title: The antinociceptive efficacy of morphine-ketamine-magnesium combination is influenced by the order of medication administration.
abstract: OBJECTIVE
  Ketamine and magnesium, both N-methyl-D-aspartate (NMDA) receptor antagonists, enhance the antinociceptive effects of opioid analgesics in different animal models of pain, as well as in humans. This study aimed at evaluating whether magnesium sulphate added to morphine-ketamine combination produces a higher level of analgesia.
  
  
  METHODS
  Analgesic activity was assessed by tail-immersion test in male Wistar rats (200-250 g).
  
  
  RESULTS
  Magnesium sulphate (0.5-60 mg/kg, s.c.) and ketamine (5-30 mg/kg, i.p.) administered alone did not produce any effect. Magnesium sulphate (5 and 60 mg/kg) and ketamine (5 and 30 mg/kg) increased the antinociceptive effect of morphine (2.6 mg/kg, i.p.). Magnesium sulphate (5 mg/kg) increased the antinociceptive effect of the morphine (2.6 mg/kg)-ketamine (2.5 or 5 mg/kg) combination when magnesium sulphate was added to morphine after, and not before ketamine. It is also demonstrated that magnesium sulphate prolonged the duration of the antinociceptive effect of the morphine-ketamine combination. Low dose of morphine (2.6 mg/kg), ketamine (5 mg/kg) and magnesium sulfate (5 mg/kg) given together did not cause motor impairment that could be verified on a rotarod test. The antinociceptive effect of the triple combination was readily antagonized with naloxone (3 mg/kg, s.c.), a nonselective antagonist of opioid receptors, indicating that the effect is mediated via opioid receptors.
  
  
  CONCLUSIONS
  This study revealed that the efficacy of the morphine-ketamine-magnesium sulphate combination in tail-immersion test in rats is influenced by the order of medication administration; a higher level of activity is demonstrated only when ketamine is added to morphine before magnesium sulphate.
authors.affiliation: Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia. svuckovic@med.bg.ac.rs.
authors.forename: S M
authors.initials: SM
authors.lastname: Vučković
authors.forename: K R
authors.initials: KR
authors.lastname: Savić Vujović
authors.forename: D P
authors.initials: DP
authors.lastname: Srebro
authors.forename: B M
authors.initials: BM
authors.lastname: Medić
authors.forename: R M
authors.initials: RM
authors.lastname: Stojanović
authors.forename: C S
authors.initials: CS
authors.lastname: Vučetić
authors.forename: N
authors.initials: N
authors.lastname: Divac
authors.forename: M S
authors.initials: MS
authors.lastname: Prostran
mesh_terms: D000698:Analgesia / Q000379:methods*; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000700:Analgesics; D007649:Ketamine; D009020:Morphine; D008274:Magnesium