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Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats

La kétamine intravasculaire inhibe l’hypersensibilité postchirurgicale par des voies inhibitrices descendantes chez les rats



Systemic ketamine suppresses several types of chronic pain. Although ketamine is used as a general anesthetic agent, the analgesic effect of systemic ketamine for early-stage postoperative pain is not clear. We investigated the efficacy and mechanism of systemic ketamine in a rat model of postoperative pain.


An incision was made in the plantar aspect of the left hind paw in male Wistar rats. Mechanical hypersensitivity was measured using calibrated von Frey filaments. The anti-hypersensitivity effect of systemic or intrathecal administration of ketamine was determined every hour after making the incision. We examined the effects of intrathecal pretreatment with yohimbine, an ?2-adrenoceptor antagonist, and methysergide, a serotonergic receptor antagonist, on the anti-hypersensitivity effect of ketamine. We also examined the effect of systemic ketamine on the c-fos immunoreactivity in the spinal cord.


Systemic administration of ketamine at doses from 3 to 30 mg·kg-1 produced anti-hypersensitivity effects in a dose-dependent manner. Intrathecal administration of ketamine had no effect. There was no significant difference between effects of pre- and post-incisional administration. Intrathecal pretreatment with yohimbine (10 μg) or methysergide (15 μg) completely reversed the anti-hypersensitivity effects of systemic ketamine. Systemic ketamine reduced fos expression in laminae I-II in the dorsal horn of the lumbar spinal cord ipsilateral to the paw incision.


The results suggest that systemic administration of ketamine perioperatively suppresses early-stage postoperative pain via monoaminergic descending inhibitory pathways.



La kétamine intravasculaire supprime certaines douleurs chroniques. Utilisée comme anesthésique général, son effet analgésique pour la douleur postopératoire de stade précoce n’est toutefois pas clair. Nous avons vérifié l’efficacité et le mécanisme de la kétamine intravasculaire chez un modèle rat de douleur postopératoire.


Une incision a été faite dans la partie plantaire de la patte arrière gauche de rats mâles Wistar. L’hypersensibilité mécanique a été mesurée à l’aide de filaments von Frey calibrés. L’effet d’antihypersensibilité de la kétamine vasculaire ou intrathécale a été déterminé toutes les heures après l’incision. Nous avons étudié les effets du prétraitement intrathécal avec yohimbine, un antagoniste des récepteurs ?2-adrénergiques, et méthysergide, un antagoniste des récepteurs sérotoninergiques, sur l’effet anti-hypersensibilité de la kétamine. Nous avons aussi vérifié l’effet de la kétamine intravasculaire sur l’immunoréactivité des c-fos dans la moelle épinière.M


L’administration intravasculaire de kétamine en doses de 3 à 30 mg·kg-1 a produit des effets d’anti-hypersensibilité reliés à la dose. La kétamine intrathécale n’a pas eu d’effet. Il n’y avait pas de différence significative entre les effets de l’administration pré-incisionnelle et post-incisionnelle. Le prétraitement intrathécal avec yohimbine (10 μg) ou méthysergide (15 μg) a complètement renversé les effets d’anti-hypersensibilité de la kétamine intravasculaire. La kétamine intravasculaire a réduit l’expression de fos dans la lame I-II de la corne supérieure de la moelle épinière lombaire homolatérale à l’incision de la patte.


Les résultats suggèrent que l’administration intravasculaire préopératoire de kétamine supprime la douleur postopératoire de stade précoce par des voies inhibitrices descendantes monoaminergiques.


  1. 1

    Stannard CF, Porter GE. Ketamine hydrochloride in the treatment of phantom limb pain. Pain 1993; 54:227–30.

  2. 2

    Eide PK, Jorum E, Stubhaug A, Bremnes J, Breivik H. Relief of post-herpetic neuralgia with the N-methyl-Daspartic acid receptor antagonist ketamine: a doubleblind, cross-over comparison with morphine and placebo. Pain 1994; 58:347–54.

  3. 3

    Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain 1995; 61:215–20.

  4. 4

    Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional pain. Pain 1996; 64:493–501.

  5. 5

    Brennan TJ, Umali EF, Zahn PK. Comparison of preversus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain. Anesthesiology 1997; 87:1517–28.

  6. 6

    Zahn PK, Brennan TJ. Lack of effect of intrathecally administered N-methyl-D-aspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 1998; 88:143–56.

  7. 7

    Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82:111–25.

  8. 8

    Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36:37–41.

  9. 9

    McQuay HJ, Dickenson AH. Implications of nervous system plasticity for pain management (Editorial). Anaesthesia 1990; 45:101–2.

  10. 10

    Woolf CJ, Chong MS. Preemptive analgesia--treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77:362–79.

  11. 11

    Dahl JB, Kehlet H. The value of pre-emptive analgesia in the treatment of postoperative pain. Br J Anaesth 1993; 70:434–9.

  12. 12

    Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses (Editorial). Br J Anaesth 1996; 77:441–4.

  13. 13

    Ren K, Williams GM, Hylden JL, Ruda MA, Dubner R. The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan- induced behavioral hyperalgesia in rats. Eur J Pharmacol 1992; 219:235–43.

  14. 14

    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.

  15. 15

    Lodge D, Johnson KM. Noncompetitive excitatory amino acid receptor antagonists. Trends Pharmacol Sci 1990; 11:81–6.

  16. 16

    Mao J, Price DD, Hayes RL, Lu J, Mayer DJ, Frenk H. Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy. Brain Res 1993; 605:164–8.

  17. 17

    Qian J, Brown SD, Carlton SM. Systemic ketamine attenuates nociceptive behaviors in a rat model of peripheral neuropathy. Brain Res 1996; 715:51–62.

  18. 18

    Klimscha W, Horvath G, Szikszay M, Dobos I, Benedek G. Antinociceptive effect of the S(+)-enantiomer of ketamine on carrageenan hyperalgesia after intrathecal administration in rats. Anesth Analg 1998; 86:561–5.

  19. 19

    Pekoe GM, Smith DJ. The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain 1982; 12:57–73.

  20. 20

    Smith DJ, Perrotti JM, Mansell AL, Monroe PJ. Ketamine analgesia is not related to an opiate action in the periaqueductal gray region of the rat brain. Pain 1985; 21:253–65.

  21. 21

    Nasstrom J, Karlsson U, Post C. Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 1992; 212:21–9.

  22. 22

    Kawamata T, Omote K, Sonoda H, Kawamata M, Namiki A. Analgesic mechanisms of ketamine in the presence and absence of peripheral inflammation. Anesthesiology 2000; 93:520–8.

  23. 23

    Okuda T. Comparison of direct and indirect depressant actions of ketamine on dorsal horn cells in rabbits. Neuropharmacology 1986; 25:433–40.

  24. 24

    Tomemori N, Komatsu T, Shingu K, Urabe N, Seo N, Mori K. Activation of the supraspinal pain inhibition system by ketamine hydrochloride. Acta Anaesthesiol Scand 1981; 25:355–9.

  25. 25

    Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation (Letter). Nature 1987; 328:632–4.

  26. 26

    Harris JA. Using c-fos as a neural marker of pain. Brain Res Bull 1998; 45:1–8.

  27. 27

    Yaksh TL, Rudy TA. Chronic catheterization of the spinal subarachnoid space. Physiol Behav 1976; 17:1031–6.

  28. 28

    Molander C, Xu Q, Grant G. The cytoarchitectonic organization of the spinal cord in the rat. I. The lower thoracic and lumbosacral cord. J Comp Neurol 1984; 230:133–41.

  29. 29

    Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, F and muscarinic receptors. Pharmacol Toxicol 1995; 77:355–9.

  30. 30

    Oatway M, Reid A, Sawynok J. Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg 2003; 97:168–73.

  31. 31

    Holthusen H, Backhaus P, Boeminghaus F, Breulmann M, Lipfert P. Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine, ketamine, and clonidine in patients undergoing transperitoneal tumor nephrectomy. Reg Anesth Pain Med 2002; 27:249–53.

  32. 32

    Dahl V, Ernoe PE, Steen T, Raeder JC, White PF. Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg 2000; 90:1419–22.

  33. 33

    Adam F, Libier M, Oszustowicz T, Lefebvre D, Beal J, Meynadier J. Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg 1999; 89:444–7.

  34. 34

    Huang W, Simpson RK Jr. Ketamine suppresses c-fos expression in dorsal horn neurons after acute constrictive sciatic nerve injury in the rat. Neurosci Lett 1999; 269:165–8.

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Correspondence to Shiro Koizuka or Hideaki Obata or Masayuki Sasaki or Shigeru Saito or Fumio Goto.

Additional information

This study was supported by a Grant-in Aid (No. 12671451) and Department Sources for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

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Koizuka, S., Obata, H., Sasaki, M. et al. Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats. Can J Anesth 52, 498 (2005).

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  • Ketamine
  • Yohimbine
  • Antinociceptive Effect
  • Intrathecal Administration
  • Methysergide