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Anesth Analg 1999;88:414
© 1999 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Pre- Versus Postinjury Effects of Intravenous GABAergic Anesthetics on Formalin-Induced Fos Immunoreactivity in the Rat Spinal Cord

Ian Gilron, MD, MSc, FRCP(C)*, Rémi Quirion, PhD{dagger}, and Terence J. Coderre, PhD{ddagger},§,||

*National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland; {dagger}Douglas Hospital Research Centre, Verdun, Québec, Canada and {ddagger}Department of Psychology, McGill University; §Pain Mechanisms Research Laboratory, Clinical Research Institute of Montréal; and ||Département de Médecine, Université de Montréal, Montreal, Quebec, Canada

Address correspondence and reprint requests to Ian Gilron, MD, MSc, FRCP(C), Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 10, Room 3C-434, 9000 Rockville Pike, Bethesda, MD 20892. Address e-mail to igilron{at}yoda.nidr.nih.gov


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We evaluated the suppression of spinal Fos-like immunoreactivity (FLI) by IV anesthetics in the rat formalin model. Preformalin injection (1.5% subcutaneously) treatment groups included IV saline controls and three IV GABAergic anesthetic groups (pentobarbital 20 mg/kg, propofol 10 mg/kg, or alphaxalone 1.5 mg/kg; n = 12 per group). After perfusion 2 h postformalin, spinal cords were dissected, sliced at 30 µm, and processed by immunoperoxidase staining with an antibody against the Fos protein. Quantification and determination of the laminar distribution of Fos-labeled nuclei were performed at the L4-5 spinal level ipsilateral to formalin injection. Drug groups demonstrating FLI suppression were comparatively studied in a 5-min postformalin treatment group. Pentobarbital pretreatment failed to suppress FLI. However, significant reductions (percent decrease) of FLI were observed with propofol (63%) and alphaxalone (30%) compared with saline controls. Pre- versus postformalin comparison studies showed that propofol, but not alphaxalone, suppressed FLI more effectively when given preformalin. Given the observed inconsistencies between this study of Fos expression and our previous behavioral study, it is questionable whether anesthetic modulation of noxious stimulus-induced FLI parallels that of behavioral responses.

Implications: In this study, we examined whether IV general anesthetics (propofol, alphaxalone, and pentobarbital) prevent injury-induced spinal cord changes. We measured spinal Fos protein after rats received anesthetics before versus after a formalin injection. Fos inhibition patterns were inconsistent with behavioral studies of these anesthetics, suggesting that Fos inhibition does not always correlate with behavioral analgesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Preclinical research on noxious stimulus-induced neuroplasticity has reinforced the concept of preemptive analgesia (1). Comparisons of pre- versus postinjury analgesic interventions have been made using the formalin test as a model for studying central sensitization (2). The role of anesthetics in nociceptive processing has long been of interest in anesthesiology. IV anesthetics that interact with the GABAA receptor include, broadly: barbiturates (e.g., pentobarbital), steroid anesthetics (e.g., alphaxalone), and propofol (3). These anesthetics enhance GABAA receptor transmission by binding to different sites on this receptor (4). Attempts to understand nociceptive modulation by GABAergic anesthetics have produced conflicting impressions. Clinically, barbiturates in subanesthetic doses have hyperalgesic effects, presumably due to suppression of descending antinociceptive pathways (5). In support of this, pharmacokinetic behavioral studies (6) have demonstrated hyperalgesia in rats with subanesthetic serum concentrations of thiopental but analgesia as thiopental concentrations approach anesthetic levels. At the spinal level, in vitro electrophysiological evidence (7) shows that propofol, pentobarbital, and thiopental depress nociceptive transmission in the rat spinal cord. Other effects of GABAergic anesthetics include analgesia after the intracerebroventricular administration of the steroid anesthetic 3a-hydroxy-5a-pregnan-20-one (8) and decreased dorsal horn neuronal activity after the IV administration of another steroid anesthetic, a combination of alphaxalone and alphaladone (9).

The effects of IV general anesthetics on sensitization have been examined in previous rat formalin studies. Although O’Connor and Abram (10) demonstrated analgesia with propofol in the late phase of the formalin test, thiopental had no analgesic effect. Conversely, Goto et al. (11) reported preemptive analgesia with pentobarbital, but propofol had no analgesic effect. Data from our laboratory, which further conflict with the above, demonstrate preemptive analgesia with alphaxalone, whereas pentobarbital and propofol showed no analgesic effect (12). Some of these discrepancies may be explained by differences in drug doses and methods of behavioral measurement (13,14). However, the apparent nonlinear relationship between anesthetic serum concentrations and analgesic effects, as well as conflicting spinal versus supraspinal interactions, indicates that pain behavior alone is an inadequate measure of anesthetic suppression of noxious stimulus-induced spinal sensitization.

In 1987, the spinal expression of Fos protein, an immediate early gene product, was demonstrated in response to both noxious and nonnoxious sensory stimulation (15). Many studies have since measured spinal Fos in different pain models, such as the intraplantar injection of formalin (16), carrageenan (17), and Freund’s adjuvant (18). Noxious stimulus-induced Fos expression is interpreted as signifying neuronal metabolic activation and is related to other events underlying central sensitization (19). Pharmacological Fos suppression has been studied with opioids such as morphine (20) and D-Ala-2, N-Methyl-Phe-4-Gly-Ol-5 Enkephalin (DAMGO) (16), as well as N-methyl-D-aspartic acid (NMDA) receptor antagonists, such as MK-801 (21).

Studies evaluating Fos suppression with general anesthetics include work by Sun et al. (22), which reported failure of Fos suppression with halothane, nitrous oxide, or a combination of the two, and the work of Hagihira et al. (23), which demonstrated suppression with both these drugs. Yi and Barr (24) reported Fos suppression with acepromazine and methoxyflurane, but not with a ketamine/xylazine mixture. Such studies question the ability of anesthetics to prevent sensitization and, perhaps, suggest that this should be one clinical objective of an anesthetic technique (25,26). Although these studies have mostly examined volatile anesthetics, little is known about IV anesthetics in this regard.

Thus, the purpose of this study was to evaluate the suppression of spinal Fos-like immunoreactivity (FLI) by anesthetic doses of IV GABAergic anesthetics and to compare these suppressive effects between conditions of pre- versus postnoxious stimulus anesthetic administration.

The utility of this study is: 1) to measure the contribution of spinal drug action in explaining the analgesic effects of anesthetics that have both spinal and supraspinal sites of action and 2) to identify anesthetics that contribute to a prolonged analgesic effect when used intraoperatively in the clinical setting. Such a prolonged effect may result in decreased postoperative pain and/or analgesic requirement in postsurgical patients.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experimental protocols were approved by the Institutional Animal Care Committee of the Clinical Research Institute of Montreal in accordance with the guidelines of the Canadian Council for Animal Care. The animals studied were male Long-Evans rats (Charles River, St. Constant, Québec, Canada) weighing 250–350 g, housed in groups of four, with free access to food and water, and maintained on a 12-h light/dark cycle.

Anesthetics and saline vehicles were administered (1–2 mL/kg) by tail vein injection over a period of 30–60 s. After immobilizing the awake rat in a cloth restrainer, the tail vein was cannulated with a 25-gauge butterfly infusion set primed with injectate. IV cannulation, as noted by free backflow of blood into the tubing, was followed by syringe attachment and injectate administration. Successful injection was confirmed by again observing blood backflow on disconnecting the syringe after injection. Rats receiving an incomplete injection because of needle dislodgment were excluded from the study.

To more specifically study the effects on sensitization (rather than effects on ongoing peripheral nociception), rats were injected with 50 µL of 1.5% formalin (a relatively low concentration compared with 5%, which is more traditionally used) subcutaneously into the plantar surface of one hindpaw using a tuberculin syringe and a 25-gauge needle.

The largest doses of alphaxalone, pentobarbital, and propofol used in our previous study (12) were tested to evaluate the suppression of formalin-induced FLI. The dose and timing of the anesthetics used in our pretreatment protocol were determined in pilot studies with the objective of producing "clinical" anesthesia (i.e., loss of righting reflex) for the duration of phase I (0–5 min) of the formalin test. Thus, in the preformalin groups, rats received IV anesthetics 1 min (alphaxalone and propofol) or 10 min (pentobarbital) before the formalin injection. Rats in the vehicle control group received 0.9% saline IV 1 min before the formalin injection. To evaluate the basal level of Fos expression in unstimulated rats, a separate group included rats that received neither formalin nor IV injections.

To evaluate preemptive effects, a preinjury group was compared with a postinjury group only when Fos suppression was observed in the preinjury group. In the postinjury groups, anesthetics were administered 5 min after formalin injection.

Rats were killed 2 h after the formalin injection in the following manner. Anesthesia with 60 mg/kg of pentobarbital intraperitoneally was followed by sternotomy, transcardiac aortic needle cannulation, and perfusion with 200 mL of phosphate-buffered saline (PBS), then by 500 mL of 4% paraformaldehyde/PBS. The lumbar spinal cord was subsequently dissected by laminectomy, postfixed for 4 h in 4% paraformaldehyde/PBS, and cryoprotected for 12 h in 30% sucrose/PBS. Extracted spinal cords were labeled with a 1-mm lateral, longitudinal incision contralateral to the side of formalin injection, then freeze-mounted in embedding matrix and sliced into 30-µm sections.

Tissue sections were washed in Tris-buffered saline (TBS) and incubated at 4°C for 48 h with a rabbit polyclonal antibody directed against residues 4–17 of the N-terminal region of Fos peptide (Ab-5 solution, diluted to 1:75,000; Oncogene Science, Boston, MA) in 0.05% Triton X-100 with 3% normal goat serum. The sections were then rinsed in TBS and incubated at 4°C for 1 h with a biotinylated goat anti-rabbit immunoglobin G (Vectastain; Vector Laboratories, Burlingame, CA) in 0.05% Triton X-100 with 3% normal goat serum. Sections were then rinsed in TBS and incubated at 4°C for 2 h in an avidin-biotin peroxidase complex (Vectastain). The sections were then rinsed in TBS, 50 mM Tris buffer, and rinsed for 10 min in 0.05% 3,3' diaminobenzidine (DAB) in 50 mM Tris. The sections were then incubated for 10 min in DAB/Tris with 0.01% H2O2 added to catalyze the DAB and 8% NiCl2 to color the DAB chromagen blue-black. The sections were then rinsed in TBS to stop the reaction and were subsequently mounted on slides, dehydrated, and coverslipped for image analysis. Negative control experiments were conducted with tissue sections from the formalin-injected saline controls by omitting the primary antibody from the above protocol and by adding 2 µg/mL N-terminal Fos peptide (Oncogene Science) to the primary antibody incubation solution. Neither of these controls resulted in any expression of FLI.

Sections from L4-5 segmental levels were evaluated, and quantification of FLI neurons was performed in the spinal gray matter ipsilateral to the formalin injection. Tissue sections were first examined using dark-field microscopy to determine the segmental level and gray matter landmarks according to the method of Molander et al. (28). To study the laminar distribution, four regions were defined: superficial dorsal horn (laminae I-II), nucleus proprius (laminae III-IV), neck of the dorsal horn (laminae V-VI), and the ventral gray (laminae VII-X). Sections were then examined with bright-field microscopy at x6.3 magnification. Each section image was digitized using the Micro-Computer Imaging Device (MCID-Imaging Research Inc., St. Catherines, Ontario, Canada) from which high-resolution printouts were produced and from which FLI neurons were quantified. A predetermined coding system labeled each section image on its underside to blind the investigator to treatment group.

Statistical analysis was performed to compare FLI (in percentage of control, calculated as the number of FLI neurons for a given slice divided by mean total number of FLI neurons for the control group x 100%) over each of the specified laminar regions in different treatment groups by using two-way repeated-measures analysis of variance (ANOVA). Any treatment group by laminar group interactions was further explored using simple main effects analysis. Post hoc comparisons were performed using Newman-Keuls multiple comparisons when indicated.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Formalin-Induced Spinal FLI
FLI neurons were distinctly recognized by their densely stained blue-black nuclei and sparsely stained cytoplasm. Figure 1 shows tissue sections from the saline control (formalin) and basal (no formalin) FLI groups. Table 1 shows FLI neuron counts, and Figure 2 shows spinal FLI expressed as a percentage of control across laminar regions for the saline control and basal FLI groups. ANOVA revealed main effects of treatment group (F[lsqb]1, 22] = 310.9, P < 0.01) and laminar distribution (F[3, 66] = 77.8, P < 0.01), as well as a group by region interaction (F[3, 66] = 74.1, P < 0.01). Newman-Keuls post hoc comparisons demonstrated increases in FLI in all laminar groups of saline controls (P < 0.05) compared with the basal FLI group.


Figure 1
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  		Figure 1. Representative saline control (formalin) and basal (no formalin) Fos-like immunoreactivity (FLI) lumbar spinal cord sections. A, Saline control 2 h after subcutaneous hindpaw formalin injection; the arrow points to the incision made contralateral to side of the formalin injection. B, Basal FLI (no formalin injection); scale bar indicates 50 µm. C, Magnification of section from A illustrating characteristic distribution of Fos-labeled neurons. D, Magnification of section from B; scale bar indicates 50 µm.

 

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  		Table 1. Basal FLI and FLI for the Study Groups
 

Figure 2
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  		Figure 2. The effect of anesthetic pretreatment on formalin-induced Fos-like immunoreactivity (FLI). Histogram plotting FLI (expressed as percentage of control) across laminar regions for basal FLI, saline control, and anesthetic pretreatment groups (n = 12 per group). *P < 0.05, Newman-Keuls post hoc comparison with control. **P < 0.05, Newman-Keuls post hoc comparison of the saline control only with basal FLI. Error bars represent SEM.

 
Preformalin Anesthetic Administration
Table 1 shows FLI neuron counts, and Figure 2 shows FLI (percent control) across laminar regions for the groups receiving preformalin administration of saline, pentobarbital, propofol, and alphaxalone. ANOVA revealed the main effects of treatment group (F[3, 44] = 8.9, P < 0.01) and laminar distribution (F[3, 132] = 84.8, P < 0.01), as well as a group by region interaction (F[9, 132] = 5.3, P < 0.01). Newman-Keuls post hoc comparisons demonstrated reductions in FLI in laminae I-II of the propofol- (P < 0.05) and alphaxalone- (P < 0.05) treated groups compared with the saline control. Propofol also produced reductions in FLI in laminae III-IV and V-VI (P < 0.05). Compared with the control, pentobarbital had no effect on Fos-immunoreactivity anywhere in the spinal gray matter (P > 0.05). Compared with the mean total number of FLI neurons in the control group, reductions in FLI were observed in the propofol (63%) and alphaxalone (30%) groups.

Pre- Versus Postformalin Propofol
ANOVA revealed the main effects of treatment group (F[2, 33] = 28.6, P < 0.01) and laminar distribution (F[3, 99] = 113.0, P < 0.01), as well as a group by region interaction (F[6, 99] = 11.2, P < 0.01). Newman-Keuls post hoc comparisons demonstrated reductions in FLI in laminae I-II of both pre- and postformalin propofol compared with control (P < 0.05), yet preformalin propofol was lower than postformalin propofol (P < 0.05). Furthermore, a reduction of FLI was observed in laminae III-IV and V-VI of the preformalin (P < 0.05), but not the postformalin, propofol group (P > 0.05). Given a more intense suppression in the pre- versus the postformalin group, this demonstrates the preemptive suppression of FLI by propofol (Figure 3).


Figure 3
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  		Figure 3. The effect of pre- versus postformalin propofol administration on formalin-induced Fos-like immunoreactivity (FLI). Histogram plotting FLI (expressed as percentage of control) across laminar groups for the control, preformalin, and postformalin propofol groups (n = 12 per group). *P < 0.05, Newman-Keuls post hoc comparison with control. +P < 0.05, Newman-Keuls post hoc comparison with the preformalin propofol group (prop pre). Error bars represent SEM.

 
Pre- Versus Postformalin Alphaxalone
ANOVA revealed no main effects of treatment group (F[2,33] = 2.6, P > 0.05), a main effect of laminar distribution (F[3, 99] = 134.6, P < 0.01), and a group by region interaction (F[6, 99] = 3.5, P < 0.01). Newman-Keuls post hoc comparisons demonstrated reductions in FLI in laminae I-II of both pre- and postformalin alphaxalone compared with control (P < 0.05), but there was no difference between the pre- and postformalin groups (Figure 4).


Figure 4
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  		Figure 4. The effect of pre- versus postformalin alphaxalone administration on formalin-induced Fos-like immunoreactivity (FLI). Histogram plotting FLI (expressed as percentage of control) across laminar groups for the control, preformalin, and postformalin alphaxalone groups (n = 12/group). * P < 0.05, Newman-Keuls post hoc comparison with control. Error bars represent SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Of the three GABAergic IV anesthetics studied, propofol and alphaxalone suppressed noxious stimulus-induced FLI, whereas pentobarbital failed to do so. The study of pentobarbital was initially motivated by the intent in our previous study (12): 1) to replicate the findings of Goto et al. (11) using our behavioral rating methods and 2) to compare these results with those of alphaxalone (12). Although the 20-mg/kg dose used with Sprague-Dawley rats in the study by Goto et al. (11) was subhypnotic in our Long-Evans rats, trials of larger doses demonstrated delayed anesthetic recovery, thus precluding their utility for phase II behavioral evaluation (12). We thus proceeded to study pentobarbital at 20 mg/kg for behavioral comparison with alphaxalone and propofol and to evaluate its effect on noxious stimulus-induced FLI under internally comparable conditions. With these constraints in mind, using a suboptimal dose is one possible explanation for the lack of antinociceptive effect of pentobarbital in our previous behavioral study (12) and in the current study of FLI suppression.

In the present study, propofol, but not alphaxalone, inhibited noxious stimulus-induced FLI by 63%. Although pentobarbital, propofol, and alphaxalone act at the GABAA receptor, they also modulate various other receptors and ion channels (7,29). Some effects of propofol distinct from its GABAergic mechanism that may explain the finding of FLI suppression (where other GABAergic anesthetics failed to do so) include the inhibition of NMDA receptor channels (30) and of calcium ion currents in primary afferent neurons (31).

Although the finding of FLI suppression with propofol is consistent with the electrophysiological work of Jewett et al. (7) and may explain the behavioral analgesia with propofol reported by O’Connor and Abram (10), it is not necessarily consistent with the lack of analgesic effect of propofol observed by Goto et al. (11) or in our behavioral study (12). To explain the lack of analgesia with propofol, one might postulate that anesthetic suppression of antinociceptive descending pathways may offset spinally mediated analgesic effects. However, previous studies have demonstrated increased noxious stimulus-induced FLI after interventions that prevent descending inhibition, such as lesions of the dorsolateral funiculus (32). Therefore, if the suppression of descending inhibition is to be the primary explanation for lack of analgesic effect with propofol, it would not be consistent with our observed finding of decreased spinal FLI. An alternative hypothesis is that although propofol decreases the number of FLI spinal neurons, disproportionately more inhibitory interneurons may be suppressed. In support of this hypothesis, the observed association between propofol use and seizures in certain circumstances (33) may suggest that propofol can produce a disproportionate suppression of inhibitory neurons.

Finally, alphaxalone demonstrated statistically significant suppression of noxious stimulus-induced FLI (30%); however, there was no significant difference between pre- versus postformalin alphaxalone administration. These findings are consistent, in part, with our previous behavioral observation of modest analgesia after preformalin administration, although there was a significant difference between pre- versus postinjury treatments in the behavioral study.

Data from our laboratory (34) evaluating Fos suppression by intrathecal lidocaine suggest that modulation of spinal Fos expression may not be a good predictor of preemptive analgesia. Using a similar experimental paradigm for the present study, we evaluated formalin-induced Fos suppression by pre- versus postnoxious stimulus IV anesthetic administration [compared with behavioral data from our lab performed under identical conditions (12)]. As previously discussed, the fact that this study demonstrated preemptive suppression of FLI with systemic propofol seems inconsistent with our previous behavioral study, which showed no behavioral analgesia with propofol (12). In addition, although alphaxalone produced behavioral preemptive analgesia (12), the present study of Fos suppression failed to show any differences between pre- versus posttreatment. Together with the lidocaine data, these results further question the likelihood that the modulation of noxious stimulus-induced FLI parallels behavioral responses.

We conclude that the data from this study provide new evidence demonstrating that anesthetic doses of either propofol or alphaxalone diminish noxious stimulus-induced Fos protein expression. Furthermore, propofol administered before a noxious stimulus inhibits FLI, which suggests maximal suppression when administered during conditions of peak noxious stimulation. Further studies are also required to elucidate the effect of barbiturates, such as pentobarbital, on noxious stimulus-induced Fos expression. Given the observed inconsistencies between this study of Fos expression and our previous behavioral study, it is questionable whether the anesthetic modulation of noxious stimulus-induced FLI parallels that of behavioral responses.


   Acknowledgments
 
This study was supported by MRC(C) funding.

The authors thank Drs. Satyabrata Kar, Jim Pfaus, and Jean-Guy Chabot for their valuable assistance with this study.


   Footnotes
 
Presented in part at the 27th annual meeting of the Society for Neuroscience, New Orleans, LA, October 1997.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 19, 1998.




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S. L. Jinks, J. F. Antognini, J. T. Martin, S.- W. Jung, E. Carstens, and R. Atherley
Isoflurane, but Not Halothane, Depresses C-Fos Expression in Rat Spinal Cord at Concentrations that Suppress Reflex Movement After Supramaximal Noxious Stimulation
Anesth. Analg., December 1, 2002; 95(6): 1622 - 1628.
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I. Gilron, R. Quirion, and T. J. Coderre
Pre- Versus Postformalin Effects of Ketamine or Large-Dose Alfentanil in the Rat: Discordance Between Pain Behavior and Spinal Fos-Like Immunoreactivity
Anesth. Analg., July 1, 1999; 89(1): 128 - 128.
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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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press