Canadian Journal of Anesthesia

, Volume 53, Issue 9, pp 891–898 | Cite as

Regional Anesthesia and Pain

Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain
  • Osamu SaitoEmail author
  • Tomohiko Aoe
  • Alan Kozikowski
  • Jayaprakash Sarva
  • Joseph H. Neale
  • Tatsuo Yamamoto
General Anesthesia



Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects ofip administration of α-2 agonists (dexmedetomidine and clonidine), N-methyl-D-aspartate (NMDA) antagonists (MK-801 and ketamine), an N-acetylaspartylglutamate peptidase inhibitor (ZJ-43), and morphine were examined in a mouse bone cancer pain model.


A bone cancer pain model was produced by injection of murine sarcoma cells into the medullary cavity of the distal femur. To estimate the level of bone cancer pain, the number of pain-related behaviours induced by repeated applications of a von Frey monofilament (0.166 g) to the site of tumour cells implantation was counted. Drugs were administered two weeks after the implantation.


Morphine produced a significant analgesic effect (P < 0.001 ). The α-2 agonists produced analgesic effects (P < 0.001 ) with an efficacy similar to that of morphine, but only at doses that produced severe sedation. MK-801 had only limited analgesic effects, while ketamine produced an analgesic effect (P < 0.001) with the same efficacy as morphine. ZJ-43 (100 mg·kg-1) had a significant analgesic effect (P < 0.05) and the effect of ZJ-43 was antagonized by the selective group II metabotropic glutamate receptor (mGluR) antagonist.


hese data suggest that α-2 agonists produce an analgesic effect only at a sedative dose and that ketamine, but not MK-801, is associated with an analgesic response without overt side effects. The effect of ZJ-43 is mediated by activating group II mGluRs.


Morphine Clonidine Naloxone Analgesic Effect Dexmedetomidine 
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La kétamine et un inhibiteur N-acétylaspartylglutamate peptidase exercent une analgésie sur la douleur du cancer des os



Les douleurs du cancer des os ne sont pas toujours soulagées par les traitements habituels. Dans la présente étude, les effets de l’administration ip d’agonistes α-2 (dexmédétomidine et clonidine), d’antagonistes N-méthyl-D-aspartate (NMDA) (MK-801 et kétamine), d’un inhibiteur de N-acétylaspartylglutamate peptidase (ZJ-43) et de morphine ont été examinés dans un modèle de douleur du cancer des os chez la souris.


Un modèle de douleur du cancer des os a été produit en injectant des cellules de sarcome d’Ewing dans la cavité médullaire distale du fémur. Pour évaluer le niveau de douleur, nous avons calculé le nombre de mouvements reliés à la douleur induite par l’application répétée d’un monofilament von Frey (0,166 g) au site de la tumeur implantée. Les médicaments ont été administrés deux semaines après l’implantation.


La morphine a produit une analgésie significative (P < 0,001). Les agonistes α-2 ont produit une analgésie (P < 0,001) similaire à celle de la morphine, mais seulement à des doses produisant une sédation importante. Le MK-801 a eu un effet limité et la kétamine a produit une analgésie aussi efficace que celle de la morphine (P < 0,001). Le ZJ-43 (100 mg·kg-1) a eu un effet analgésique significatif (P < 0,05) contré par l’antagoniste sélectif des récepteurs de glutamate métabotropique (mGluR) de groupe II.


Les agonistes α-2 produisent un effet analgésique à des doses sédatives seulement et la kétamine, mais non le MK-801, est associée à une réaction analgésique sans effets secondaires apparents. L’effet du ZJ-43 origine de l’activation des mGluR de groupe II.


  1. 1.
    Brescia FJ, Adler D, Gray G, Ryan MA, Cimino J, Mamtani R. Hospitalized advanced cancer patients: a profile. J Pain Symptom Manage 1990; 5:221–7.PubMedCrossRefGoogle Scholar
  2. 2.
    World Health Organization. Cancer Pain Relief, 2nd ed. Geneva: World Health Organization; 1996.Google Scholar
  3. 3.
    Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997; 69:1–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imid-azoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia 1999; 54:146–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003; 97:1108–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Neugebauer V. Metabotropic glutamate receptors- important modulators of nociception and pain behavior. Pain 2002; 98:1–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Yamamoto T, Yaksh TL. Comparison of the antinociceptive effects of pre- and posttreatment with intrathecal morphine and MK801, an NMDA antagonist, on the formalin test in the rat. Anesthesiology 1992; 77:757–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Yamamoto T, Yaksh TL. Spinal pharmacology of thermal hyperesthesia induced by constriction injury of sciatic nerve. Excitatory amino acid antagonists. Pain 1992; 49:121–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Jane DE, Jones PL, Pook PC, Tse HW, Watkins JC. Action of two new antagonists showing selectivity for different sub-types of metabotropic glutamate receptor in the neonatal rat spinal cord. Br J Pharmacol 1994; 112:809–16.PubMedGoogle Scholar
  10. 10.
    Neale JH, Bzdega B, Wroblewska B. N-acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J Neurochem 2000; 75:443–52.PubMedCrossRefGoogle Scholar
  11. 11.
    Neale JH, Olszewski RT, Gehl LM, Wroblewska B, Bzdega T. The neurotransmitter N-acetylaspartyl-glutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol Sci 2005; 26:477–84.PubMedGoogle Scholar
  12. 12.
    Wroblewska B, Wroblewski JT, Pshenichkin S, Surin A, Sullivan SE, Neale JH. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J Neurochem 1997; 69:174–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Yamamoto T, Nozaki-Taguchi N, Sakashita Y, Inagaki T. Inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test. Neuroscience 2001; 102:473–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Yamamoto T, Nozaki-Taguchi N, Sakashita T Spinal N-acetyl-alpha-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat. Brain Res 2001; 909:138–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Carpenter KJ, Sen S, Matthews EA, et al. Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat. Neuropeptides 2003; 37:298–306.PubMedCrossRefGoogle Scholar
  16. 16.
    Yamamoto T, Hirasawa S, Wroblewska B, et al. Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors, ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model. Eur J Neurosci 2004; 20:483–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Schwei MJ, Honore P, Rogers SD, et al. Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain. J Neurosci 1999; 19:10886–97.PubMedGoogle Scholar
  18. 18.
    Vermeirsch H, Nuydens RM, Salmon PL, Meert TF. Bone cancer pain model in mice: evaluation of pain behavior, bone destruction and morphine sensitivity. Pharmacol Biochem Behav 2004; 79:243–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Luger NM, Sabino MA, Schwei MJ, et al. Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs. inflammatory pain. Pain 2002; 99:397–406.PubMedCrossRefGoogle Scholar
  20. 20.
    Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem 2004; 89:876–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Saito O, Aoe T, Yamamoto T. Analgesic effects of nonsteroidal antiinflammatory drugs, acetaminophen, and morphine in a mouse model of bone cancer pain. J Anesth 2005; 19:218–24.PubMedCrossRefGoogle Scholar
  22. 22.
    Cortinez LI, Hsu YW, Sum-Ping ST, et al.Dexmedetomidine pharmacodynamics: Part II. Crossover comparison of the analgesic effect of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology 2004; 101:1077–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Hao JX, Xu XJ. Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered excitatory amino acid receptor antagonists. Pain 1996; 66:279–85.PubMedCrossRefGoogle Scholar
  24. 24.
    Suzuki R, Matthews EA, Dickenson AH. Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 2001; 91:101–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Valivullah HM, Lancaster J, Sweetnam PM, Neale JH. Interactions between N-acetylaspartylglutamate and AMPA, kainate, and NMD A binding sites. J Neurochem 1994; 63:1714–9.PubMedGoogle Scholar
  26. 26.
    Westbrook GL, Mayer ML, Namboodiri MA, Neale JH. High concentrations of N-acetylaspartylglutamate (NAAG) selectively activate NMD A receptors on mouse spinal cord neurons in cell culture. J Neurosci 1986; 6:3385–92.PubMedGoogle Scholar
  27. 27.
    Losi G, Vicini S, Neale J. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons. Neuropharmacology 2004; 46:490–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Bergeron R, Coyle JT, Tsai G, Greene RW. NAAG reduces NMDA receptor current in CA1 hippocampal pyramidal neurons of acute slices and dissociated neurons. Neuropsychopharmacology 2005; 30:7–16.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 2006

Authors and Affiliations

  • Osamu Saito
    • 1
    Email author
  • Tomohiko Aoe
    • 1
  • Alan Kozikowski
    • 2
  • Jayaprakash Sarva
    • 2
  • Joseph H. Neale
    • 3
  • Tatsuo Yamamoto
    • 1
  1. 1.Department of AnesthesiologyGraduate School of Medicine, Chiba UniversityChiba-shiJapan
  2. 2.Department of Medical ChemistryUniversity of Illinois at ChicagoChicagoUSA
  3. 3.Department of BiologyGeorgetown UniversityWashingtonUSA

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