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Anesth Analg 2003;97:436-441
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effects of Isoflurane on Conditioned Inhibition by Dorsal Column Stimulation

Toshiyuki Tobita, MD, Manabu Okamoto, MD, Miyako Shimizu, MD, Tomohiro Yamakura, MD PhD, Hideyoshi Fujihara, MD PhD, Koki Shimoji, MD PhD, FRCA, and Hiroshi Baba, MD PhD

Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Address correspondence and reprint requests to Koki Shimoji, MD, PhD, FRCA, Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahi-machi, Niigata 951-8510, Japan. Address e-mail to koki-shimoji{at}nifty.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Spinal dorsal column stimulation (DCS) modulates sensory transmission, including pain, at the dorsal horn of the cord. However, the mechanisms of DCS modulatory actions and the effects of anesthetics on these mechanisms remain to be investigated. We studied the effects of isoflurane (1.0% and 2.0%) on conditioned inhibition, the amplitude decrease of the spinal cord potentials (SCPs) after a conditioning volley (DCS), in the ketamine-anesthetized rat by recording the sharp negative (N) and slow positive (P) waves of the SCPs evoked by conditioning dorsal column (DC) and testing segmental stimulations. The N wave is believed to be the synchronized activity of the dorsal horn neurons, and the P wave, primary afferent depolarization (PAD), reflecting presynaptic inhibition. The P potentials evoked by either DC or segmental stimulation were depressed by isoflurane, whereas the N waves remained unchanged, indicating that the pharmacological characteristics of these N and P waves are similar between DC-evoked and segmentally evoked SCPs. The conditioned inhibition of segmental N and P waves by DC stimulation was almost completely suppressed by 2.0% isoflurane. The conditioned inhibition of the segmental N wave was not changed by spinal cord transection, whereas the conditioned inhibition of the segmental P wave was decreased. The results indicate that isoflurane depresses presynaptic inhibition without affecting the synchronized activity of dorsal horn neurons and, most profoundly, depresses the conditioned inhibition by DC stimulation of the dorsal horn neurons and PAD. Further, the results indicate that conditioned inhibition by DC stimulation of PAD receives a facilitatory influence from the supraspinal structures, whereas that of the synchronized activity of the dorsal horn neurons does not.

IMPLICATIONS: To investigate how anesthetics affect supraspinal modulation of sensory transmission in the spinal cord, the spinal cord potential (SCP) evoked by dorsal cord stimulation (DCS) and segmentally evoked SCP conditioned by DCS were recorded in intact and spinal cord-transected rats during isoflurane anesthesia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Although influences of the supraspinal structures on sensory transmission in the spinal cord are well documented, the underlying mechanisms remain unclear. For instance, spinal dorsal column stimulation (DCS) modulates sensory transmission, including nociception at the dorsal horn of the spinal cord (1–6). However, the segmental and supraspinal mechanisms of the modulatory actions of DCS have not been investigated (3,5,7). This laboratory has shown, in the rat spinal slice preparation, that substantia gelatinosa neurons in the dorsal horn play an important role in inhibitory sensory modulation by DCS (7). The inhibitory action by antidromic stimulation of primary afferent or by DCS can be demonstrated as a slow positive wave (P) of the spinal cord potential (SCP), similar to the segmentally evoked positive wave (P2) recorded from the dorsal spinal cord surface in animals (8–10) and humans (11–15). The DCS from the posterior epidural space at upper spinal levels produces inhibition of the segmentally evoked negative wave (N1) and potentiation of the P2 wave after a transient inhibition in humans (16). There have been several reports about the effects of anesthetics on segmentally evoked SCPs (8,9,13,17–19). Influences of the supraspinal structures on spinal sensory transmission in the spinal cord can be tested through the investigation of the modulatory actions of DCS by recording segmental SCPs (segSCPs) (16,18), because the N1 and P2 of segSCP are thought to reflect the synchronized activity of dorsal horn neurons and primary afferent depolarization (PAD), respectively (8–13). There are no data, however, on how influences of the supraspinal structures on the sensory transmission in the spinal cord are affected by anesthetics. The main purpose of this study was to examine the effects of isoflurane on these factors, because inhaled anesthetics differentially and concentration-dependently affect spinal neuron activities (20–23). Thus, this study was performed by recording the DCS-evoked SCP and segmentally evoked SCP conditioned by DCS in intact and spinal cord-transected rats during background ketamine anesthesia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Approval of the institutional committee on animal experimentation was obtained, and institutional guidelines for the use of laboratory animals were observed and followed during all aspects of this study. Anesthetic and surgical procedures were similar to those described in our previous studies (17–19). The study was performed on 22 male Sprague-Dawley rats weighing 330–400 g. After an intraperitoneal injection of 120 mg/kg of ketamine hydrochloride with 0.1 mg/kg of atropine sulfate, intratracheal intubation was made through a tracheotomized orifice and connected to a Harvard animal ventilator (Harvard Apparatus, Holliston, MA). The ventilation volume was adjusted to maintain a normal PaCO2 value (35–40 mm Hg). The animals were paralyzed by IV injection of pancuronium bromide (0.2 mg · kg-1 · h-1).

The left femoral artery and vein were cannulated for monitoring of arterial blood pressure and blood gases and continuous infusion of lactated Ringer’s solution (2 mL · kg-1 · h-1) and ketamine (30 mg · kg-1 · h-1). Preliminary experiments had demonstrated that the electroencephalogram and somatosensory evoked potentials from the skull showed no significant changes with stable arterial blood pressure throughout several hours at this infusion rate of ketamine (17–19). A cannula was also inserted into the urinary bladder for monitoring urine volume. Electrocardiogram recorded through stainless needle electrodes, 0.3 mm in diameter, inserted into the subcutaneous tissues of the thorax, was continuously monitored with blood pressure on a polygraph (Nihon Kohden, Ltd., Tokyo, Japan). Rectal temperature was maintained at 37.0°C–38.0°C by means of a homeothermic blanket system manufactured in this laboratory.

Animals were mounted on a stereotactic head frame, and laminectomies were performed on the C2 to C4 and T12 to L2 vertebrae to expose the cervical and lumbar cord. The spinal cord was exposed and covered with prewarmed (37.0°C) mineral oil. Spinal cord transection was performed by an electrical cutter (GT-1; Mizuho Ikakogyo, Tokyo, Japan) at the rostral edge of the laminectomized wound (C2) during the administration of 2.0% isoflurane under background anesthesia with ketamine for studying the effects of supraspinal structures on DCS. At the site of transection, a small amount of 1% lidocaine (0.1–0.2 mL) was injected into the cord to minimize blood pressure changes and possible spinal shock. After waiting for >3 min to confirm the recovery of the segSCP amplitude after spinal cord transection, to avoid the acute effects of spinal injury, DCS was tested.

Flexible ball-tip AgAgCl electrodes 0.5 mm in diameter with 0.3-mm silver leads, made in this laboratory, were placed on the cervical (C4 to C5 vertebral level) and lumbar (L1 to L2 vertebral level) cord surface at midline for DCS and recording of the segSCPs and DCS-evoked SCPs, respectively (Fig. 1A). The reference needle electrodes were inserted into nearby muscles. Two needle electrodes were placed at the left frontal and parietal areas for monitoring electroencephalogram and cortical evoked potentials. The right hindpaw was electrically stimulated by a stimulator (SEN-7103; Nihon Kohden) through an isolation unit at 0.5 Hz with the nonpolarizable needle electrodes inserted subcutaneously into the first and fifth digits. The stimulus intensity for the segSCPs was adjusted approximately to 25 times the threshold strength for the segmental negative cord dorsum potential (N1), and that for DCS was approximately 5 times for the DCS-evoked negative potential. The intervals between the conditioned DCS and testing stimulation to the hindpaw were set at 0–150 ms (Fig. 1). All evoked potentials were amplified (WS681G; Nihon Kohden), averaged (ATAC-1300; Nihon Kohden), and plotted on an x-y plotter. In all experiments, a partial or complete recovery of the wave form of the N1 potential was achieved after the termination of inhalation of isoflurane, even after spinal transection. All electrical background activities with arterial blood pressure were continuously recorded on a polygraph.



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  		Figure 1. The effect of isoflurane on the conditioned inhibition by dorsal column stimulation (DCS) of the segmental spinal cord potential (segSCP). A, Schematic diagram of the experimental arrangements. DCS-evoked SCP = spinal cord potential evoked by DCS. B, Recording trace of segSCP at the L1 level in response to hindpaw (HP) stimulation in the rat with the intact spinal cord under ketamine anesthesia. {blacktriangledown} = points of stimulus. C, Recording trace of the preceding DCS-evoked SCP and subsequent segSCP obtained from the same rat as in (B) under ketamine anesthesia. The conditioned inhibition of the segSCP by DCS at the C5 level, which was delivered 40 ms before HT stimulation is noted. Note that DCS-evoked SCP is similar in waveform to the segmentally evoked SCP. Note also that the segmentally evoked N1, believed to be synchronized activity of the dorsal horn neurons, and P2, indicating primary afferent depolarization (PAD) and reflecting presynaptic inhibition, waves are inhibited by the preceding DCS, which also produces N and P potentials.

 
All evoked responses were averaged (n = 20–32). The averaged evoked responses were recorded consecutively three to five times before (control) and during inhalation of the stepwise increased concentration of isoflurane. Because three to five averaged responses showed almost the same value during each time period in the same animals, the last responses in each concentration of isoflurane were taken for comparison. Arterial blood concentrations of isoflurane were measured by a gas chromatograph (GC-6AM; Shimadzu, Kyoto, Japan) equipped with a blood gas sampler (BGS-1A; Shimadzu). The samples were collected after 20 min of inhalation of 1.0% and 2.0% isoflurane, during which the effects of conditioned DCS were tested.

Percentage changes in the amplitude of the segmental N1 and P2 waves by conditioned DCS in comparison to those caused by unconditioned stimuli were calculated from the averaged responses obtained before and during 15–20 min of inhalation of 1.0% and 2.0% isoflurane. A two-way analysis of variance was performed to identify any significant differences in amplitude changes between conditioned and unconditioned SCPs after isoflurane administration. The analysis was followed by a least significant differences test for multiple comparisons (24) when significant differences were found. Nonparametric Mann-Whitney U-tests (25) were used to calculate the statistical significance from the unconditioned values. A P value <0.05 was considered to be significant.


   Results
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 Abstract
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 Methods
 Results
Discussion
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Hindpaw stimulation produced segSCP composed of the initially positive spike (P1), which sometimes was not visible, followed by an N1 and P2 wave in the dorsal surface of the lumbar enlargement (Fig. 1). The DCS produced a characteristic sequence of potentials: the initially positive spike, which was sometimes not visible, followed by a sharp N and slow P wave. The potentials were similar to the segSCP in wave form and inhibited the subsequent segSCP (Fig. 1). As shown in Table 1, the DCS-evoked P-wave amplitude was decreased by isoflurane similar to that of the segmentally activated P2 wave, which was demonstrated in our previous study (17). In contrast, there were no significant changes in the amplitude of the DCS-evoked N wave, just the same as that of segmental N1 wave (Table 1).


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  		Table 1. Percentage Changes from Control Values Before Isoflurane in Amplitude of Segmental SCP (N1 and P2 Waves) and DCS-Evoked SCP (N and P Waves) at 1.0% and 2.0% Isoflurane
 
The degree of inhibition caused by the conditioned DCS was more prominent in the P2 wave than in the N1 wave (Fig. 2A). Before isoflurane, the inhibitory effects were observed over more than 50 and 100 ms in N1 and P2 waves, respectively, after the conditioning stimulation (Fig. 2A). Isoflurane attenuated and completely blocked the inhibitory effect of the conditioning DCS at 1.0% and 2.0% concentrations, respectively (Fig. 2, B and C). Immediately after the spinal cord was transected at the C2 level during partial recovery from isoflurane anesthesia, the amplitudes of the N and P waves were transiently suppressed but returned to the values before transection within a few minutes. The conditioned inhibition by DCS of the N1 wave was not significantly different from that before the spinal transection (control), whereas the inhibition of the P2 wave was attenuated after the spinal transection (Fig. 2D).



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  		Figure 2. The effects of isoflurane and spinal cord transection on the conditioned inhibition of the segmental spinal cord potential (sgSCP) by dorsal column stimulation (DCS). A, Inhibitions (recovery curves) of the N1 and P2 waves by conditioning stimulation to DCS before the inhalation of isoflurane (control). Abscissa = interval between conditioning (DCS) and testing (hindpaw) stimuli. Ordinate = the percentage ratio of the amplitudes (N1 and P2) with conditioning stimuli to those without conditioning stimuli. B and C, The same recovery curves as in (A) during 1.0% and 2.0% isoflurane, respectively. Note that the inhibitory effects of DCS on both the N1 and P2 waves were attenuated by the drug at 1.0% (B) and completely disappeared at 2.0% (C). D, The same curves 1 h after the transection of the cord at the C2 level and discontinuation of isoflurane. Note a significant attenuation of inhibition on the P2 wave, but not on the N1 wave. Comparisons were made between the amplitudes evoked only by test stimulation and those evoked by conditioning-test stimulations (*P < 0.05; **P < 0.01; ***P < 0.001). Comparisons were also made for the degree of inhibition in terms of amplitude before and after inhalation of isoflurane and before (A) and after (D) spinal cord transection (#P < 0.05; ##P < 0.01; ###P < 0.001). dcSCP = the spinal cord potential evoked by descending volley to the spinal dorsal column; sgN1 = the N1 potential of the segmental spinal cord potential; dcN = the negative(N) potential of dcSCP.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
These results indicate that isoflurane depresses PAD, a reflection of presynaptic inhibition (measured by the segmental P2 and DCS-evoked P potentials), without affecting the synchronized activity of dorsal horn neurons (measured by the segmental N1 and DCS-evoked N potentials), and, most profoundly, depresses the conditioned inhibition by DCS of the dorsal horn neurons and PAD. However, the results also indicate that conditioned inhibition by DCS of PAD receives a facilitatory influence from supraspinal structures (which leads to potentiation of inhibition) (26–31), whereas synchronized activity of the dorsal horn neurons does not (Fig. 2D).

This mechanism may play a role, at least in a part, in the clinical setting for treatment of patients with chronic pain. Further, this feedback inhibitory action provoked by DCS and the segmental inhibitory action were very vulnerable to isoflurane (Fig. 2, B and C), which suggests that combined use of some sedatives or tranquilizers affects the effect of DCS.

The inhibition by DCS of N1 and P2 waves of the segSCP is thought to be brought about through direct antidromic volleys, as well as orthodromically activated feedback volleys via supraspinal structures (4–6,14–19,32–35). In our previous study in awake humans (16), the P2 wave recorded from the posterior epidural space was potentiated after a transient inhibition by DCS. This study, however, demonstrated that the P2 wave was always inhibited by DCS. These different results may be due to the effects of ketamine on supraspinal structures, distinct from the wakeful state (19), because the effects of DCS on the N1 wave in this study are similar to those in awake humans (16) or because of species differences, as demonstrated in heterosegmentally activated P waves (29,31). However, these differences between awake humans and ketamine-anesthetized rats remain to be investigated.

Although the supraspinal nuclei sending inhibitory feedback volleys to the spinal cord (Fig. 1A), which would be affected by isoflurane, were not determined in the present study, several pieces of evidence (17,18,33–35) suggest that isoflurane should affect the DCS-evoked slow P wave, not only at the spinal level but also via the supraspinal structures. The effects of isoflurane on central nervous system functions, such as electroencephalogram (36,37), somatosensory (38–40) or visual (41) evoked potentials, and auditory evoked brainstem responses (42–44), have been studied in animals and humans. However, no attempts have been made to study the influences of supraspinal structures on the conditioned inhibitions by DCS and the interactions with anesthetics.

Several lines of evidence have suggested that spinal dorsal horn neurons, particularly high-threshold neurons, are under the tonic inhibition descending from the brainstem reticular formation (45,46). Spinal transection by surgery and administration of drugs have proved this theory (17–19). Anesthetics are suggested to block the descending inhibitory action and thus modulate neuronal activities in the dorsal horn (17–19). The high vulnerability of the DCS-evoked P wave to isoflurane without a significant change in the DCS-evoked N wave could be explained by this theory. Our data suggesting that the N wave was not affected by isoflurane are conceivable, because the N wave may reflect the synchronized activity of dorsal horn neurons activated by DCS, which is similar to the N1 wave of segSCP activated predominantly by large sensory fibers.

The inhibition by DCS of the segSCP was attenuated by isoflurane (Fig. 2). The inhibitory effect of DCS on sensory information, including pain, has been well documented, although the site and mode of its action have raised several controversial hypotheses (1–6,16). This study did not attempt to deal with this mechanism but, rather, with the effects of isoflurane and supraspinal structures on the inhibition by DCS of the segSCP. The results of spinal cord transection experiments suggest that the inhibition by DCS of the N1 wave takes place at the spinal level, whereas that of the P wave occurs via both the spinal mechanism and the supraspinally activated feedback system.

In addition, the effects of ketamine used as the background anesthetic must be considered, although the drug largely preserves SCPs (19). This study showed that suppression by DCS of the P2 wave (Fig. 2A) was greatly reduced after spinal cord transection (Fig. 2D) without affecting suppression of the N1 wave. Profound blockade by isoflurane of the DCS-conditioned inhibition of the N1 and P2 waves may be partly due to the additional effects of ketamine. Nevertheless, the complete recovery of the inhibitory curve of the N1 wave by DCS after discontinuation of isoflurane inhalation indicates that the ketamine anesthetic was appropriate to maintain spinal cord function even after transection (Fig. 2D) (17,18).

Insignificant effects even by the spinal cord transection on the DCS-induced inhibition of the N1 wave are conceivable, because the segmental N1 wave is thought to reflect the synchronized activity of dorsal horn neurons (including excitatory and inhibitory interneurons) with a relatively short latency, having one or two synapses (8–10). However, the P2 wave is believed to reflect the PAD (which causes the presynaptic inhibition of primary afferent volleys) with a longer latency, having at least two synapses for the activation, and is tonically influenced by the descending inhibitory systems coming from the supraspinal structures (8–10,17,19). Current studies, however, suggest that slow inhibitory postsynaptic potentials (IPSPs), generated in substantia gelatinosa neurons (7), could also be an additional component of the slow P wave. The contribution to the slow IPSPs wave, if any, remains to be investigated. Perhaps the early component of the P (or P2) wave, like that of the dorsal root potential, is dependent on {gamma}-aminobutyric acid-A receptors and the residual component on N-methyl-D-aspartic acid receptors (47).

Both N1 and P2 waves are thought to be produced mostly via activations of the large afferent fibers in their potential configurations, although intense stimulations were applied in this study (29). It also remains to be investigated how much the activities provoked by A {delta} afferent fibers were involved in the later phases of the N1 and P2 waves in this study. However, the inhibitory effects of DCS on spinal interneurons are more prominent in the activities evoked by smaller fibers than by larger fibers (5,7). Therefore, the inhibitory effects of DCS on the N1 and P2 waves would be more pronounced in neuronal activities associated with pain.


   Acknowledgments
 
Supported in part by Grant 10307035 from the Japanese Ministry of Education, Science, Culture and Sports (KS).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 13, 2003.




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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 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press