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Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats

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Abstract

Purpose

Ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist, has been used for the treatment of cancer pain as an analgesic adjuvant to opioids. However, ketamine is known to produce psychotomimetic side effects including cognitive impairments under a high-dose situation, presumably as the result of cortical dysfunction. Here, we investigated whether low-dose ketamine was useful as an analgesic adjuvant to morphine for pain control, focusing on frontocortical function.

Methods

To assess the analgesic effects of ketamine with or without morphine, we performed behavioral and histochemical experiments, using the hot plate test and c-Fos expression analysis in rats. The effect on cortical function was also determined by prepulse inhibition (PPI) of the acoustic startle and evoked potentials in the hippocampal CA1-medial prefrontal cortex (mPFC) synapses as measures of synaptic efficacy.

Results

Coadministration of ketamine as a subanalgesic dose significantly enhanced intraperitoneal morphine-induced antinociceptive response, which was measured as the increased reaction latency in the hot plate test. In addition, the noxious thermal stimulus-induced c-Fos expression in the ventrolateral periaqueductal gray matter was significantly suppressed by concomitant ketamine and morphine. In contrast, the subanalgesic dose of ketamine did not impair PPI and synaptic efficacy in the mPFC.

Conclusion

The present results indicate that the morphine-induced analgesic effect is enhanced by a concomitant subanalgesic dose of ketamine without affecting cortical function. Our findings possibly support the clinical notion that low-dose ketamine as an analgesic adjuvant has therapeutic potential to reduce opioid dosage, thereby improving the quality of life in cancer pain patients.

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References

  1. De Kock MF, Lavand’homme PM. The clinical role of NMDA receptor antagonists for the treatment of postoperative pain. Best Pract Res Clin Anaesthesiol. 2007;21(1):85–98.

    Article  PubMed  Google Scholar 

  2. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004;99(2):482–495.

    Google Scholar 

  3. Salas S, Frasca M, Planchet-Barraud B, Burucoa B, Pascal M, Lapiana JM, Hermet R, Castany C, Ravallec F, Loundou A, Auquier P, Duffaud F, Baumstarck K. Ketamine analgesic effect by continuous intravenous infusion in refractory cancer pain: considerations about the clinical research in palliative care. J Palliat Med. 2012;15(3):287–93.

    PubMed  Google Scholar 

  4. Luginbühl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003;96(3):726–732.

    Google Scholar 

  5. Bell R, Eccleston C, Kalso E. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev 2003(1):CD003351.

  6. Kissin I, Bright CA, Bradley EL. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg. 2000;91(6):1483–8.

    Article  CAS  PubMed  Google Scholar 

  7. Célèrier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92(2):465–72.

    Article  PubMed  Google Scholar 

  8. Laulin JP, Maurette P, Corcuff JB, Rivat C, Chauvin M, Simonnet G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg 2002;94(5):1263–1269.

    Google Scholar 

  9. Rivat C, Laulin JP, Corcuff JB, Célèrier E, Pain L, Simonnet G. Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-d-aspartate receptor antagonist ketamine. Anesthesiology. 2002;96(2):381–91.

    Article  CAS  PubMed  Google Scholar 

  10. Pelissier T, Laurido C, Kramer V, Hernández A, Paeile C. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol. 2003;477(1):23–8.

    Article  CAS  PubMed  Google Scholar 

  11. Mehta AK, Halder S, Khanna N, Tandon OP, Singh UR, Sharma KK. Role of NMDA and opioid receptors in neuropathic pain induced by chronic constriction injury of sciatic nerve in rats. J Basic Clin Physiol Pharmacol. 2012;23(2):49–55.

    Article  CAS  PubMed  Google Scholar 

  12. Tandon OP, Mehta AK, Halder S, Khanna N, Sharma KK. Peripheral interaction of opioid and NMDA receptors in inflammatory pain in rats. Indian J Physiol Pharmacol. 2010;54(1):21–31.

    CAS  PubMed  Google Scholar 

  13. Rodríguez-Muñoz M, Sánchez-Blázquez P, Vicente-Sánchez A, Berrocoso E, Garzón J. The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control. Neuropsychopharmacology. 2012;37(2):338–49.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Morris BJ, Cochran SM, Pratt JA. PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol. 2005;5(1):101–6.

    Article  CAS  PubMed  Google Scholar 

  15. Javitt DC, Rabinowicz E, Silipo G, Dias EC. Encoding vs. retention: differential effects of cue manipulation on working memory performance in schizophrenia. Schizophr Res. 2007;91(1-3):159–68.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Mandillo S, Rinaldi A, Oliverio A, Mele A. Repeated administration of phencyclidine, amphetamine and MK-801 selectively impairs spatial learning in mice: a possible model of psychotomimetic drug-induced cognitive deficits. Behav Pharmacol. 2003;14(7):533–44.

    Article  CAS  PubMed  Google Scholar 

  17. Seillier A, Giuffrida A. Evaluation of NMDA receptor models of schizophrenia: divergences in the behavioral effects of sub-chronic PCP and MK-801. Behav Brain Res. 2009;204(2):410–5.

    Article  CAS  PubMed  Google Scholar 

  18. Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999;20(2):106–18.

    Article  CAS  PubMed  Google Scholar 

  19. Morgan CJ, Riccelli M, Maitland CH, Curran HV. Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users. Drug Alcohol Depend. 2004;75(3):301–8.

    Article  CAS  PubMed  Google Scholar 

  20. Yoshizawa K, Mori T, Ueno T, Nishiwaki M, Shibasaki M, Shimizu N, Narita M, Suzuki T. Involvement of serotonin receptor mechanisms in the discriminative stimulus effects of ketamine in rats. J Pharmacol Sci. 2013;121(3):237–41.

    Article  CAS  PubMed  Google Scholar 

  21. Williams GV, Goldman-Rakic PS. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature (Lond). 1995;376(6541):572–5.

    Article  CAS  Google Scholar 

  22. Kesner RP, Hunt ME, Williams JM, Long JM. Prefrontal cortex and working memory for spatial response, spatial location, and visual object information in the rat. Cereb Cortex. 1996;6(2):311–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ragozzino ME, Kesner RP. The effects of muscarinic cholinergic receptor blockade in the rat anterior cingulate and prelimbic/infralimbic cortices on spatial working memory. Neurobiol Learn Mem. 1998;69(3):241–57.

    Article  CAS  PubMed  Google Scholar 

  24. Volk DW, Pierri JN, Fritschy JM, Auh S, Sampson AR, Lewis DA. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex. 2002;12(10):1063–70.

    Article  PubMed  Google Scholar 

  25. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet. 2003;361(9355):417–9.

    Article  CAS  PubMed  Google Scholar 

  26. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6(4):312–24.

    Article  CAS  PubMed  Google Scholar 

  27. Suzuki Y, Jodo E, Takeuchi S, Niwa S, Kayama Y. Acute administration of phencyclidine induces tonic activation of medial prefrontal cortex neurons in freely moving rats. Neuroscience. 2002;114(3):769–79.

    Article  CAS  PubMed  Google Scholar 

  28. Jackson ME, Homayoun H, Moghaddam B. NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sci USA. 2004;101(22):8467–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Koch M. The neurobiology of startle. Prog Neurobiol. 1999;59(2):107–28.

    Article  CAS  PubMed  Google Scholar 

  30. Kamiyama H, Matsumoto M, Otani S, Kimura SI, Shimamura KI, Ishikawa S, Yanagawa Y, Togashi H. Mechanisms underlying ketamine-induced synaptic depression in rat hippocampus-medial prefrontal cortex pathway. Neuroscience. 2011;177:159–69.

    Article  CAS  PubMed  Google Scholar 

  31. Shikanai H, Yoshida T, Konno K, Yamasaki M, Izumi T, Ohmura Y, Watanabe M, Yoshioka M. Distinct neurochemical and functional properties of GAD67-containing 5-HT neurons in the rat dorsal raphe nucleus. J Neurosci. 2012;32(41):14415–26.

    Article  CAS  PubMed  Google Scholar 

  32. Shikanai H, Izumi T, Matsumoto M, Togashi H, Yamaguchi T, Yoshida T, Yoshioka M. Diazepam-induced increases of synaptic efficacy in the hippocampal-medial prefrontal cortex pathway are associated with its anxiolytic-like effect in rats. J Pharmacol Sci. 2010;114(3):341–6.

    Article  CAS  PubMed  Google Scholar 

  33. Swerdlow NR, Braff DL, Geyer MA. Cross-species studies of sensorimotor gating of the startle reflex. Ann N Y Acad Sci. 1999;877:202–16.

    Article  CAS  PubMed  Google Scholar 

  34. Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001;156(2-3):194–215.

    Article  CAS  Google Scholar 

  35. Kumari V, Gray JA, Geyer MA, ffytche D, Soni W, Mitterschiffthaler MT, Vythelingum GN, Simmons A, Williams SC, Sharma T. Neural correlates of tactile prepulse inhibition: a functional MRI study in normal and schizophrenic subjects. Psychiatry Res. 2003;122(2):99–113.

    Article  PubMed  Google Scholar 

  36. Swerdlow NR, Bakshi V, Waikar M, Taaid N, Geyer MA. Seroquel, clozapine and chlorpromazine restore sensorimotor gating in ketamine-treated rats. Psychopharmacology (Berl). 1998;140(1):75–80.

    Article  CAS  Google Scholar 

  37. Fejgin K, Safonov S, Pålsson E, Wass C, Engel JA, Svensson L, Klamer D. The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice. Psychopharmacology (Berl). 2007;191(2):377–85.

    Article  CAS  Google Scholar 

  38. Cilia J, Hatcher P, Reavill C, Jones DN. Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics. J Psychopharmacol. 2007;21(3):302–11.

    Article  CAS  PubMed  Google Scholar 

  39. Ma J, Leung LS. The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats. Psychopharmacology (Berl). 2007;191(4):961–74.

    Article  CAS  Google Scholar 

  40. Matsumoto M, Shikanai H, Togashi H, Izumi T, Kitta T, Hirata R, Yamaguchi T, Yoshioka M. Characterization of clozapine-induced changes in synaptic plasticity in the hippocampal-mPFC pathway of anesthetized rats. Brain Res. 2008;1195:50–5.

    Article  CAS  PubMed  Google Scholar 

  41. Lovick TA. Integrated activity of cardiovascular and pain regulatory systems: role in adaptive behavioural responses. Prog Neurobiol. 1993;40(5):631–44.

    Article  CAS  PubMed  Google Scholar 

  42. Bandler R, Shipley MT. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci. 1994;17(9):379–89.

    Article  CAS  PubMed  Google Scholar 

  43. Depaulis A, Keay KA, Bandler R. Longitudinal neuronal organization of defensive reactions in the midbrain periaqueductal gray region of the rat. Exp Brain Res. 1992;90(2):307–18.

    Article  CAS  PubMed  Google Scholar 

  44. Yaksh TL, Al-Rodhan NR, Jensen TS. Sites of action of opiates in production of analgesia. Prog Brain Res. 1988;77:371–94.

    Article  CAS  PubMed  Google Scholar 

  45. Curran T, Morgan JI. Fos: an immediate-early transcription factor in neurons. J Neurobiol. 1995;26(3):403–12.

    Article  CAS  PubMed  Google Scholar 

  46. Sánchez-Blázquez P, Rodríguez-Muñoz M, Berrocoso E, Garzón J. The plasticity of the association between mu-opioid receptor and glutamate ionotropic receptor N in opioid analgesic tolerance and neuropathic pain. Eur J Pharmacol. 2013.

  47. Su YL, Huang J, Wang N, Wang JY, Luo F. The effects of morphine on basal neuronal activities in the lateral and medial pain pathways. Neurosci Lett. 2012;525(2):173–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research to H.T. (No. 24590117) from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan and a Grant-in-Aid for the 2012–2013 Research Project of the Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Japan.

Conflict of interest

The authors declare no conflict of interest associated with this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu, 061-0293, Japan

    Hiroki Shikanai, Sachiko Hiraide, Hidekazu Kamiyama, Tsukasa Kiya, Yoshiki Yanagawa, Kei-ichi Shimamura & Hiroko Togashi

  2. Department of Pharmacy, Sapporo City General Hospital, Sapporo, 060-8604, Japan

    Hidekazu Kamiyama & Yoshikazu Goto

  3. Department of Palliative Care, Sapporo City General Hospital, Sapporo, 060-8604, Japan

    Koji Oda & Yukiko Goda

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  1. Hiroki Shikanai
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  2. Sachiko Hiraide
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  3. Hidekazu Kamiyama
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  4. Tsukasa Kiya
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  8. Kei-ichi Shimamura
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  10. Hiroko Togashi
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Corresponding author

Correspondence to Hiroko Togashi.

Additional information

H. Shikanai, S. Hiraide, and H. Kamiyama contributed equally to the study.

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Shikanai, H., Hiraide, S., Kamiyama, H. et al. Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats. J Anesth 28, 390–398 (2014). https://doi.org/10.1007/s00540-013-1722-5

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  • DOI: https://doi.org/10.1007/s00540-013-1722-5

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