This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Miyazaki, Y. Articles by Segawa, H. Search for Related Content PubMed PubMed Citation Articles by Miyazaki, Y. Articles by Segawa, H.

---

GENERAL ARTICLES

Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan

Address correspondence to Takehiko Adachi, MD, Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Address e-mail to adachi @kuhp.kyoto-u.ac.jp.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Xenon (Xe) suppresses wide dynamic range neurons in cat spinal cord to a similar extent as nitrous oxide (N₂O). The antinociceptive action of N₂O involves the descending inhibitory system. To clarify whether the descending inhibitory system is also involved in the antinociceptive action of Xe, we compared the effects of Xe on the spinal cord dorsal horn neurons with those of N₂O in spinal cord-transected cats anesthetized with -chloralose and urethane. We investigated the change of wide dynamic range neuron responses to touch and pinch by both anesthetics. Seventy percent Xe significantly suppressed both touch- and pinch-evoked responses in all 12 neurons. In contrast, 70% N₂O did not show significant suppression in touch- and pinch-evoked responses. These results suggest that the antinociceptive action of Xe might not be mediated by the descending inhibitory system, but instead may be produced by the direct effect on spinal dorsal horn neurons.

Implications: Xenon (Xe) is an inert gas with anesthetic properties. We examined the antinociceptive effects of Xe and nitrous oxide (N₂O) in spinal cord-transected cats. Our studies indicate that Xe has a direct antinociceptive action on the spinal cord that is greater than that of N₂O.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Xenon (Xe) has many interesting characteristics as an inhaled anesthetic and theoretically could be a suitable replacement for nitrous oxide (N₂O) (1). Compared with N₂O, Xe has some advantages; it is nontoxic (2) and nonreactive (1), and its anesthetic potency (minimum alveolar anesthetic concentration 71% in human) (3) is higher than that of N₂O (MAC 104%) (4). Furthermore, Xe has a low blood/gas partition coefficient (0.14) (5). Although high cost is likely to be a major impediment to the regular use of Xe, this may be minimized by using a low-flow or closed-circuit anesthetic system (6,7). Despite its usefulness in clinical settings, the precise mechanism of the antinociceptive effects of Xe is unclear. We compared the effects of Xe on the spinal cord dorsal horn neurons with those of N₂O in spinal cord-intact cats and concluded that Xe and N₂O suppressed the spinal cord dorsal horn neurons to a similar degree (8). The antinociceptive action of N₂O involves the descending inhibitory system from the brainstem (9,10). To clarify whether the descending inhibitory system is also involved in the antinociceptive actions of Xe, we compared the effects of Xe with those of N₂O on the spinal cord dorsal horn neurons in spinal cord-transected cats.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Eight cats of either sex (3.2–5.1 kg) were used in this study, which was approved by our institutional committee on animal research. Cats were first anesthetized by ketamine hydrochloride (20 mg/kg), and atropine sulfate (0.01 mg/kg) was administered IM. The trachea was intubated after IV vecuronium (0.02 mg/kg) administration, and the lungs were mechanically ventilated. Vecuronium was supplemented as required during this experiment. Surgical procedures were performed under halothane (1.0%–2.0%)/100% oxygen anesthesia until spinal cord transection. After spinal cord transection, anesthesia was changed to the IV administration of 3.5 mL/kg -chloralose and urethane solution (-chloralose 10 mg/mL and urethane 125 mg/mL). Ventilation was controlled to keep the end-tidal carbon dioxide at approximately 30 mm Hg. The rectal temperature was maintained at 37.5 ± 0.5°C using a feedback-controlled radiant heater and a blanket (11). The right common carotid artery was cannulated for continuous blood pressure monitoring, and the right external jugular vein was also cannulated for the IV administration of fluid and drugs. Bilateral pneumothorax was performed to minimize the change of intraperitoneal pressure, which causes spinal cord movements during mechanical ventilation. After stereotaxic fixation, the spinal cord was transected at the level of T10–12. After the transection of the spinal cord, a lumbar laminectomy was performed to expose the lumbar enlargement of the spinal cord. Two stainless steel needles were placed 1 cm apart near the superficial peroneal (SP) nerve. A silver ball electrode was placed on the ipsilateral side of the lumbar enlargement, and the compound action potential was recorded during electrical stimulation (10 V, 500 µs, 0.33 Hz) of the SP nerve percutaneously. At the site at which the largest compound action potential was recorded, the dura was locally opened, and the spinal cord was exposed and bathed in warm liquid paraffin. Approximately 2 h after the transection of the spinal cord, extracellular single-unit recordings were made with glass capillary microelectrodes (5–10 M) filled with 2% pontamine sky blue in 0.5 M sodium acetate. The microelectrode was advanced vertically in 10-µm steps using an electronically controlled microstepping drive (ME-71; Narishige, Tokyo, Japan) until a spinal dorsal horn neuron was identified. The neuronal activity from the microelectrode was amplified with the time constant set at 0.01 s. The amplified signals were fed into a memory oscilloscope (VC-11; Nihon Kohden, Tokyo, Japan), a loudspeaker, and a computer through an analog-to-digital converter (Mac-Lab/8S; AD Instruments, Castle Hill, Australia). Neurons were identified by observing the oscilloscope and listening to the sound resulting from peripheral tactile stimulation of a hindpaw. Neuronal impulses were counted using a window discriminator in the computer program and stored on a hard disk.

Wide dynamic range (WDR) neurons were selected by the evoked responses to peripheral stimuli of light touch and pinch. WDR neurons showed increased discharge rate with increasing stimulus intensity and showed maximal responses to noxious stimulation. Touch and pinch stimuli were administered by applying a paintbrush and serrated forceps, respectively, to the center of the receptive field of a hindpaw. To analyze the effects of Xe and N₂O, each stimulus was carefully administered for 10 s with constant strength throughout the experiment. The experiments were performed 30 min after isolation of the WDR neuron.

Concentration of 70% Xe or 70% N₂O in oxygen were administered using a nonrebreathing respiration circuit under mechanical ventilation. Concentrations of oxygen, carbon dioxide, N₂O, and Xe were monitored continuously, with the gas sample obtained at the proximal end of the tracheal tube using an anesthetic gas monitor (Type 1304; Brüel and Kjær, Nærum, Denmark) and/or a Xe gas monitor (Anzai Sogyo, Tokyo, Japan). Both Xe and N₂O were administered for 20 min in a random sequence to the same animal. The interval between Xe and N₂O inhalation was at least 30 min. The responses of WDR neurons evoked by touch and pinch stimuli were recorded every 5 min until 20 min after anesthetic gas administration. The number of neuronal impulses was counted for 10 s during each cutaneous stimulation and was expressed as a percentage of the baseline value, which was the average of two responses before anesthetic gas administration. The response just before anesthetic inhalation served as a control. After the experiments, recording sites were marked by an electrophoretic infiltration of pontamine sky blue from the electrode tip, passing a negative current of 5 µA for 10 min.

After killing the animals with an overdose of thiopental, the spinal cord was removed and fixed with 10% formalin. Serial frozen sections (20 µm thick) were made and stained with cresyl violet or neutral red, and the locations of recording sites were identified.

Results are expressed as mean ± SEM. The statistical significance was calculated using analysis of variance or 2 test. When appropriate, a post hoc comparison was performed using Fisher’s protected least significant difference test. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Twelve WDR neurons were recorded from the spinal dorsal horn in eight cats. In four animals, two neurons were studied bilaterally (one neuron from each side). All of the WDR neurons studied in this experiment were located in the dorsal horn around laminae V (12).

When neuronal responses to mechanical stimuli (touch, pinch) were suppressed to <80% of the baseline response at any time during anesthetic inhalation, the response was defined as being suppressed by the anesthetic gas (8). In touch-evoked responses, all 12 neuronal responses were suppressed by Xe. Of the 12 neurons, 6 were suppressed and 6 were not suppressed by N₂O (Table 1). In pinch-evoked responses, all 12 neuronal responses were also suppressed by Xe. Of the 12 neurons, 4 were suppressed and 8 were not suppressed by N₂O (Table 2). The differences in the number of suppressed neurons between Xe and N₂O were statistically significant in both touch- and pinch-evoked responses (P < 0.05).

View larger version (20K): [in this window] [in a new window]   Figure 1. Examples of typical responses of wide dynamic range neurons to mechanical stimuli (T = touch, P = pinch) that were suppressed by 70% Xe and not suppressed by 70% N2O. a, Before anesthetic administration. b, 20 min after anesthetic administration. c, 20 min after discontinuation of anesthetic administration.

View larger version (18K): [in this window] [in a new window]   Figure 2. Examples of typical responses of wide dynamic range neurons to mechanical stimuli (T = touch, P = pinch) that were suppressed by both 70% Xe and 70% N2O. a, Before anesthetic administration. b, 20 min after anesthetic administration. c, 20 min after discontinuation of anesthetic administration.

View larger version (19K): [in this window] [in a new window]   Figure 3. A, The effect of Xe or N2O on the responses to touch stimuli of wide dynamic range neurons (n = 12). B, The effect of Xe or N2O on the responses to pinch stimuli of wide dynamic range neurons (n = 12). The average of two points recorded before anesthetic administration was used as a baseline (expressed as 100%). All subsequent responses were expressed as a percentage of baseline value. Data are expressed as mean ± SEM. * P < 0.05, significantly different from the control value (just before anesthetic inhalation).

Physiological signs (blood pressure, heart rate) were stable during the experiments. Blood gas analysis results of the Xe and N₂O series were within the physiologic range (Xe versus N₂O: pH 7.39 ± 0.05 vs 7.39 ± 0.03, PaCO₂ 33 ± 4 vs 35 ± 4 mm Hg, PaO₂ 143 ± 25 vs 118 ± 21 mm Hg). There were no significant differences in these variables between Xe and N₂O.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The main findings of this study in spinal cord-transected cats are that all WDR neuronal responses to touch and pinch stimuli were suppressed by Xe. In contrast, N₂O suppressed touch-evoked response in 6 of 12 neurons and suppressed the pinch-evoked response in only 4 of 12 neurons. These results contrast with the results obtained in spinal cord-intact cats, which showed that Xe and N₂O suppressed spinal cord WDR neurons to a similar extent (8). These findings suggest that there are different effects from brain to spinal dorsal horn neurons between Xe and N₂O and that Xe has a suppressive effect on dorsal horn neurons at the spinal cord level.

To clarify the pure pharmacological effects of Xe and N₂O on spinal neurons, we would have to add decerebration to spinalization to perform experiments without anesthesia. In this study, because we planned to compare our results with those of a previous article using the same conditions (8), we chose -chloralose and urethane as basal anesthesia.

The mechanism of the analgesic properties of Xe is still unknown. In particular, there are few articles regarding the antinociceptive action of Xe. Ohara et al. (13) reported that Xe exerted potent antinociceptive action in rats and that its mechanism was not related to opioid receptors or ₂-receptors. It was also reported that the subanesthetic concentration of Xe produced antinociception comparable to that of N₂O in human volunteers (14). The results of this study suggest that the descending inhibitory system is not involved in the antinociceptive actions of Xe.

We recently reported that Xe has a stimulating effect on midbrain reticular neurons, but its potency is weaker than N₂O (15). Activation of the descending inhibitory system from the midbrain by Xe, if it exists, is thus thought to be weaker than that of N₂O. It was also reported that the effects of Xe in the brain were unstable and have both stimulating and suppressive action, especially when light anesthesia is used (15). In contrast to the variable suppressive action of Xe on WDR neurons in spinal cord-intact cats, the constant inhibitory action of Xe to spinal dorsal horn neurons was observed in this experiment. It is possible that the suppressive action on the brain by Xe modified the direct suppressive action of Xe on spinal WDR neurons in spinal cord-intact cats.

Although the antinociceptive properties of N₂O have been known for many years, the mechanism is unclear. Some reports have suggested that the antinociceptive effects of N₂O are mediated through the intrinsic opioid system (16–18), but others have indicated that naloxone does not antagonize the antinociceptive effect of N₂O (19–21). Komatsu et al. (9) reported that the descending inhibitory system is involved in the antinociceptive effects of N₂O. The antinociceptive response of N₂O is mediated by supraspinal opiate and spinal ₂-adrenergic receptors in rats, and a possible mechanism may involve a descending inhibitory noradrenergic pathway that may be activated by opiate receptors in the periaqueductal gray region of the brainstem in rats after exposure to N₂O (10,22). However, as 1/2 (touch) and 1/3 (pinch) of the responses of WDR neurons were inhibited by N₂O in spinal cord-transected cats in this study, there may be some direct suppressive action of N₂O on spinal dorsal horn neurons. Some reports have also indicated that N₂O suppresses spinal cord WDR neurons in spinalized cats (23,24).

In conclusion, the antinociceptive action of Xe is not mediated by the descending inhibitory system, but Xe has a direct suppressive action on spinal dorsal horn neurons that is greater than that of N₂O.

	Acknowledgments

 
This work was supported by Grant in Aid for Scientific Research 10671411 from the Ministry of Education, Science, and Culture of Japan.

Xenon was kindly provided by Nippon Sanso Corporation, Tokyo, Japan.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Kennedy RR, Stokes JW, Downing P. Anaesthesia and the ‘inert’ gases with special reference to xenon. Anaesth Intensive Care 1992;20:66–70.[Web of Science][Medline]
2. Lane GA, Nahrwold ML, Tait AR, et al. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 1980;210:899–901.[Abstract/Free Full Text]
3. Cullen SC, Eger EI, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969;31:305–9.[Web of Science][Medline]
4. Lachmann B, Armbruster S, Schairer W, et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet 1990;335:1413–5.[Web of Science][Medline]
5. Steward A, Allott PR, Cowles AL, Mapleson WW. Solubility coefficients for inhaled anaesthetics for water, oil and biological media. Br J Anaesth 1973;45:282–93.[Free Full Text]
6. Luttropp HH, Rydgren G, Thomasson R, Werner O. A minimal-flow system for xenon anesthesia. Anesthesiology 1991;75:896–902.[Web of Science][Medline]
7. Saito H, Saito M, Goto T, Morita S. Priming of anesthesia circuit with xenon for closed circuit anesthesia. Artif Organs 1997;21:70–2.[Web of Science][Medline]
8. Utsumi J, Adachi T, Miyazaki Y, et al. The effect of xenon on spinal dorsal horn neurons: a comparison with nitrous oxide. Anesth Analg 1997;84:1372–6.[Abstract]
9. Komatsu T, Shingu K, Tomemori N, et al. Nitrous oxide activates the supraspinal pain inhibition system. Acta Anaesthesiol Scand 1981;25:519–22.[Web of Science][Medline]
10. Guo TZ, Poree L, Golden W, et al. Antinociceptive response to nitrous oxide is mediated by supraspinal opiate and spinal alpha 2 adrenergic receptors in the rat. Anesthesiology 1996;85:846–52.[Web of Science][Medline]
11. Herbert D, Mitcell R. Blood gas tensions and acid-base balance in awake cat. J Appl Physiol 1971;30:434–6.[Free Full Text]
12. Rexed B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 1954;100:297–379.[Web of Science][Medline]
13. Ohara A, Mashimo T, Zhang P, et al. A comparative study of the antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg 1997;85:931–6.[Abstract]
14. Yagi M, Mashimo T, Kawaguchi T, Yoshiya I. Analgesic and hypnotic effects of subanaesthetic concentrations of xenon in human volunteers: comparison with nitrous oxide. Br J Anaesth 1995;74:670–3.[Abstract/Free Full Text]
15. Utsumi J, Adachi T, Kurata J, et al. The effects of xenon on central nervous system electrical activity during sevoflurane anaesthesia in cats; a comparison with nitrous oxide. Br J Anaesth 1998;80:628–33.[Abstract/Free Full Text]
16. Berkowitz BA, Finck AD, Ngai SH. Nitrous oxide analgesia: reversal by naloxone and development of tolerance. J Pharmacol Exp Ther 1977;203:539–47.[Abstract/Free Full Text]
17. Gillman MA. Nitrous oxide, an opioid addictive agent: review of the evidence. Am J Med 1986;81:97–102.[Web of Science][Medline]
18. Quock RM, Graczak LM. Influence of narcotic antagonist drugs upon nitrous oxide analgesia in mice. Brain Res 1988;440:35–41.[Web of Science][Medline]
19. Smith RA, Wilson M, Miller KW. Naloxone has no effect on nitrous oxide anesthesia. Anesthesiology 1978;49:6–8.[Web of Science][Medline]
20. Shingu K, Osawa M, Omatsu Y, et al. Naloxone does not antagonize the anesthetic-induced depression of nociceptor-driven spinal cord response in spinal cats. Acta Anaesthesiol Scand 1981;25:526–32.[Web of Science][Medline]
21. Adachi T, Miyazaki Y, Kurata J, et al. Nitrous oxide depresses somatocardiac sympathetic A- and C-reflexes in anesthetized rats. Neurosci Lett 1996;213:57–60.[Web of Science][Medline]
22. Fang F, Guo TZ, Davies MF, Maze M. Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats. Eur J Pharmacol 1997;336:137–41.[Web of Science][Medline]
23. Jong RH, Robles R, Morikawa KI. Actions of halothane and nitrous oxide on dorsal horn neurons ("The Spinal Gate"). Anesthesiology 1969;31:205–12.[Web of Science][Medline]
24. Kitahata LM, Taub A, Sato I. Lamina-specific suppression of dorsal horn unit activity by nitrous oxide and by hyperventilation. J Pharmacol Exp Ther 1971;176:101–8.[Abstract/Free Full Text]

This article has been cited by other articles:

				A. R. Barakat, M. N. Schreiber, J. Flaschar, M. Georgieff, and S. Schraag The Effective Concentration 50 (EC50) for Propofol with 70% Xenon Versus 70% Nitrous Oxide Anesth. Analg., March 1, 2008; 106(3): 823 - 829. [Abstract] [Full Text] [PDF]

				J. F. Antognini, R. J. Atherley, R. C. Dutton, M. J. Laster, E. I. Eger II, and E. Carstens The Excitatory and Inhibitory Effects of Nitrous Oxide on Spinal Neuronal Responses to Noxious Stimulation Anesth. Analg., April 1, 2007; 104(4): 829 - 835. [Abstract] [Full Text] [PDF]

				C. Vahle-Hinz, O. Detsch, C. Hackner, and E. Kochs Corresponding minimum alveolar concentrations of isoflurane and isoflurane/nitrous oxide have divergent effects on thalamic nociceptive signalling Br. J. Anaesth., February 1, 2007; 98(2): 228 - 235. [Abstract] [Full Text] [PDF]

				J. Benrath, C. Kempf, M. Georgieff, and J. Sandkuhler Xenon Blocks the Induction of Synaptic Long-Term Potentiation in Pain Pathways in the Rat Spinal Cord In Vivo Anesth. Analg., January 1, 2007; 104(1): 106 - 111. [Abstract] [Full Text] [PDF]

				R. D. Sanders, N. Patel, M. Hossain, D. Ma, and M. Maze Isoflurane exerts antinociceptive and hypnotic properties at all ages in Fischer rats Br. J. Anaesth., September 1, 2005; 95(3): 393 - 399. [Abstract] [Full Text] [PDF]

				R. D. Sanders, D. Ma, and M. Maze Xenon: elemental anaesthesia in clinical practice Br. Med. Bull., February 22, 2005; 71(1): 115 - 135. [Abstract] [Full Text] [PDF]

				R. D. Sanders, N. P. Franks, and M. Maze Xenon: no stranger to anaesthesia Br. J. Anaesth., November 1, 2003; 91(5): 709 - 717. [Abstract] [Full Text] [PDF]

				T. Fukuda, C. Nishimoto, S. Hisano, M. Miyabe, and H. Toyooka The Analgesic Effect of Xenon on the Formalin Test in Rats: A Comparison with Nitrous Oxide Anesth. Analg., November 1, 2002; 95(5): 1300 - 1304. [Abstract] [Full Text] [PDF]

				D. D. Koblin Urethane: Help or Hindrance? Anesth. Analg., February 1, 2002; 94(2): 241 - 242. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Miyazaki, Y. Articles by Segawa, H. Search for Related Content PubMed PubMed Citation Articles by Miyazaki, Y. Articles by Segawa, H.