BJA Advance Access published online on August 20, 2008
British Journal of Anaesthesia, doi:10.1093/bja/aen243
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Intrathecal lidocaine elevates prostaglandin E2 levels in cerebrospinal fluid: a microdialysis study in freely moving rats
1 Department of Anaesthesiology and Pain Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, Belgium
2 J&J Pharmaceutical Research and Development, Beerse, Belgium
3 Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
* Corresponding author. E-mail: vincent.umbrain{at}uzbrussel.be
Accepted for publication June 20, 2008.
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Abstract |
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Background: In this study, we have investigated whether intrathecal (i.t.) lidocaine administration is accompanied with changes of cerebrospinal fluid (CSF) prostaglandin E2 (PGE2) levels.
Methods: Rats were anaesthetized for i.t. implantation of a triple-lumen spinal loop dialysis catheter. CSF changes in PGE2 after i.t. injection of saline, 400, or 1000 µg of lidocaine were measured. The impact of i.t. pretreatment with 5 µg MK801 (N-methyl-D-aspartate glutamate antagonist) or 10 µg SC76309A (COX-2 inhibitor) was also investigated. CSF dialysates for measurement of PGE2 were collected for 4 h. During the whole procedure, motor and sensory blocks were evaluated. A separate group receiving i.t. lidocaine 400 µg (without dialysate sampling) was assessed for mechanical (Von Frey) and radiant heat pain.
Results: PGE2 levels increased to 400% of baseline and remained elevated for 90–120 min after i.t. lidocaine at both doses. Pretreatment with SC76309A and MK801 attenuated this increase. A 40 min period of enhanced pain response was observed after Von Frey filament stimulation during and after sensory and motor block recovery.
Conclusions: I.T. lidocaine (400 or 1000 µg) increases PGE2 levels in the CSF for 90–120 min along with a transient period of mechanical hyperalgesia after sensory and motor block recovery.
Keywords: measurement techniques, microdialysis; pharmacology, lidocaine; pharmacology, prostaglandins
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Introduction |
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Lidocaine has been used for spinal anaesthesia, acting mainly through inhibition of the voltage-gated sodium channel, for more than 50 yr. But, its use for spinal anaesthesia has been reduced as it is implicated in the appearance of transient neurological symptoms (TNS) such as pain, sensory abnormalities in the lower back, buttock, or lower extremities, or both, which appear within a few hours until approximately 24 h after full recovery from an uneventful spinal anaesthesia. TNS pain intensity varies from light to severe. Remarkably, neurophysiological evaluation during TNS did not reveal abnormalities in somatosensory evoked potential, electromyography, or nerve conduction.1 Nerve inflammation induced by intrathecal (i.t.) lidocaine injection has been reported2 with magnetic resonance imaging, and a hypothesis of reversible inflammation induced by i.t. lidocaine with the potential to produce TNS has been proposed.3 TNS was also interpreted as a sign of possible neurotoxicity of lidocaine,4 but the exact mechanism is still unknown.
Both glutamate and prostaglandin E2 (PGE2) levels in cerebrospinal fluid (CSF) may be considered as surrogates for assessing central hypersensitivity of the spinal cord. Increased glutamate levels were reported in different animal pain models suggesting their contribution in nociceptive synaptic processing of the central nervous sytem.5 6 Alternatively, PGE2 is a key mediator for peripheral and central pain sensitization.7 8 Its direct application to the spinal cord yields mechanical allodynia and thermal hyperalgesia.9–14 Increased PGE2 levels were reported in CSF after surgery15 or peripheral inflammation,16 17 or were related to abnormal pain hypersensitivity.18
Spinal lidocaine administration was recently reported to increase CSF glutamate levels in the absence of peripheral nociceptive activation.19 Its potential role in the induction of TNS has also been discussed.20 However, there is no literature reporting the possible involvement of PGE2, although non-steroidal anti-inflammatory drugs are considered an optional treatment for TNS in the clinic arena.
The objective of the present investigation was therefore to monitor the possible changes in CSF PGE2 levels after i.t. lidocaine administration in a spinal cord microdialysis model in freely moving rats. We verified the time profile of CSF PGE2 changes in vivo and the potential relationship between the motor and sensory blocks associated with i.t. lidocaine administration. PGE2 release after i.t. lidocaine was further investigated with pretreatment of MK801, an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, or of SC76309A, a COX-2 enzyme inhibitor. Moreover, we observed the behavioural changes in response to mechanical and thermal stimuli after i.t. administration of lidocaine.
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The Bioethical Committee for animal experimentation of the Vrije Universiteit Brussel approved the experimental protocol that complied with the guidelines for animal experimentation of the International Association for the Study of Pain and with the guidelines of the Belgian Ministry of Agriculture.
Implantation of the i.t. triple loop microdialysis probe
Male Wistar rats (
300 g; B&K Universal Limited, UK) were anaesthetized with sodium pentobarbital (60 mg kg–1) for i.t. implantation of a triple-loop microdialysis probe (Marsil Scientific, San Diego, CA, USA). This probe consists of i.t tubing with attached inlet and outlet tubes including an active loop dialysis fibre. This triple-lumen catheter permits simultaneous acute i.t. drug delivery and chronic CSF dialysate sampling. The catheter was introduced via the atlanto-occipital membrane as described previously.21 In short, the loop of the catheter was placed at the rostral margin of the lumbar enlargement and its free ends were externalized through the skin at the top of the skull. Surgery ended with a 50 µl s.c. injection of buprenorphine (Temgesic® 0.3 mg ml–1, Schering-Plough, Brussels, Belgium) for postoperative analgesia.
Microdialysis experiment
After surgery, the rats were allowed to recover for 5 days. Rats showing neurological dysfunction were discarded.
The rats were placed in a microdialysis cage (Freely Moving System BAS/Microdialysis, West Lafayette, IN, USA) in the microdialysis room the evening before the experiment to enable them to acclimatize to their new surrounding.
On the day of the experiment, the dialysis probes were connected to a microdialysis pump (CMA 100, CMA/Microdialysis, Stockholm, Sweden) and perfused with a modified Ringer’s solution (NaCl 147 mM, KCl 4 mM, and CaCl2 2.3 mM) at a flow rate of 7.5 µl min–1 for at least 60 min.
Lidocaine investigations
Baseline measurements were followed by either a 20 µl (Lido 400 µg) or a 50 µl (Lido 1000 µg) i.t. injection of preservative-free lidocaine (Linisol® 2% pro injection, B.Braun, Melsungen, Germany). The control group received 50 µl saline (Saline) i.t. All solutions were injected manually by bolus injection at a rate of approximately 10 µl 40 s–1. CSF dialysates after i.t. injection were sampled at 10 min intervals for the first hour and at 30 min for a further 3 h.
All samples were collected on ice and stored at –70°C for subsequent analysis.
MK801 or SC76309A administration before lidocaine
In two separate sets of rats, we injected i.t. 10 µl of either the NMDA receptor antagonist dizocilpine (5 µg) (MK-801, Sigma®, Germany) or the water-soluble COX-2 enzyme inhibitor SC76309A (10 µg) (Pfizer®, NY, USA) dissolved in saline after 1 h baseline sampling. The doses were chosen based on the previous in vivo studies with MK80122 or COX-2 enzyme inhibitors.23 A second i.t. injection consisting of 20 µl of lidocaine (Lido 400 µg) was given 10 min later. Dialysate samples were collected at 10 min intervals during the first hour after MK801 or SC76309 and at 30 min intervals for the remaining 3 h of the experiment.
Assay of CSF PGE2 concentrations
The concentration of PGE2 in the microdialysate samples was quantified with a commercially available Correlate-EIA PGE2 (competitive immunoassay) kit in accordance with manufacturer’s protocol (Assay Design, Inc., USA). The concentration of PGE2 was calculated from the measured optical density by means of four-parameter logistic regression. A standard curve was constructed between 39.4 and 5000 pg ml–1.
Behavioural analysis
Sensory and motor function testing
Sensory and motor function tests were made immediately before spinal injection, then every 3 min after i.t. injection for the following 45 min. Sensory function was evaluated by seeking an aversive response to pinprick stimulation with a 23-gauge needle, progressing from sacral to cervical dermatomes. The sensory function score was assessed using a three-point grading scale: 2, normal; 1, diminished response is present; and 0, no response is present.
Hind-limb motor function was assessed using a five-point grading scale proposed by Drummond and Moore:24 4, normal motor function; 3, ability to draw legs under body and hop, but not normally; 2, some lower-extremity function with good antigravity strength, but inability to draw legs under body; 1, poor lower-extremity motor function, weak antigravity movement only; and 0, paraplegic with no lower-extremity motor function.
Von Frey and radiant heat testing
Rats were subjected to Von Frey and radiant heat tests25 before and after i.t injection of 400 µg lidocaine. For the Von Frey test, unrestricted rats were placed in a clear plastic chamber on an elevated wire grid and allowed to acclimatize. Von Frey monofilament fibres with forces of 0.017–57.5 g (Stoelting®, IL, USA) were applied in ascending force order to the frontal portion of the plantar hind paw of the injected side until the animal withdrew its paw. The withdrawal threshold was determined as the lowest force (withdrawal threshold in grams) that evoked a clear withdrawal response at least twice in 10 applications.
Thermal sensitivity was assessed using an infrared noxious heat stimulus. In short, animals were placed in a clear plexiglass box (23x18x14 cm) with a dry glass floor and allowed to acclimatize for 15 min or until exploratory behaviour ceased. A focused beam of radiant heat at a constant temperature of 46°C and a wavelength of 50 nm was applied to the plantar surface of the paw. The hind paw withdrawal latency (s) to this stimulus was tested. The device has an automatic cut-off at 22 s to avoid the risk of thermal injury to the skin.
Baseline values of either the heat withdraw latency time (s) or the Von Frey mechanical withdraw latency (g) were taken 60, 40, and 20 min before administration of 20 µl (400 µg) i.t lidocaine. Further changes were investigated at 20, 40, 60, 90, 120, 150, or 180 min after injection.
Verification of probe positioning
The animals were killed after each experiment with an overdose of pentobarbital. That part of the spinal cord containing the i.t. catheter membrane was dissected and the position confirmed by injecting methylene blue.
Data analysis
Data were analysed with SPSS 12 for Windows (SPSS® Lead Tools 1991-2000 LT, Inc.).
To evaluate the effects of lidocaine injection, we averaged PGE2 baseline responses and set this average to 100%. Drug effects were expressed as per cent change of baseline values. PGE2 data are presented as per cent change (SEM). Statistical significance of any differences was accepted at P<0.05.
Tests used for analysing the within-group differences of the PGE2 data were repeated-measures general linear model with post hoc analysis using the Bonferroni corrected test at each time interval. Group differences of PGE2 between Lido 1000 µg, Lido 400 µg, saline, MK801, and SC76309A pretreatment were analysed using one-way analysis of variance. Mann–Whitney test was performed to detect the between-group differences at fixed time intervals and also at selected intervals. Kruskal–Wallis test was used to assess the between-group differences for the sensory and motor block data. Wilcoxon test was used to assess the within-group differences of blocks at the different intervals and of mechanical pain and radiant heat stimulation.
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Thirty-six rats without procedural neurological sequelae were selected for lidocaine microdialysis (n=8 per group, 400 and 1000 µg lidocaine and saline control) and the MK801 or SC76309A (n=6 per group) investigations.
An additional 11 rats were included for Von Frey and radiant heat testing.
Baseline levels
Baseline CSF dialysate PGE2 concentrations were 112 (6) pg ml–1 in all 36 rats tested [mean (SE)]. As the individual baseline value varied from one rat to another (33–220 pg ml–1), we opted to express our results in percentages of the mean baseline for further analysis.
Changes in CSF PGE2 concentrations
PGE2 concentrations after i.t. injection of saline did not change. In both Lido 400 µg and Lido 1000 µg groups, spinal PGE2 levels increased reaching a peak value of approximately 400% at 20 min (Fig. 1). PGE2 concentrations gradually decreased to baseline values within the following 90 and 120 min in Lido 400 µg and Lido 1000 µg groups, respectively. No significant differences were observed in PGE2 responses when comparing these two groups.
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Peak CSF PGE2 concentrations were attenuated after pretreatment with MK801 (250%) (Fig. 2) or SC76309A (260%) (Fig. 3) compared with the lidocaine 400 µg group (400%). PGE2 levels after pretreatment with SC76309A tended to be lower than after pretreatment with MK801.
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Behavioural testing
Sensory and motor function tests
Sensory blocks after i.t. injection and before total recovery lasted 19 min in the lidocaine 400 µg and 23 min in the lidocaine 1000 µg groups, respectively. Rats began to move after 10 min, but the effects lasted 23 min in the lidocaine 400 µg and 26 min in the lidocaine 1000 µg groups before total recovery (data not shown). In both lidocaine groups, spinal PGE2 increases clearly outlasted the duration of sensory and motor block.
Radiant heat test and Von Frey test
After Von Frey filaments stimulation, the mechanical withdraw latency (g) was decreased in the lidocaine 400 µg group at 20, 40, and 60 min compared with the saline group (Fig. 4A). After radiant heat application, the lidocaine 400 µg group had a shorter withdraw latency time compared with the saline group at 40 min (11 s compared with 15 s) (Fig. 4B).
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Discussion |
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We have demonstrated that i.t. lidocaine in rats is accompanied by a 90–120 min MK801 and SC76309A sensitive increase in CSF PGE2 levels. In addition, there was a transient period of mechanical hyperalgesia and increased sensitivity to radiant heat during the recovery period. Lidocaine-mediated increases in PGE2 initially coincided with the onset of lidocaine-induced motor and sensory block, but the PGE2 elevation outlived both sensory and motor block duration, implicating no direct causal relationship.
Increased CSF glutamate has previously been observed after i.t. administration of several local anaesthetics, including lidocaine.19 26 To further elucidate the consequences of this elevation, we focused on a possible downstream mechanism of action, and in particular on its relationship to PGE2 release. We found that i.t. lidocaine induces the activation of dorsal horn neuronal circuitry in which PGE2 is implicated. A possible explanation linking glutamate and PGE2 is as follows: glutamate released by i.t. lidocaine injection induces a postsynaptic depolarization leading indirectly to an increase in intracellular calcium, which in turn results in the activation of a number of intracellular enzymes, including phospholipase A2 (PLA2). PLA2 activation then induces an increase in cytosolic arachidonic acid, which will enter the cyclooxygenase cascade leading to the synthesis of a variety of prostaglandins that gain access to the extracellular space. Prostanoids then affect presynaptic prostanoid E receptors that further increase intracellular calcium in sensory afferents and depolarize dorsal horn neurones and increase spinal excitability.8 In agreement with this view, we found that i.t. MK801 decreased CSF PGE2 levels.
Another explanation is that i.t. lidocaine may directly increase PGE2. It is possible that PGE2 increases could be the consequence of a direct biochemical effect of lidocaine on the dorsal horn neuronal cell membrane, as recently suggested27 with a cell culture investigation,28 which demonstrated increased calcium levels after lidocaine (>5 mg ml–1) administration. The calcium increase and its intensity were dose-related lasting 5 min with 300 µg lidocaine and being sustained for more than 60 min with 1500 µg lidocaine. Johnson and colleagues29 speculated that the observed calcium increase might initiate a period of enhanced electrical responsiveness by the neurone and cause hyperalgesia or transient nerve irritation. Alternatively, this calcium increase might induce COX-2 m-RNA transcription30 and subsequently PGE2 increases in CSF. Prostanoid induction is observed when the integrity of the cell membrane is jeopardized, as in cases of inflammation or trauma affecting the cell.31 The amphipathic character of local anaesthetics affecting cell membrane lipid bi-layer permeability32 when given i.t. might explain the PGE2 increases. Recent reports19 29 showing a direct effect of lidocaine on the cell membrane of spinal cells and ending with a direct induction of prostanoids is therefore plausible. Whether the source of this lidocaine-induced spinal prostanoid induction relies on neuronal or glial expression could not be established in the present study. In agreement with this, we showed that the water-soluble COX-2 enzyme inhibitor SC76309A given before i.t. lidocaine attenuated PGE2 release.
Both pretreatments attenuated PGE2 release when given before i.t. lidocaine. On the contrary, the lack of complete block of the PGE2 may be related to COX-1 up-regulation. Interestingly, the Von Frey and to a lesser extent the radiant heat test demonstrated that rats had a transient increased mechanical and thermal hyperalgesia sensitivity after i.t. injection. Together with the observed transient increases of PGE2 values, this demonstrates that i.t. lidocaine induces a temporary state of spinal cord sensitization.
We believe that these surprising changes of spinal PGE2 levels after i.t. injection of lidocaine merit further investigations. The observed changes might simply reflect the reaction of the spinal cord to a foreign chemical substance such as our preservative-free lidocaine. But alternatively, i.t lidocaine may trigger a lidocaine-induced physicochemical reaction. As these changes were not observed after i.t. saline, we could exclude injection pressure and volume- related changes.
In vitro lidocaine produces conduction failure, membrane damage and loss of membrane potential, enzyme leakage, intracellular calcium release, growth cone collapse, and neurone degeneration and cell death. Recently, in rat dorsal root ganglion cell lines, lidocaine has been shown to produce a dose-dependent sodium-channel-independent mitochondrial dysfunction leading to the induction of apoptopic pathways.33 We speculate that the observed PGE2 increases in the CSF in our study reflect a lidocaine-induced effect on the spinal cell. PGE2 increases could be an initiating signal of the effect of lidocaine on the spinal cell before it further affects the mitochondria of glial cells, astrocytes, or neurones.
The previously established role of PGE2 in the CSF as a central pain sensitizer and the observed short-lived dose-independent changes in PGE2 levels, together with our observed behavioural changes suggest a relationship with the TNS observed in the clinical arena after i.t. lidocaine anaesthesia. However, the observed phenomena in rats were of shorter duration. Clinical confirmation with other species/gender studies is therefore suggested before human extrapolation.
Our data contrast with the current knowledge in the field, as some authors34 35 report that local anaesthetics inhibit NMDA receptors. For instance, lidocaine inhibits NMDA receptor signalling, but these investigations were obtained either in vitro with recombinant human NMDA-receptors in Xenopus laevis oocytes or using ventral root potential recordings in hemisected spinal cord preparations. Therefore, they might not be applicable to this in vivo study in rat spinal cord. Also, in contrast to our findings is a recent report36 where i.t. lidocaine reversed tactile allodynia after an established spinal nerve injury. It was speculated that lidocaine down-regulated prostagladin (PG) systems either by inhibition of the production or the release of PGs or by EP1 receptor inhibition. In contrast to their investigation, our rats were not hypersensitive before lidocaine administration, which may explain the differences.
One shortcoming of our study is that we only investigated two doses of lidocaine. One small prospective study reported that TNS incidence after lidocaine spinal anaesthesia did not change after the modest lidocaine dose reduction from 75 to 60 mg.37 Similarly, diluting spinal lidocaine from 5% to 2%38 or from 2% to 0.5%39 also failed to alter the incidence of TNS. In our study, however, we observed a prolonged duration of spinal PGE2 increases in the lidocaine 1000 µg group. This may imply that the observed PGE2 changes are dose-dependent. Further studies with other lidocaine doses therefore seem justified before linking spinal PGE2 increases to TNS.
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Fonds voor Wetenschappelijk Onderzoek (FWO).
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We thank Professor Martin Zizi of the Department of Neurophysiology (VUB) for allowing us to perform rat surgery and PGE2 measurements in his department. I.S. is a postdoctoral research fellow of the FWO Vlaanderen.
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This work was partly presented as an oral abstract at the Annual Neuroscience Meeting of Washington on November 14, 2005. 
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