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Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain

[La kétamine et un inhibiteur N-acétylaspartylglutamate peptidase exercent une analgésie sur la douleur du cancer des os]

Osamu Saito, MD^*, Tomohiko Aoe, MD^*, Alan Kozikowski, PhD, Jayaprakash Sarva, PhD, Joseph H. Neale, PhD and Tatsuo Yamamoto, MD^*

^* From the Department of Anesthesiology, Graduate School of Medicine, Chiba University, Chiba, Japan; the
Department of Medical Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA; and the
Department of Biology, Georgetown University, Washington, DC, USA.

Address correspondence to: Dr. Tatsuo Yamamoto, Department of Anesthesiology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8670, Japan. Phone: +81-43-226-2155; Fax: +81-43-226-2156; E-mail: yamamotot{at}faculty.chiba-u.jp

Purpose: Not all bone cancer pain can be effectively treated with current therapies. In the present study, the effects of ip administration of -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.

Methods: 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.

Results: Morphine produced a significant analgesic effect (P < 0.001). The -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.

Conclusion: These data suggest that -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.