JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yasuda, T.
Right arrow Articles by Matsuki, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yasuda, T.
Right arrow Articles by Matsuki, A.
Related Collections
Right arrow Pharmacology

Anesth Analg 2002;95:952-955
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Tumor Necrosis Factor-{alpha} Reduces Ketamine- and Propofol-Induced Anesthesia Time in Rats

Tadanobu Yasuda, Satoshi Takahashi, and Akitomo Matsuki

Department of Anesthesiology, University of Hirosaki School of Medicine, Japan

Address correspondence and reprint requests to T. Yasuda, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, 5 Zaifu-Cho, Hirosaki 036-8216, Japan. Address e-mail to masuika{at}cc.hirosaki-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Tumor necrosis factor-{alpha} (TNF{alpha}) is a crucial neuromodulator in the brain. TNF{alpha} is involved in many physiological events including pain response and sleep. However, the interactions between TNF{alpha} and anesthetics have not been elucidated yet. In the present study, we investigated the effects of four intracerebroventricular (ICV) doses (1, 10, and 100 pg, and 1 ng) and two intraperitoneal (IP) doses (10 and 100 ng) of TNF{alpha} on anesthesia time of ketamine (100 mg/kg IP) and propofol (80 mg/kg IP) in rats. All ICV doses of TNF{alpha} reduced anesthesia time of ketamine and propofol compared with the saline ICV group (ketamine control group, 45.4 ± 6.5 min; propofol control group, 43.5 ± 11.0 min). The maximum effect was obtained after the ICV injection of 10 pg of TNF{alpha} (76% and 54% of ketamine and propofol control groups, respectively). Anesthesia time of ketamine or propofol was also decreased by IP injection of TNF{alpha} in a dose-dependent manner. Injection of 100 ng of TNF{alpha} IP reduced anesthesia time of ketamine and propofol by 67% and 64% of each control group, respectively. These data show that TNF{alpha} can modulate the anesthesia time of IV anesthetics, suggesting that anesthetic requirements might be altered in the presence of cerebral or systemic inflammation.

IMPLICATIONS: Tumor necrosis factor alpha (TNF{alpha}) regulates many physiological events in the brain. We investigated the effects of TNF{alpha} on anesthesia time in rats. Both central and peripheral administration of TNF{alpha} decreased anesthesia time induced by ketamine and propofol.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Tumor necrosis factor-{alpha} (TNF{alpha}) is a proinflammatory cytokine that is released from activated macrophages and lymphocytes. TNF{alpha} stimulates a number of chemotactic factors that enhance the recruitment of inflammatory cells. Considerable evidence shows that TNF{alpha} is not only an inflammatory mediator, but also a crucial neuromodulator in the central nervous system (CNS) (1). Neurons, astroglia, and microglia can produce TNF{alpha}. Both TNF{alpha} messenger RNA and TNF receptor messenger RNA are also expressed in the normal brain (1). Brain TNF{alpha} is involved in the regulation of many physiological events including sleep/wake cycle, body temperature, pain response, and food intake (2–4). Further, peripheral TNF{alpha} can also affect the CNS. For instance, intraperitoneal (IP) injection of TNF{alpha} induces hyperalgesia in rats (5). The systemic administration of TNF{alpha} increases the time spent in non-rapid eye movement sleep in many species (3,6). Although TNF{alpha} is not likely to cross the brain-blood barrier (BBB), peripheral signals of TNF{alpha} are thought to convey to the brain via vagal afferents or circumventricular sites lacking BBB (6).

TNF{alpha} activates nuclear factor-{kappa}B (NF{kappa}B), a transcriptional factor that is involved in the expression of nitric oxide synthase (NOS)-2 and cycloxygenase-2, resulting in the increased production of nitric oxide (NO) and prostaglandins (3,7). These mediators are thought to be downstream events responsible for the CNS effects of TNF{alpha}.

Ketamine and propofol are now widely used IV anesthetics. Although the CNS mechanisms of these anesthetics have not been fully elucidated, N-methyl-D-aspartate (NMDA) receptor antagonism (8) and {gamma}-aminobutyric acid (GABA)A receptor stimulation (9) might be responsible for the mechanism for ketamine and propofol anesthesia, respectively. It was reported that anesthetic requirements of these anesthetics were affected by the activity of NOS (10). Accumulated evidence suggests that NO modulates NMDA and GABAA receptor pathways (11). Thus, the neuromodulators that affect NO in the CNS might alter the potency of these anesthetics; however, there is no study to investigate the interactions between exogenous TNF{alpha} and anesthesia time. We report here that subhypnotic doses of TNF{alpha} shortened ketamine- and propofol-induced anesthesia time in rats.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This experiment was approved by the Committee of Ethics on Animal Experiments in Hirosaki University, School of Medicine, Japan. Rat recombinant TNF{alpha} was purchased from Peprotech (Rocky Hill, NJ). It was dissolved in physiologic saline solution (PSS) and stored at -80°C until the experiments. Ketamine and propofol were obtained from Sankyo Co, Ltd (Tokyo, Japan) and AstraZeneka (Osaka, Japan), respectively.

Male Sprague-Dawley rats (Japan Clea, Kyoto, Japan) weighing 300–350 g were used. They were kept on a 12:12-h light-dark cycle (lights on at 8 AM) at 22°C ± 1°C ambient temperature with 60%–70% humidity. They had free access to water and food. Under pentobarbital anesthesia (40 mg/kg IP), a 26-gauge stainless steel cannula was stereotaxically placed in the left lateral ventricle with the following coordinate (A: -0.8 mm, L: 1.5 mm, V: 3.5–4.0 mm) from the bregma for the rats in Experiment I. This cannula was attached to the skull by using acrylic dental cement. After the surgery, rats were singly housed at least 7 days before the experiment. Further, on the fourth day after the surgery, the patency of the intracerebroventricular (ICV) guide cannula was verified by the ICV injection of 40 ng of angiotensin II in 4 µL of PSS (12). If the cannula was correctly placed in the left lateral ventricle, the rat showed a water-drinking response immediately. The rats that did not show a drinking response were excluded from Experiment I. On the experimental day, each rat was placed in a clear plastic chamber for 30 min before the experiment for the adaptation to the experimental environment.

Experiment I: Effects of ICV Administration of TNF{alpha} on Ketamine- and Propofol-Induced Anesthesia Time
The rats were randomly allocated to five groups. The rats in the control group (n = 11) received 5 µL of PSS ICV for 1 min. For the rats in the other four groups, four different doses of TNF{alpha} (1 pg [n = 11], 10 pg [n = 11], 100 pg [n = 11], or 1 ng [n = 10] in 5 µL of PSS) were injected ICV for 1 min. A 100-mg/kg dose of ketamine was injected IP 10 min after the ICV injection, and then anesthetic time was measured in each rat. Anesthetic time was defined as the time between the loss of righting reflex and recovery of the ability to perform three successive righting tests, as previously described (13). For the other five groups (n = 9 in each group), a similar experiment was performed for propofol anesthesia (80 mg/kg IP).

Experiment II: Effects of IP Administration of TNF{alpha} on Ketamine- and Propofol-Induced Anesthesia Time
In Experiment II, each group consisted of 10 rats. Each rat received one of three doses of TNF{alpha} (0, 10, and 100 ng) IP. Ketamine 100 mg/kg was injected IP 10 min after the TNF{alpha} injection. For another 30 rats, a similar experiment was performed for propofol anesthesia (80 mg/kg IP). After the injection of the anesthetic, anesthesia time was measured.

One-way analysis of variance (ANOVA) was used for statistical analysis. Dunnett’s test was used as a post hoc test for the comparison with the control group. A significant level of P < 0.05 was accepted. All data were expressed mean ± SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The results in Experiment I are shown in Figure 1. The 2 middle doses of TNF{alpha} (10 pg and 100 pg) significantly shortened ketamine-induced anesthesia time (control, 45.4 ± 6.5 min; 10 pg, 34.3 ± 4.1 min; and 100 pg, 34.3 ± 9.0 min; ANOVA; F4,49 = 4.07; P < 0.01). The smallest and largest dose of TNF{alpha} also reduced ketamine-induced anesthesia time but failed to reach significance. In the propofol group, similar results were obtained. All doses of TNF{alpha} reduced propofol-induced anesthesia time (control, 43.5 ± 11.0 min; 1 pg, 29.2 ± 9.7 min; 10 pg, 25.3 ± 8.3 min; 100 pg, 26.4 ± 8.2 min; and 1 ng, 31.6 ± 6.6 min; ANOVA; F4,40 = 6.34; P < 0.0005). The 2 middle doses of TNF{alpha} showed the strongest effects. In Experiment II, the IP administration of TNF{alpha} decreased ketamine-induced anesthesia time in a dose-dependent manner (control, 37.1 ± 4.5 min; 10 ng, 28.9 ± 7.1 min; and 100 ng, 24.8 ± 6.7 min; ANOVA; F2,27 = 10.08; P < 0.0005) (Fig. 2). The changes induced by these two doses were significant. Similar effects were also observed in the propofol group (control, 32.5 ± 3.8 min; 10 ng, 24.9 ± 5.5 min; and 100 ng, 20.9 ± 5.9 min; ANOVA; F2,27 = 13.06; P < 0.0001)(Fig. 2).



View larger version (24K):
[in this window]
[in a new window]
  		Figure 1. Effects of intracerebroventricular (ICV) injection of tumor necrosis factor-{alpha} (TNF{alpha}) on anesthesia time of ketamine and propofol. Values are mean ± SD. *P < 0.05 versus physiologic saline solution (PSS) group.

 


View larger version (23K):
[in this window]
[in a new window]
  		Figure 2. Effects of intraperitoneal (IP) injection of tumor necrosis factor-{alpha} (TNF{alpha}) on anesthesia time of ketamine and propofol. Values are mean ± SD. *P < 0.05 versus physiologic saline solution (PSS) group.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The main finding of the present study is that TNF{alpha} reduced anesthesia time induced by ketamine and propofol in rats. These effects were observed even after the IP injection, suggesting that both central and peripheral TNF{alpha} can affect the anesthetics. The doses of ketamine and propofol in the present study are compatible with our previous study (13). Further, the doses of TNF{alpha} are also compatible with the other study (4). Because large doses of TNF{alpha} have a hypnotic property (more than 100 ng for ICV dose and more than 50 µg/kg for IP dose), in the present study, we administered much smaller doses of TNF{alpha} than those in other studies producing a hypnotic state (2,6). Recently, Nader et al. (14) reported that TNF{alpha} normally exists in the cerebrospinal fluid and plasma at the concentration of picogram per milliliter range in humans. TNF{alpha} concentration in the cerebrospinal fluid increases after surgery by surgical stress as well as during an inflammatory state (14). Thus, the doses of TNF{alpha} in the present study are likely to be found in various clinical settings.

In Experiment I, the inhibitory effect of TNF{alpha} showed a U shaped dose-response. This result is not beyond our expectation because biological effects of cytokines do not always show a linear dose-response. For instance, Oka et al (4) reported that an ICV injection of TNF{alpha} has a hyperalgesic effect in rats, and it also shows a similar U shaped dose-response. Although the mechanism responsible for this effect is unclear, it might be caused by co-existence of different biological cascades activated by TNF{alpha}. It is speculated that some of them are associated with an antagonistic effect for anesthesia and the others an agonistic effect.

TNF{alpha} interacts with a complex network of other mediators. The interaction with interleukin-1 (IL-1) is essential for its action. After TNF{alpha} binds to the 55-kDa receptor, TNF{alpha} activates NF{kappa}B, which is involved in the regulation of many neuromodulators including IL-1, NO, and prostaglandins (1,7). It was reported that TNF{alpha} induces IL-1 (15). Some CNS effects of TNF{alpha} are antagonized by the inhibition of IL-l. For instance, the TNF{alpha}-induced hyperalgesic effect is suppressed by the pretreatment of IL-1 receptor antagonist (4,5). Further, the TNF{alpha}-induced hypnotic effect was inhibited by the pretreatment of anti-IL-l antibodies (16). TNF{alpha} is thought to have a synergic interaction with IL-1 because IL-1 also activates NF{kappa}B, resulting in the amplification of inflammatory reactions. Thus, some CNS effects of TNF{alpha} might be partly mediated by the endogenous release of IL-1.

Although the mechanism responsible for the antianesthetic action of TNF{alpha} remains unclear, several mechanisms are possible. At first, subhypnotic doses of TNF{alpha} may activate brain arousal systems. For example, prostaglandin E2 (PGE2) is a humoral mediator that maintains wakefulness. Matsumura et al. (17,18) demonstrated that continuous ICV infusion of PGE2 or microinjection of PGE2 into the preoptic area (POA) inhibits sleep in rats. TNF{alpha} activates PGE2 production (15). Thus, it is possible that TNF{alpha} induced an overproduction of PGE2 and thereby facilitated wakefulness in the present study. An alternative possible mechanism involves NO. TNF{alpha} and IL-1 can activate NF{kappa}B and thereby induce NOS-2, resulting in enhanced production of NO in the brain (7). NO is a neurotransmitter to enhance sleep in many species (19,20). However, evidence suggests that the NO-cyclic guanosine monophosphate (cGMP) signaling pathway has an opposite effect on anesthetic action. Tonner et al. (10) reported that inhibition of NOS activity enhanced anesthetic potency of ketamine, propofol, and thiopental. Furthermore, IV anesthetics including ketamine, etomidate, midazolam, and thiopental decrease NOS activity in the rat brain (21). Propofol, ketamine, and midazolam suppress cGMP formation in the rat brain (22). The brain NO pathway is linked with NMDA and GABAA receptor, and GABAA receptor activity is decreased by the activation of the NO-cGMP pathway. Moreover, activation of the NMDA receptor stimulates the NO-cGMP pathway as a downstream event (11). Because the anesthetic action of ketamine and propofol are thought to be caused by a NMDA receptor antagonism and a GABAA receptor stimulation, respectively, it is relevant that activation of NOS-2 induced by TNF{alpha} reduces the anesthesia time of ketamine and propofol.

In the present study, peripheral administration of TNF{alpha} was also effective to antagonize the anesthesia time of ketamine and propofol. Because the brain is the effective site of the anesthetic, TNF{alpha} injected IP is likely to have some interaction with those anesthetics within the brain. Although an active transport system of TNF{alpha} in the brain has been reported (23), it is questionable whether it is sufficient to elucidate some biological responses. Alternatively, TNF{alpha} can access the brain via a circumventricular area lacking BBB. For example, the neurons in the organum vasculosum laminae terminals are sensitive to cytokines. The organum vasculosum laminae terminals is located in the midline of the POA lacking BBB, including an increase in PGE2 in the POA (24). The other mechanism would involve a neuronal pathway. Thus, vagal afferents are important pathways for cytokine-to-brain communication. The peripheral signal of TNF{alpha} conveys to the nucleus tractus solitarius via vagal afferents. Subdiaphragmatic vagotomy blocks some CNS effects induced by peripherally-administered TNF{alpha} including conditioned taste aversion (25), hyperalgesia (5), and hypnotic responses (6). Thus, peripheral administration of TNF{alpha} can affect the anesthetic potency in the brain by the humoral or neural mechanism.

In conclusion, we reported that TNF{alpha} reduced the duration of ketamine and propofol anesthesia. This study provides the first evidence that TNF{alpha} can interact with the anesthetic state even in subhypnotic doses, suggesting that the appropriate dose of anesthetics might be altered in the presence of CNS and systemic inflammation.


   Acknowledgments
 
Supported, in part, by Grant-in-Aid for Scientific Research No.13557128 and 12671449 from the Ministry of Education, Science and Culture, Japan.

We thank Dr. James M. Krueger (Department of VCAPP, Washington State University) for his helpful suggestion in writing the paper.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Pan W, Zadina JE, Kastin AJ, et al. Tumor necrosis factor-{alpha}: a neuromodulator in the CNS. Neurosci Biobehav Rev 1997; 21: 603–13.[ISI][Medline]
  2. Kapás L, Hong L, Krueger JM, et al. Somnogenic, pyrogenic, and anorectic activities of tumor necrosis factor-{alpha} and TNF-{alpha} fragments. Am J Physiol 1992; 263: R708–1515.[Abstract/Free Full Text]
  3. Krueger JM, Obál F Jr, Fang J. Humoral regulation of physiological sleep: cytokines and GHRH. J Sleep Res 1999; 8 (suppl 1): 53–9.
  4. Oka T, Wakugawa Y, Hosoi M, et al. Intracerebroventricular injection of tumor necrosis factor-{alpha} induces thermal hyperalgesia in rats. Neuroimmunomodulation 1996; 3: 135–40.[ISI][Medline]
  5. Watkins LR, Goehler LE, Maier SF, et al. Mechanisms of tumor necrosis factor-{alpha} (TNF-{alpha}) hyperalgesia. Brain Res 1995; 692: 244–50.[ISI][Medline]
  6. Kubota T, Fang J, Krueger JM, et al. Vagotomy attenuates tumor necrosis factor-{alpha} induced sleep and EEG {delta}- activity in rats. Am J Physiol 2001; 280: R1213–20.
  7. O'Neill LA, Kaltschmidt C. NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci 1997; 20: 252–8.[ISI][Medline]
  8. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth 1996; 77: 441–4.[Free Full Text]
  9. Concas A, Santoro G, Biggio G, et al. The action of the general anesthetic propofol on GABAA receptors. Adv Biochem Psychopharmacol 1992; 47: 349–63.[ISI][Medline]
  10. Tonner PH, Scholz J, Schlamp N, et al. Inhibition of nitric oxide synthase decreases anesthetic requirements of intravenous anesthetics in Xenopus laevis. Anesthesiology 1997; 87: 1479–85.[ISI][Medline]
  11. Johns RA. Nitric oxide, cyclic guanosine monophosphate, and the anesthetic state. Anesthesiology 1996; 85: 457–9.[ISI][Medline]
  12. Kubota T, Kushikata T, Krueger JM, et al. A nuclear factor-{kappa}B (NF-{kappa}B) inhibitor peptide inhibits spontaneous and interleukin-1ß-induced sleep. Am J Physiol 2000; 279: R404–13.[Abstract/Free Full Text]
  13. Kubota T, Hirota K, Matsuki A, et al. Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. Psychopharmacology (Berl) 1999;146:335–8.
  14. Nader ND, Ignatowski TA, Kurek CJ, et al. Clonidine suppresses plasma and cerebrospinal fluid concentration of TNF-{alpha} during the perioperative period. Anesth Analg 2001; 93: 363–9.[Abstract/Free Full Text]
  15. Bachwich PR, Chensue SW, Kunkel SL, et al. Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun 1986; 136: 94–101.[ISI][Medline]
  16. De Sarro G, Gareri P, Rotiroti D, et al. Comparative, behavioral and electrocortical effects of tumor necrosis factor-{alpha} and interleukin-1 microinjected into the locus coeruleus of rat. Life Sci 1997; 60: 555–64.[ISI][Medline]
  17. Matsumura H, Goh Y, Hayaishi O, et al. Awaking effect of PGE2 microinjected into the preoptic area of rats. Brain Res 1998; 444: 265–72.
  18. Matsumura H, Honda K, Hayaishi O, et al. Awaking effect of prostaglandin E2 in freely moving rats. Brain Res 1989; 481: 242–9.[ISI][Medline]
  19. Datta S, Patterson EH, Siwek DF. Endogenous and exogenous nitric oxide in the pedunculopontine tegmentum induces sleep. Synapse 1997; 27: 69–78.[ISI][Medline]
  20. Kapás L, Krueger JM. Nitric oxide donors SIN-1 and SNAP promote nonrapid-eye-movement sleep in rats. Brain Res Bull 1996; 41: 293–8.[ISI][Medline]
  21. Galley HF, Webster NR. Brain nitric oxide synthase activity is decreased by intravenous anesthetics. Anesth Analg 1996; 83: 591–4.[Abstract]
  22. Miyawaki I, Nakamura K, Mori K, et al. Suppression of cyclic guanosine monophosphate formation in rat cerebellar slices by propofol, ketamine and midazolam. Can J Anaesth 1997; 44: 1301–7.[Abstract/Free Full Text]
  23. Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor {alpha} is transported from blood to brain in the mouse. J Neuroimmunol 1993; 47: 169–76.[ISI][Medline]
  24. Shibata M. Hypothalamic neuronal responses to cytokines. Yale J Biol Med 1990; 63: 147–56.[ISI][Medline]
  25. Goehler LE, Busch CR, Watkins LR, et al. Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication. Neurosci Lett 1995; 185: 163–6.[ISI][Medline]
Accepted for publication May 31, 2002.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
J. S. Kroin, A. Buvanendran, D. E. Watts, C. Saha, and K. J. Tuman
Upregulation of cerebrospinal fluid and peripheral prostaglandin E2 in a rat postoperative pain model.
Anesth. Analg., August 1, 2006; 103(2): 334 - 43, table of contents.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yasuda, T.
Right arrow Articles by Matsuki, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yasuda, T.
Right arrow Articles by Matsuki, A.
Related Collections
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press