Intrathecal co-administration of morphine and nimodipine produces higher antinociceptive effect by synergistic interaction as evident by injecting different doses of each drug in rats

Earlier, we reported that morphine–nimodipine combination produces significantly higher antinociception after intrathecal but not after systemic administration in mice. Different doses of morphine and nimodipine (5 μg of morphine, 5 μg of nimodipine, 5 μg each of morphine and nimodipine, 10 μg of morphine, 10 μg of nimodipine, 10 μg morphine with 5 μg nimodipine and 5 μg of morphine with 10 μg of nimodipine) were now injected intrathecally in Wistar rats to further characterise this antinociceptive effect. The acute antinociceptive effect was measured by the tail-flick test between 15 min to 7 h. The onset of maximum antinociception (100% MPE) was earlier (by 15 min) in nimodipine (5 μg) than in morphine (5 μg) treated group (by 30 min). Though earlier in onset, 5 μg nimodipine produced transient antinociception, which was significantly higher than saline treated controls for the initial 30 min only. Morphine (5 μg) produced significantly higher antinociception between 15 min to 3:30 h in comparison to control animals. However, co-administration of both morphine and nimodipine led to significantly higher antinociception than morphine alone at 4:00 h and also between 5:00 to 6:30 h. Interestingly, the combined antinociceptive action of morphine and nimodipine was not significantly different from 10 μg of morphine, which indicated synergistic interaction. Naloxone (5 mg/kg) could reverse this antinociceptive effect of morphine–nimodipine combination though it failed to reverse nimodipine (5 μg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 μg did not increase antinociception except between 6:30–7:00 h. No obvious side effect was noted after administration of either morphine or nimodipine or both.