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

Eur J Pharmacol. 2007 Apr 30;561(1-3):46-53. doi: 10.1016/j.ejphar.2007.01.023. Epub 2007 Jan 23.

Abstract

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 microg of morphine, 5 microg of nimodipine, 5 microg each of morphine and nimodipine, 10 microg of morphine, 10 microg of nimodipine, 10 microg morphine with 5 microg nimodipine and 5 microg of morphine with 10 microg 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 microg) than in morphine (5 microg) treated group (by 30 min). Though earlier in onset, 5 microg nimodipine produced transient antinociception, which was significantly higher than saline treated controls for the initial 30 min only. Morphine (5 microg) 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 microg 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 microg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 mug 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / adverse effects
  • Calcium Channel Blockers / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Routes
  • Drug Synergism
  • Injections, Spinal
  • Male
  • Morphine / administration & dosage
  • Morphine / adverse effects
  • Morphine / pharmacology*
  • Motor Activity / drug effects
  • Naloxone
  • Narcotic Antagonists
  • Nimodipine / administration & dosage
  • Nimodipine / adverse effects
  • Nimodipine / pharmacology*
  • Pain / drug therapy*
  • Pain Measurement
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, mu / drug effects
  • Tail

Substances

  • Analgesics, Opioid
  • Calcium Channel Blockers
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Naloxone
  • Nimodipine
  • Morphine