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Anesth Analg 2002;95:1300-1304
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Analgesic Effect of Xenon on the Formalin Test in Rats: A Comparison with Nitrous Oxide

Taeko Fukuda, MD*, Chikako Nishimoto, MD*, Setsuji Hisano, PhD{dagger}, Masayuki Miyabe, MD*, and Hidenori Toyooka, MD*

*Department of Anesthesiology, Institute of Clinical Medicine; and {dagger}Laboratory of Neuroendocrinology, Institute of Basic Medical Sciences, Tsukuba University, Tsukuba-city, Japan

Address correspondence and reprint requests to Taeko Fukuda, MD, Department of Anesthesiology, Institute of Clinical Medicine, Tsukuba University, Tsukuba-city, 305-8575 Japan. Address e-mail to taekof{at}md.tsukuba.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To investigate the analgesic effects of xenon, we performed formalin tests in rats under 0.5 minimum alveolar anesthetic concentration xenon or nitrous oxide and stained the lumbar spinal cord for c-fos (n = 18) and the phosphorylated N-methyl-D-aspartate (NMDA) receptor (n = 24) by using the avidin-biotin-peroxidase method. After 20 min of 79% xenon, 68% nitrous oxide, or 100% inhaled oxygen, 10% formalin (100 µL) was injected into the left rear paw of the animals except for a control group. Nociceptive behavior was observed for 1 h. The rats were killed 2 h after the formalin injection, and the lumbar spinal cord was stained for c-fos or the phosphorylated NMDA receptor immunohistochemically. Animals in the xenon and nitrous oxide groups showed less nociceptive behavior than did the oxygen group. Although the number of c-fos-positive cells in the lumbar spinal cord in the nitrous oxide group was not decreased, that in the xenon group decreased. The number of phosphorylated NMDA receptor-positive cells in the xenon group was significantly less than in the nitrous oxide and oxygen groups. Inhaled xenon suppressed nociceptive behaviors, c-fos expression, and activation of the NMDA receptor during the formalin test in rats. These results confirm that xenon’s analgesic effects result from inhibition of the NMDA receptor.

IMPLICATIONS: Inhaled xenon suppressed nociceptive behaviors, c-fos expression, and activation of the N-methyl-D-aspartate receptor during the formalin test in rats. Xenon’s analgesic effect was speculated to result from the inhibition of the N-methyl-D-aspartate receptor in vivo.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Xenon has attracted interest as an anesthetic despite its expense. It has many advantages, such as nontoxicity, no environmental pollution, and rapid induction and control of anesthesia because of its low blood-gas partition coefficient (1). Several studies have determined which neuronal area or receptor type is involved in xenon’s anesthetic and analgesic effects (2–5). Franks et al. (2) reported that xenon exerts its effects mainly by powerful inhibition of N-methyl-D-aspartate (NMDA) receptors. However, Hapfelmeier et al. (3) reported that xenon increases the efficacy of {gamma}-aminobutyric acid (GABA) at the GABAA receptor and enhances inhibitory GABAergic synaptic transmission. These studies used sophisticated techniques involving cultured cells and/or recombinant receptors. However, there are no published reports describing the investigation of the molecular mechanisms underlying xenon’s anesthetic or analgesic activity in vivo. In the present study, we aimed to investigate the features of xenon’s analgesic effects in a whole animal, and to compare them with that of nitrous oxide.

The expression of c-fos is a good functional marker for identifying the activity of spinal neurons in response to noxious stimulation. However, it is nonspecific and appears in the nociceptive system and antinociceptive system simultaneously. In other words, some portion of nociception-induced spinal c-fos expression is related to antinociceptive processes (6). Therefore, if an anesthetic with analgesic effects increases c-fos expression in the spinal cord, these might be the result either of enhancement of the antinociceptive system or inhibition of synaptic transmission. However, a decrease of c-fos expression might mean that anesthetics directly suppress the nociceptive system or excitatory synaptic transmissions. On the basis of this hypothesis, we performed formalin tests in rats anesthetized with 0.5 minimum alveolar anesthetic concentration (MAC) xenon or nitrous oxide and stained the lumbar spinal cord for c-fos in Experiment 1. Furthermore, in Experiment 2, we performed a double staining of c-fos and the GABA receptor (glutamic acid decarboxylase: a rate-limiting enzyme for GABA synthesis) contingent on whether the c-fos-stained cells showed an increase in Experiment 1, and performed a staining of the phosphorylated NMDA receptor if a decrease of c-fos-stained cells was seen.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All experimental methods were approved by our institutional animal care committee. Forty-two adult male Sprague-Dawley rats weighing 300–350 g were used in Experiments 1 and 2.

For Experiment 1 (c-fos staining), 18 rats were divided into 3 groups: an oxygen group (n = 6), a xenon group (n = 6), and a nitrous oxide group (n = 6). For Experiment 2 (phosphorylated NMDA receptor staining), 24 rats were divided into 4 groups: a control group (n = 6), an oxygen group (n = 6), a xenon group (n = 6), and a nitrous oxide group (n = 6). Because some NMDA receptors are presumably active in normal conditions, a control (no-formalin test and air) group was necessary in addition to the oxygen group.

Formalin Test and Nociceptive Behaviors
For the administration of 0.5 MAC xenon, 0.5 MAC nitrous oxide, or 100% oxygen, the animals were placed in a clear plastic chamber that was connected to a modified minimal-flow system of Luttropp’s circuit (7). Xenon or nitrous oxide concentration in the circuit was feedback controlled by a computer (PC-9821Xs/U7W; NEC, Tokyo, Japan) that delivered inhaled anesthetics or oxygen as needed via magnetic valves. Oxygen, xenon, and nitrous oxide concentrations in the system were measured by using an anesthetic agent monitor (AM-1; Acoma Medical Industry Co., Tokyo, Japan), an exhaled xenon gas monitor (AZ-5000; Anzai Medical Co., Tokyo, Japan), and a Capnomac Ultima (Datex, Helsinki, Finland), respectively.

After inhalation of 0.5 MAC (79%) xenon in oxygen (8), 0.5 MAC (68%) nitrous oxide in oxygen (9), or 100% oxygen for 20 min, 10% formalin (3.7% formaldehyde solution, 100 µL) was injected subcutaneously via a 26-gauge needle into the plantar surface of the left rear paw of the rats in all groups except for the control group.

After the formalin injection, rats were returned to the clear plastic chamber of the modified Luttropp’s circuit and the observation of the formalin test was started immediately. Nociceptive behaviors were rated for 1 h, 6 times for each 5-min period, by using the modified behaviors criteria described by Dubuisson and Dennis (10):1 = normal weight bearing on the injected paw, 2 = limping during locomotion or resting the paw lightly on the floor, and 3 = elevation of the injected paw. Licking and flinching responses were counted simultaneously.

Numeric ratings were calculated by using the following formula:

equation


where T1, T2, and T3 are the durations (s) spent in categories 2 and 3 or licking and flinching responses, respectively, during each observation period of 300 s. All testing was conducted between 9:00 AM and 5:00 PM. The room temperature was maintained at 24° ± 2°C.

Immunohistochemistry Study
The rats were deeply anesthetized with pentobarbital (60 mg/kg intraperitoneally) and killed at 2 h after the formalin injection. The animals were perfused through the ascending aorta with 500 mL of phosphate-buffered saline (PBS) (pH 7.4), followed by 500 mL of 4% paraformaldehyde fixative in a 0.1 M phosphate buffer. After perfusion, the lumbar spinal cord was removed and postfixed in the same fixative for 2 h, after which it was cryoprotected overnight in 20% glycerol in a 0.1 M phosphate buffer. Twelve sections (40 µm) were taken at 400-µm intervals from the whole lumbar spinal cord and processed for c-fos or phosphorylated NMDA receptor immunohistochemistry by using the avidin-biotin-peroxidase method. The tissue sections were washed with a solution of 0.05 M PBS with 3% peroxidase and 0.2% Triton-X (Sigma, St. Louis, MO) and then incubated for 1 h at room temperature in a blocking solution of 3% normal goat serum in 0.05 M PBS with 0.2% Triton-X. The sections were incubated overnight at 4°C in PBS containing a polyclonal primary antibody to Fos (Ab-2, 1:1000 dilution; Oncogene Research Products, San Diego, CA) or a polyclonal primary antibody to the phosphorylated NMDA receptor (phosphor-NR1, 1:4000 dilution; Upstate Biotechnology, Lake Placid, NY) (11). They were then processed according to the usual protocol for the avidin-biotin-peroxidase method (Vectastatin kit; Vector Laboratories, Burlingame, CA), with diaminobenzidine tetrahydrochloride as a chromogen. Every tissue was reacted for the same period and the same reagents were used. We quantified the effect of the inhaled anesthetics on both stainings by counting all labeled cells plotted in the surface (laminae I–III) and deep (laminae IV–VI) dorsal horn. Throughout the data collection phase, the investigators were blinded to the animals’ conditions.

Data were presented as mean ± SD. Statistical analyses were performed by using a two-way analysis of variance for licking behavior and immunohistochemistry study, and the Kruskal-Wallis test was used to analyze the pain scores. After all analysis of variance calculations were performed, post hoc comparisons were made using the Bonferroni test. A probability of < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1
Mean concentrations of xenon and nitrous oxide were 76.6% ± 2.9% and 69.5% ± 1.8%, respectively. Animals in the xenon and nitrous oxide groups showed less nociceptive behavior than those in the oxygen group (Fig. 1). Xenon especially decreased licking responses in the first phase of the formalin test as compared with nitrous oxide. The pain score of the xenon group also showed a significant reduction compared with the oxygen group (Fig. 2).



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  		Figure 1. Time course of the licking frequency (upper graph) and licking duration (lower graph) after formalin injection. Each data point represents the amount of time the animals licked the injected paw during a 5-min observation period. • = Oxygen group, {blacksquare} = nitrous oxide group, and • = xenon group. Error bars are SD. *P < 0.05 versus the oxygen group, #P < 0.05 versus the nitrous oxide group.

 


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  		Figure 2. Time course of the pain score after injection of formalin. • = Oxygen group, {blacksquare} = nitrous oxide group, and • = xenon group. Error bars are SD. *P < 0.05 versus the oxygen group, #P < 0.05 versus the nitrous oxide group.

 
Whereas the c-fos expression of the nitrous oxide group did not decrease, xenon inhalation decreased the c-fos-positive cell number in the dorsal horn of the lumbar spinal cord (Fig. 3).



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  		Figure 3. Quantification of the effect of nitrous oxide or xenon inhalation on the number of c-fos immunoreactive neurons in 12 sections of the spinal cord after formalin injection to the left hind paw. Slashed columns = oxygen group, cross-slashed columns = nitrous oxide group, and solid columns = xenon group. Lt = left, Rt = right. Error bars are SD. *P < 0.05.

 
Experiment 2
Mean concentrations of xenon and nitrous oxide were 77.6% ± 1.9% and 68.5% ± 2.2%, respectively. Nociceptive behavior and the pain score of the xenon and nitrous oxide groups were significantly less than that of the oxygen group in a manner similar to that seen in Experiment 1 (data not shown).

The number of phosphorylated NMDA receptor-positive cells in the control group was approximately 400 per 12 sections and 800 per 12 sections in the superficial and deep lamina of the lumbar dorsal horn, respectively. There was no significant difference in positive cell number between the ipsilateral and contralateral sides in the control group. The phosphorylated NMDA receptor-positive cell number in the xenon group was significantly less than that in the oxygen groups in the ipsilateral superficial lamina. The number of activated NMDA receptor-positive cells in the xenon group was significantly less than those of the oxygen and nitrous oxide groups in the contralateral deep sides. In the oxygen group, the number of activated NMDA receptor-positive cells in the ipsilateral surface lamina was significantly more than that in the contralateral side (Fig. 4).



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  		Figure 4. Quantification of the effect of nitrous oxide or xenon inhalation on the number of phosphorylated N-methyl-D-aspartate (NMDA) receptor-positive cells in 12 sections of the spinal cord after formalin injection to the left hind paw. Open columns = control group, slashed columns = oxygen group, cross-slashed columns = nitrous oxide group, and solid columns = xenon group. Lt = left, Rt = right. Error bars are SD. *P < 0.05

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, xenon and nitrous oxide decreased nociceptive behaviors during the formalin test. Xenon remarkably suppressed licking responses in the first phase. Despite the same MAC, xenon showed more potent analgesic effects than did nitrous oxide at the first phase. Because xenon has been reported to have a strong hypnotic effect (12), and licking involves highly coordinated movements, the extent of licking reactions under xenon might have been modified by the hypnotic effect. Another possibility is that xenon and nitrous oxide differ in regard to their suppressive actions on the central nervous system (CNS) or the spinal cord. Seventy percent xenon was reported to have more potent suppressive actions on CNS reactive capability than does 70% nitrous oxide (13). Miyazaki et al. (14) also reported that 70% xenon has a greater direct antinociceptive action on the spinal cord than 70% nitrous oxide in cats. Because xenon works more potently on the CNS or spinal cord than does nitrous oxide at the same concentrations, a larger concentration of xenon might show a more potent analgesic effect than nitrous oxide. Another possible reason may involve the first phase reaction of formalin test reportedly being caused predominantly by C-fiber activation (15). Reactions to tail-pinch in the MAC determinant are speculated to be caused mainly by A-{delta} fiber activation. The difference of the first phase reaction between the xenon and nitrous oxide groups might be attributable to these characteristic differences between the formalin test and MAC as described above.

General anesthetics are currently considered to act on one or more ligand-gated ion channel families, for example, GABAA, glycine, nACh, 5-HT3, and glutamate receptors (16,17). Among the ligand-gated ion channels, the GABAA and NMDA have been considered as prime targets of volatile anesthetics (18–21). In the present study, xenon inhibited c-fos expression and activation of NMDA receptors by noxious stimulation in the lumbar spinal cord. These results suggest that xenon exerts its analgesic effects mainly via the suppression of NMDA receptor activity. We did not include a xenon group without noxious stimulation in the present study. However, xenon inhalation per se seems not to have changed c-fos expression, because no difference between the oxygen and xenon groups was seen in regard to c-fos cell number on the right side. A large concentration of oxygen might activate the NMDA receptor via reactive oxygen species. However, ipsilateral c-fos expression of the oxygen group does not differ from our past data of air inhalation rats (no-anesthetic 10% formalin group) (22). Therefore, we think that the short-time 100% oxygen inhalation did not affect the NMDA receptor activity.

The double staining of c-fos and the NMDA receptor is desirable for direct assessment of Experiments 1 and 2. However, because NMDA receptors exist on the cell membrane, the cytoplasm of the c-fos-positive neuron is not stained with ordinary NMDA antibodies. Furthermore, because the sensory neurons in the surface lamina of the dorsal horn are small and exist in close proximity to each other, it is impossible to demonstrate the colocalization of c-fos and NMDA receptors precisely by using a confocal microscope. We then used a polyclonal primary antibody to the phosphorylated NMDA receptor. The NMDA receptors in rat spinal cord comprise five subunits (NR1, NR2A, NR2B, NR2C, and NR2D), but only the NR1 subunit is distributed abundantly in the dorsal horn (23). The NMDA receptor (NR1) subunit is phosphorylated by PKC on Ser-890 and -896 and by PKA on Ser-897. We chose the phosphor-NR1 antibody which is selective for the Ser-897 (PKA) site, because activation by PKA is related to noxious stimulation (24,25).

The nitrous oxide group that showed analgesic effects, however, did not decrease either c-fos or phosphorylated NMDA receptor-positive cell number in the dorsal horn. These data show that the main mechanism of the analgesic effects of nitrous oxide is different from that of xenon. Nagata et al. (26) reported that xenon inhibited ketamine-induced c-Fos expression in the brain but nitrous oxide enhanced it. Because nitrous oxide had a tendency to increase the number of c-fos-positive cells in the surface lamina, its analgesic effects might be dependent on inhibitory synaptic transmissions. This speculation is in agreement with previous reports (3,27).

In conclusion, xenon inhalation suppressed nociceptive behaviors, c-fos expression, and activation of the NMDA receptor during the formalin test in rats. Xenon’s analgesic effect was speculated to result from the inhibition of the NMDA receptor.


   Acknowledgments
 
The authors thank Mrs. Yumi Isaka and Mr. Yasuyuki Baba for their technical assistance.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication July 9, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press