1 Stanford University, Stanford, CA, USA. 2 Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. 3 Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA. 4 Section of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA
* Corresponding author: Department of Anesthesiology and Pain Medicine, University of California, Davis, One Shields Drive, Davis, CA 95616, USA. E-mail: jfantognini{at}ucdavis.edu
Accepted for publication January 14, 2005.
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Abstract |
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Methods. We recorded 18 nociceptive dorsal horn neurones exhibiting windup to 1 Hz electrical hindpaw stimuli in rats. Effects of 0.8 and 1.2 MAC isoflurane and halothane were recorded in the same neurones (counterbalanced, crossover design). Windup was calculated as the total number of C-fibre (100400 ms latency) plus afterdischarge (4001000 ms latency) spikes/20 stimuli (area under curve, AUC) or absolute windup (C-fibre plus afterdischarge20xinitial response).
Results. Increasing isoflurane from 0.8 to1.2 MAC did not affect AUC, but increased absolute windup from 429 (62) to 618 (84) impulses/20 stimuli (P<0.05) and depressed the initial C-fibre response from 14 (3) to 8 (2) impulses (P<0.05). Increasing halothane from 0.8 to1.2 MAC depressed AUC from 690 (79) to 537 (65) impulses/20 stimuli (P<0.05) and the initial response from 18 (2) to 13 (2) impulses (P<0.05), but absolute windup was not affected. Absolute windup was 117% greater during 1.2 MAC isoflurane compared with 1.2 MAC halothane.
Conclusions. Windup was significantly greater under isoflurane than halothane anaesthesia at 1.2 MAC, whereas the initial C-fibre response was suppressed more by isoflurane. These findings suggest that these two anaesthetics have mechanistically distinct effects on neuronal windup and excitability.
Keywords: anaesthetics volatile, halothane ; anaesthetics volatile, isoflurane ; model, rat, spinal cord ; pain ; windup
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Introduction |
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Windup is the progressive increase in nociceptive neuronal responses to repeated stimulation of C-fibre intensity, and is thought to result from the temporal summation ofN-methyl-D-aspartate (NMDA)- and neurokinin-1 (NK-1)-receptor-mediated slow cumulative depolarizations of spinal neurones evoked by nociceptive primary afferent input.1118 Windup may underlie the temporal summation of pain19 20 and its suppression may be an important mechanism by which volatile anaesthetics produce immobility. Because volatile anaesthetics affect NMDA receptor-mediated function2123 and an NMDA receptor antagonist, MK-801, suppresses temporal summation and the minimum alveolar concentration required to prevent movement to a noxious stimulus in 50% of subjects (MAC),24 volatile anaesthetics might be expected to suppress windup. Based on our prior results suggesting that halothane has a greater depressant effect on neuronal response compared with isoflurane,5 9 we hypothesized that halothane, but not isoflurane, would depress neuronal windup between 0.8 and 1.2 MAC. We employed a crossover technique that permitted us to compare the effects of each anaesthetic on the same neurones, as our prior data comparing halothane and isoflurane were obtained in separate animals.5
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Methods |
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Surgery
Rats were initially anaesthetized with isoflurane or halothane 34% delivered in a balance of oxygen at 1 litre min1 in a chamber, then moved to mask anaesthesia (isoflurane 22.5%, halothane 1.52%) during surgery. Anaesthetic concentration was adjusted as needed so that a strong tail or paw pinch failed to evoke a withdrawal response. A tracheostomy tube was implanted, the jugular vein was cannulated with PE-50 tubing for fluid delivery, and wound clips were used to close the incision. The L6S1 intervertebral space was identified by palpation of the spinous processes and the posterior superior iliac spines, and a midline skin incision was made from L6 to T11 spinous processes. The paraspinous muscles were dissected free from the L2T12 spinous processes on both sides, and the transverse processes were exposed by scraping off attached connective tissues. L1 and T13 spinous processes were cut and removed, and a bilateral laminectomy was performed at both levels under a dissecting microscope with micro-rongeurs.
Recording and unit characterization
The animal was placed in a stereotaxic frame with vertebral clamps on T12 and L2 vertebral bodies and the S1 spinous process. The dura overlying the exposed spinal cord was opened with fine forceps and microscissors, and warm (36.537°C) agar was placed over the site to a depth of 23 mm to prevent cord movement during respiration and desiccation of the tissue. Core body temperature was monitored rectally using a BAT-12 (Physitemp, Clifton, NJ, USA) and maintained at 37 (0.2)°C with a lamp and heating pad. The animal was ventilated using a positive-pressure pump (Harvard Apparatus, Holliston, MA, USA) and end-expired carbon dioxide was monitored with a calibrated Rascal II gas analyser (Ohmeda, Helsinki, Finland) and maintained between 30 and 40 mm Hg by adjustment of respiratory rate and/or tidal volume. The animal was given pancuronium bromide (0.20.3 ml of 1 mg ml1 i.v.; Baxter, Deerfield, IL, USA) to reduce respiration against the ventilator if present. In no case was the end-tidal anaesthetic below 1.1% isoflurane (
0.8 MAC) or 0.7% halothane (
0.8 MAC),5 10 25 concentrations well above that which suppresses memory and consciousness.26
A Teflon-coated tungsten microelectrode (impedance811 M, diameter at tip
3 µm; FHC, Bowdoinham, ME, USA) was then advanced into the dorsal horn of the spinal cord with a hydraulic microdrive (Kopf Instruments, Tujunga, CA, USA) to record single-unit activity of dorsal horn neurones. Action potentials were amplified and displayed by conventional means and recorded (along with ECG and blood pressure when monitored) with a Powerlab interface and Chart software (AD Instruments, Grand Junction, CO, USA), and stored for off-line spike discrimination and analysis. Recording depth was estimated from the microdrive depth reading; in some experiments an electrolytic lesion was made through the microelectrode and recording sites were histologically confirmed to lie within the deep dorsal horn.
Single units were searched for and isolated using innocuous mechanical stimulation of the plantar surface of the ipsilateral hind paw. Units isolated for study were always at depths <1 mm. Units with receptive field areas corresponding to the L4L6 spinal cord were chosen, based upon previous dermatomal mapping studies.27 28 Of these, only units that responded to graded non-noxious (brushing, 412 g von Frey) and noxious (76 g von Frey, pinch) [wide-dynamic range (WDR) neurones] or to only noxious [nociceptive-specific (NS) neurones] mechanical stimuli were considered for further study. Cells were further tested with constant-current electrical stimulation using an S48 stimulator (Grass, West Warwick, RI, USA) and stimulus isolation unit with constant current output (Grass model PS1U6), administered by subcutaneous needle electrodes inserted within the receptive field area. Only units exhibiting a reproducible discharge occurring 100400 ms (C-fibre latency)29 after the stimulus were investigated further. The C-fibre threshold was determined by delivering an ascending series of paired electrical pulses (
1 s interval between pulses,
3 s between pairs) at 12 V intervals. The intensity that evoked
1 spike at the C-fibre latency in one of the two trials was considered the C-fibre threshold.16 A 1 Hz stimulus train (20 pulses; 0.5 ms pulse duration) was then delivered at three times the C-fibre threshold to assess windup.12 29 30
Isofluranehalothane crossover protocol
We used a crossover, counterbalanced experimental design. Depending upon the anaesthetic used for induction, windup responses to 1 Hz stimulation were first recorded under either halothane (n=8) 0.7% (0.8 MAC) and 1.1% (
1.2 MAC) or isoflurane (n=10) 1.1% (
0.8 MAC) and 1.7% (
1.2 MAC); the approximate MAC fractions are based on MAC values obtained in adult rats studied in our laboratory.5 10 25 When changing the isoflurane concentration,
15 min was allowed to elapse after the desired concentration reading (end-tidal) was obtained from the gas analyser before testing was performed, whereas
20 min was allowed for halothane concentration changes. We chose a longer equilibration period for halothane because of its greater blood:gas solubility coefficient compared with that of isoflurane. The order in which different halothane and isoflurane concentrations were tested (i.e. 0.8 vs 1.2 MAC) was altered from experiment to experiment to minimize any time effects. After completion of the windup stimulation series at 0.8 and 1.2 MAC, the anaesthetic agent was changed while maintaining a stable recording from the same neurone. Approximately 3040 min was required when changing from halothane to isoflurane, whereas 4060 min was usually needed for a stable end-tidal concentration to be reached when changing from isoflurane to halothane. Spontaneous neural activity always returned to its low rate during the transition from one anaesthetic to the other. Windup to 1 Hz electrical stimulation was then reassessed while under the new anaesthetic, at concentrations corresponding to approximately 0.8 and 1.2 MAC. In one animal we studied three neurones that produced action potentials that could be discriminated. Upon completion of the experiment each animal was killed by overdose of pentobarbital i.v.
Data analysis and statistics
An analysis of the action potential data was performed for each latency range (0100, 100400, 4001000 and 1001000 ms after each stimulus, for A-fibre, C-fibre, afterdischarge and C-fibre plus afterdischarge responses, respectively) by summing (for all 20 stimuli) the evoked action potentials within that range [referred to hereafter as area under the curve (AUC) for that latency]. The AUC calculation reflects effects on windup and responses to the first stimulus. These values were compared using repeated measures ANOVA with the post hoc StudentNewmanKeuls test. Windup was also quantified using a method described previously,31 32 whereby absolute windup is equal to the total train response minus 20x input, where input equals the number of action potentials evoked by the first stimulus. For the absolute windup calculation the evoked action potentials occurring during the C-fibre plus afterdischarge range (1001000 ms) were combined.16 30 33 The absolute windup values during 0.8 and 1.2 MAC isoflurane and halothane concentrations were compared using repeated measures ANOVA with the post hoc StudentNewmanKeuls test. Spontaneous firing rates at each anaesthetic concentration were compared by summing the total number of action potentials during the 30 s before the first electrical stimulus and using two-tailed paired t-tests. Comparisons of the C-fibre latency response with the first stimulus in the train (i.e. neuronal excitability) were made for 0.8 vs 1.2 MAC and halothane vs isoflurane using two-tailed pairedt-tests. Differences were considered significant with P<0.05. All data are mean (SE) unless otherwise indicated.
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Results |
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Figure 1A shows an example of windup during isoflurane anaesthesia. Increasing the concentration of isoflurane from 0.8 to 1.2 MAC enhanced windup. When anaesthesia was switched to 0.8 MAC halothane, the neurone exhibited windup similar to that which occurred with 0.8 MAC isoflurane; however, increasing halothane to 1.2 MAC depressed responses, as seen in Figure 1B.
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Discussion |
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Isoflurane and halothane suppressed the C-fibre latency response to the first stimulus. In general, anaesthetics hyperpolarize neuronal membranes,34 35 an effect that would depress neuronal excitability and is consistent with the depression of the response to the first stimulus presently observed. In contrast, absolute windup was enhanced by isoflurane but not by halothane. This suggests that, if general neuronal excitability is suppressed, it does not predict the degree or rate of windup or the maximal firing rate reached. This is consistent with the results of Sivilotti et al.,13 who found that only the rate of cumulative depolarization, not the absolute resting membrane potential, was a predictor of dorsal horn neuronal windup in vitro. Our data are also similar to the effect of intrathecal morphine, which decreases the initial response more than windup itself.36
The technique of extracellular recording currently used does not allow us to differentiate between changes in presynaptic input from changes in the intrinsic properties of the postsynaptic neurone itself. There is some evidence that isoflurane might depress presynaptic input. For isoflurane, a small depression of the presynaptic action potential, possibly via inhibition of Na+ channels or activation of K+ channels, translates into a large reduction of presynaptic neurotransmitter release, ultimately reducing the excitatory postsynaptic potential.37 This possibility has not yet been explored for halothane. Alternatively, isoflurane and halothane could mediate their immobilizing effects by depression of peripheral nociceptor activity. This seems unlikely, however, since volatile anaesthetics enhance, rather than suppress, activity of C- and A primary afferent fibres.38 39
The finding that isoflurane enhances, rather than suppresses, absolute windup is surprising since isoflurane suppresses function of the NMDA receptor in vitro,2123 which has been suggested to play an important role in windup.11 12 40 Isoflurane also suppresses behavioural responses, increasing the latency for rats to withdraw from repetitive noxious tail stimulation, indicating the importance of temporal summation for isoflurane MAC.24 The NMDA receptor antagonist MK-801 produced a MAC-sparing effect, suggesting involvement of this receptor in the relationship between temporal summation and MAC observed for isoflurane.24 However, although most studies have found that NMDA receptor antagonists suppress windup,11 12 40 41 others have reported either no change or even enhanced windup after NMDA receptor antagonism.14 32 At 2.5 µg kg1 min1, MK-801 infusion caused a marked decrease in temporal summation and isoflurane MAC after 60 min,24 whereas a comparable dose by i.v. bolus (0.1 mg kg1) caused negligible suppression of dorsal horn neuronal windup at 2050 min.42 The present study is limited in addressing these various scenarios from a mechanistic perspective. Further work will be required to determine how NMDA receptor modulation alters neuronal sensitivity to halothane and isoflurane when a windup paradigm is used.
In the present study halothane did not significantly depress absolute windup, a result that is seemingly at odds with our recent report that increasing halothane from 0.9 to 1.1 MAC depressed absolute windup in the mouse.9 However, the difference between these studies is more quantitative than qualitative. In both studies the initial response was significantly depressed and the windup curve was shifted downward, with decreases in absolute windup of 28% in the mouse9 vs 14% in the rat.
The finding that halothane and isoflurane differentially affect windup is consistent with several recent studies,5 9 10 and provides further evidence that these two volatile anaesthetics might have different mechanisms of producing immobility. It is possible that the suppression of nociceptive dorsal horn responses (as judged by AUC) partly accounts for the immobilizing effect of halothane, whereas isoflurane (which did not affect AUC) acts at more ventral sites within the spinal cord. In one study we reported that isoflurane had variable effects on windup, some neurones being more depressed than others.43 While we cannot completely reconcile the present results with our prior data,43 it is noteworthy that the majority of neurones in the present study were WDR neurones, while NS neurones represented the majority in our prior study.43 To our knowledge, there are no data to indicate if WDR and NS neurones differ in their anaesthetic sensitivity. Although we pooled the data from 16 WDR and two NS neurones, exclusion of the data from the latter group did not affect the overall data interpretation and conclusions. Furthermore, WDR and NS neurones both participate in nociception and there was no a priori reason to exclude NS neurones from the analysis.
Interestingly, spontaneous neural activity, while low, was greater during halothane anaesthesia than during isoflurane anaesthesia. We have observed this effect before, but its cause is unclear.5 We cannot rule out the possibility of the surgical wound providing continuous noxious input; however, similar spontaneous activity in spinal neurones has been observed in chronic preparations in which there had probably been no nociceptive input.44 Halothane and isoflurane can sensitize peripheral nociceptors and it is possible that a peripheral anaesthetic action might increase synaptic input onto neurones in the spinal cord.38 In clinically relevant concentrations (<1.5 MAC), however, halothane and isoflurane are not different with respect to sensitization of peripheral nociceptors.38
Interpretation of our prior report5 is limited in that effects of halothane and isoflurane on neuronal responses to noxious stimulation were studied in separate groups of neurones, however, the present data confirm and extend our prior data. Although we did not investigate anaesthetic effects below 0.8 MAC, there is abundant evidence that halothane and isoflurane depress lumbar neuronal responses to noxious stimulation in the 00.8 MAC range.4 7 45
While a windup paradigm is used as an experimental tool, repetitive noxious stimuli are often applied to patients in the operating room. For example, during closure of a skin incision, grabbing the wound edges and passing the suture needle through the skin can occur at around 1 Hz. In addition, this might happen during the period when the anaesthetic is being decreased, in anticipation of awakening the patient. Hence, whether the patient moves during this period could relate to the ability of the anaesthetic to diminish neuronal windup. Lastly, although we have emphasized our data from the perspective of immobility, effects on neuronal excitability might be important to other clinical scenarios, including pre-emptive analgesia and postoperative pain.
In summary, similar windup was observed under 0.8 MAC halothane and isoflurane, but there was significantly more windup at 1.2 MAC isoflurane than at 1.2 MAC halothane. The C-fibre response to the initial stimulus was significantly suppressed by both halothane and isoflurane. Also, the C-fibre response to the first stimulus, as well as spontaneous firing rate, was greater under halothane than isoflurane. These results are consistent with differing sites of action for halothane and isoflurane anaesthesia to prevent movement resulting from noxious stimulation.
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Acknowledgments |
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References |
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