid that caused antinociceptive effects at nonsedative doses. Alphadolone 10 mg/kg intraperitoneally caused significant antinociceptive effects in the electrical test but alphaxalone did not. All three opioid dose-response curves for TFL antinociception were shifted to the left by coadministration of alphadolone even though alphadolone alone had no effect on TFL. Alphaxalone given alone had no antinociceptive effects at nonsedative doses and it had no effect on opioid antinociception. Neither neurosteroid caused sedative effects when combined with opioids. We conclude that coadministration of alphadolone, but not alphaxalone, with morphine, fentanyl, or oxycodone potentiates antinociception and that this effect is not caused by an increase in sedation.