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Anesth Analg 2005;100:774-780 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000143570.75908.7F
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Abstract |
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Resiniferatoxin (RTX) is a vanilloid agonist with a unique spectrum of activities. Vanilloids bind to the transient receptor potential ion channel subtype 1, a nonselective cation ionophore important in the integration of different noxious signals. Vanilloid agonists selectively decrease sensitivity to noxious stimuli. In this study, we sought to determine whether perineural RTX prevents hyperalgesia in a model of incisional pain. In a rat model, RTX was administered percutaneously to the sciatic and saphenous nerves before the plantar incision. The withdrawal response to von Frey filaments, the struggle response to pressure on the paw, and pain scoring based on weight bearing were measured before RTX and at various intervals for 8 days after RTX. A percutaneous injection of RTX (0.0003%) to the sciatic (0.1 mL) and saphenous (0.05 mL) nerves completely prevented incisional hyperalgesia. Two hours after incision, the withdrawal threshold was 51 mN without and 456 mN with RTX (P < 0.0001). RTX also prevented the incision-induced decrease in struggle threshold and abolished the pain behavior associated with weight bearing. We conclude that RTX provides a type of neural blockade when postoperative pain is abolished and that nonpainful sensations and motor functions are preserved.
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Introduction |
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Resiniferatoxin (RTX) is a vanilloid agonist with a unique spectrum of activities (1,2). Vanilloid agonists can produce selective and long-lasting neural blockade (1). Several studies have demonstrated that perineural administration of another vanilloid, capsaicin, can selectively block the conduction of impulses in the C fibers and A-
fibers at the site of capsaicin application (3–5). The question central to the prospective use of vanilloid agonists for neural blockade in postoperative pain is their ability to inhibit mechanical hyperalgesia during incisional inflammation. Reports on the effect of capsaicin-induced nerve blockade are usually limited to studies of the blockade of the responses to noxious heat stimuli. Previous studies have reported contradictory results regarding the effect of capsaicin (applied to a peripheral nerve) on responses to noxious mechanical stimuli; Fitzgerald and Woolf (6) reported that noxious mechanical stimuli were unaffected by capsaicin, whereas Chung et al. (4) observed an inhibitory effect. In our previous study (7), the percutaneous administration of RTX (0.001%) to a peripheral nerve in rats provided long-lasting suppression of not only thermal, but also mechanical nociception (although to a lesser degree). We also found that a perineural injection of RTX completely prevented carrageenan-induced hyperalgesia (including mechanical hyperalgesia) without producing any abnormality in walking. The primary aim of this study was to determine whether perineural RTX prevents mechanical hyperalgesia in a model of incisional pain. The other aim of the study was to determine dose dependency in the effect of perineural RTX on the responses to noxious mechanical stimuli (in comparison with the effect on the responses to noxious heat stimuli).
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Methods |
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Male Sprague-Dawley rats weighing 275–325 g were used for the experiments. The rats were housed with a 12-h light/dark cycle, and food and water were available ad libitum. The protocol for this study was approved by the Institutional Panel on Laboratory Animal Care.
Four tests were used to assess pain behavior: struggle response to noxious pressure, withdrawal response to application of von Frey filaments, withdrawal response to noxious heat, and pain scoring based on weight bearing. The response to noxious pressure on the paw was determined by measuring the threshold for coordinated struggle to increasing pressure with the use of an Analgesy-Meter® (Ugo Basile, Milan, Italy). The threshold was measured by positioning the hindpaws on a Teflon platform and directing the device's 2-mm pressure cone on its dorsal surface, between the third and fourth metatarsal bones.
The response to von Frey filament application was measured as described by Brennan et al. (8). Briefly, rats were placed individually on an elevated plastic mesh floor covered with a clear plastic cage top (21 x 27 x 15 cm) and allowed to acclimate. Withdrawal responses to punctate mechanical stimulation were assessed by applying calibrated von Frey filaments (23, 41, 45, 50, 72, 122, and 205 mN bending force; Stoelting, Wood Dale, IL) from underneath the mesh to the plantar aspect of the proximal part of the paw. Each filament was applied once, starting with a force of 23 mN and continuing until a withdrawal response occurred or a force of 205 mN was reached. If no withdrawal response occurred, the force of the next filament (456 mN) was assigned. The least force from the three trials was considered the withdrawal threshold.
The response to noxious heat stimulation was determined with the hotplate modified as described by Wilder et al. (9). A hotplate (Model DS37; Ugo Basile) was heated to 56°C. The rat, wrapped in a towel, was held so that one hind foot was resting on the plate and the other was on a block of wood at room temperature. The time the rat's foot was placed on the hotplate to the time it lifted its foot was recorded.
The weight-bearing score after paw incision was determined by a cumulative pain score as described by Brennan et al. (8). Unrestrained rats were placed on a plastic mesh floor (8 x 8-mm openings). An angled magnifying mirror was used to view the incised and nonincised paw, and both paws of each rat were closely observed during a 1-min period repeated every 5 min for 1 h. A score of 0, 1, or 2 was given depending on the position in which each paw was found during most of the 1-min scoring period. The paw was considered full weight bearing (score = 0) if the wound was blanched or distorted by the mesh. If the paw was completely off the mesh, a score of 2 was recorded. If the area of the wound touched the mesh without blanching or distorting it, a score of 1 was given.
Plantar incision was performed under 2% halothane anesthesia through the skin, fascia, and muscle starting 0.5 cm from the proximal edge of the heel and extending toward the toes, as described by Brennan et al. (8).
RTX was injected in various concentrations percutaneously at the sciatic or the sciatic and saphenous nerves (in the third series of experiments). Injections were made with animals under brief halothane (2%) anesthesia; the sciatic nerve was injected at the greater trochanter level (0.1 mL), and the saphenous nerve was injected at the midthigh level (0.05 mL). The administration of RTX was preceded (5 min) by bupivacaine (Bup) blockade to prevent the initial excitatory effect of RTX. Bup (0.25%) was injected in a volume of 0.1 mL at the sciatic nerve and 0.05 mL at the saphenous nerve (providing blockade for approximately 1 h).
Three series of experiments were performed. Two investigated the dose dependency of the effect of perineural RTX on responses to mechanical noxious stimulation: one was a study of the hypoalgesic effect of RTX, and the other was a study of complete blockade of noxious responses. The third series was performed to determine whether perineural RTX prevents mechanical hyperalgesia in a model of incisional pain.
In the series of experiments on the dose dependency of the hypoalgesic effect of RTX (Series 1; n = 20), RTX was administered only to the sciatic nerve. Responses to noxious mechanical stimuli (struggle threshold to gradually increasing pressure on the paw) were determined and compared with responses to noxious heat stimuli (withdrawal threshold to heat [56°C]). The responses to stimulation were measured before and at various times after RTX administration until the thresholds returned to the baseline levels. The total duration of hypoalgesia and the duration of profound hypoalgesia (when the threshold was at least 100% higher than the baseline value) were determined. There were three groups of rats. Each received a dose of RTX at a concentration of 0.00003%, 0.0003%, or 0.003%, all in 0.1 mL of vehicle (see below). Vehicle alone was used in the controls.
In the series of experiments on dose dependency with RTX-induced blockade of nociceptive responses (Series 2; n = 30), the absence of the struggle response to pressure up to 500 g (cutoff level) was determined as the blockade to pressure. Absence of the withdrawal response to heat stimulation (56°C) for 12 s (cutoff level) was determined as the blockade to heat. The responses to stimulation were determined before and at various times after RTX administration. The rats were randomly assigned to 1 of 6 groups with the following RTX concentrations: 0.00003%, 0.0001%, 0.0003%, 0.001%, 0.003%, and 0.01%. The injection volume was 0.1 mL for each concentration.
In the series of experiments on the effect of perineural RTX with a model of incisional pain (Series 3; n = 40), it was administered at both the sciatic nerve (0.1 mL) and the saphenous nerve (0.05 mL) at a concentration of 0.0003% (chosen on the basis of the experiments on dose dependancy in the effect of RTX). This concentration of RTX is three times smaller than that reported in the previous study with carrageenan-induced hyperalgesia (7). The rats were randomly assigned to one of four groups. In Group 1 (Bup-RTX + plantar incision (Inc)), after baseline measurements of the struggle response to noxious pressure and the withdrawal response to von Frey filament application, Bup 0.25% was injected (0.1 and 0.05 mL to the sciatic and saphenous nerves, respectively), and the completeness of sciatic and saphenous nerve blockade was confirmed (by first- and fifth-digit pinch). RTX injection followed 5 min after Bup injection, and behavioral variables were measured 3.5 h later. Four hours after injection of RTX, the plantar incision was performed with animals under halothane (2%) anesthesia, and the behavioral variables were measured 2 h later. They were also measured on the next day, on the third or fourth day, and on the seventh or eighth day after RTX administration. In Group 2 (Bup-RTX), the administration of both drugs was not followed by incision, and the measurements were the same as in Group 1. In Group 3 (Bup-dimethyl sulfoxide in saline (Sal) and Tween 80 (Veh) + Inc), the injection of Bup was followed by the injection of Veh (for RTX) and incision. In Group 4 (Sal-Veh), Sal was used instead of Bup, and Veh was used instead of RTX.
RTX was purchased from Sigma (St. Louis, MO), dissolved in dimethyl sulfoxide (Sigma) to a concentration of 1 µg/µL, and stored at –80°C under nitrogen. It was diluted to a required concentration before the experiment in 0.9% Sal with 0.3% Tween 80. Bup was purchased from Abbott Laboratories.
The data in series 1 were analyzed with nonparametric statistics. The median and its 95% confidence intervals were determined with the methods of Hahn and Meeker (10). Comparison of median values among groups used the nonparametric analysis of variance of ranks of the observations as described in Conover and Iman (11). The data were analyzed with a two-way (group and time) analysis of variance, with the time treated as a repeated-measures factor. Comparisons between group medians at each time were performed with a one-way analysis of variance. Multiple comparisons used the Fisher's protected least significant difference method. The RTX time course curves determined in Series 2 were modeled and compared by logistic regression analysis for a multivariate model as described in Hosmer and Lemeshow (12). In Series 3, the data on struggle threshold and withdrawal threshold were summarized and analyzed as in Series 1. Comparisons of pain scores based on weight bearing between the Bup-RTX + Inc group and the Bup-Veh + Inc group were based on analysis of variance for mean values. Results were considered statistically significant if P < 0.05.
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Results |
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RTX-induced hyperalgesia was dose dependent. Figure 1 illustrates the duration of profound hypoalgesia when the threshold to pressure or latency to heat was at least 100% higher than the baseline value. Profound hypoalgesia to noxious pressure lasted a median of 4 h (95% CI, 2.5–6 h) with 0.00003% RTX, 6 h (95% CI, 3–48 h) with 0.0003% RTX (P < 0.05 versus 0.00003% RTX), and 24 h (95% CI, 24–48 h) with 0.003% RTX (P < 0.005 versus 0.00003% RTX). The total duration of hypoalgesia to pressure was much longer: 24 h (95% CI, 3–48 h) with 0.00003% RTX, 30 h (95% CI, 24–78 h) with 0.0003% RTX, and 47 h (95% CI, 24–72 h) with 0.003% RTX. It is interesting that there was no important difference between the total duration of suppression of pressure responses and heat responses at the smaller concentrations of RTX. For example, at an RTX concentration of 0.00003%, the duration of both deficits was 24 h. There were also no significant differences between heat and pressure hypoalgesia at an RTX concentration of 0.0003%. However, when the concentration of RTX was increased to 0.003%, the duration of the effects on responses to heat and pressure became very different—648 h (95% CI, 72–888 h) and 47 h (95% CI, 24–72 h), respectively. The same type of concentration-dependent difference in the duration of the effects was seen with profound hypoalgesia when the criterion was a twofold increase in the threshold above baseline (Fig. 1).
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Complete blockade (cutoff, 500 g) of responses to noxious pressure (Series 2) was also concentration dependent (Fig. 2). Similar durations of complete blockade of responses to pressure and heat were observed only at a concentration of 0.00003%. When the RTX concentration was increased, especially beyond 0.0003%, the difference in response to pressure and heat was profound. Blockade of the pressure response did not last longer than 48 h, even with the largest RTX concentration (0.01%), whereas the blockade of the heat response with this concentration could last 3 weeks. In 2 rats (RTX 0.003% and 0.01%), the duration of blockade to heat was even longer than 3 weeks, indicating that this concentration range can potentially produce irreversible blockade of thermal nociception, although responses to noxious mechanical stimulation reappeared after even the largest RTX dose. The range of RTX concentrations that produced hypoalgesia or complete reversible (
3 wk) blockade of nociceptive responses was rather wide: from 0.00003% to 0.001%.
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The results of experiments with the model of incisional pain (Series 3) are presented in Figures 3 and 4. In the Bup-Veh + Inc group (incision without RTX pretreatment), the median withdrawal threshold to von Frey filaments decreased from 456 mN before surgery to 51 mN (P < 0.0001) 2 h after the incision (Fig. 4). Hyperalgesia was persistent; the withdrawal threshold was approximately at that level throughout the day of surgery. Twenty-four hours later, the withdrawal threshold was 122 mN (P < 0.0001 versus preincision), and the process of the threshold recovery continued for several days. In the Bup-RTX + Inc group, with the use of RTX at a concentration three times smaller than in our previous experiments (7) with carrageenan-induced inflammation, the prevention of hyperalgesia was complete (Fig. 4). Six hours after the injection of RTX, the median withdrawal threshold in the Bup-RTX + Inc group was 456 mN (95% CI, 122–456 mN), which was the same as that in the Bup-RTX group or the Sal-Veh group and was significantly different (P < 0.0005) from that in the Bup-Veh + Inc group.
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Perineural RTX prevented mechanical incision-induced hyperalgesia (Fig. 3). In the Bup-Veh + Inc group, the median struggle threshold to pressure decreased from 112 g before surgery to 86 g (P < 0.0001) 2 h after incision, and the process of the threshold recovery was completed by the seventh to eighth day. In the Bup-RTX + Inc group, the response to noxious pressure was completely blocked (with a cutoff of 250 g) for approximately 5 to 6 h. Twenty-four hours after the RTX injection, the struggle threshold was measurable but much greater than the baseline value. By the third to fourth day, the struggle threshold was the same as in the Bup-RTX or Sal-Veh groups. The thresholds in the Bup-RTX + Inc and Bup-Veh + Inc groups at 24 h were 212 g (95% CI, 120–250 g) and 101 g (95% CI, 95–121 g), respectively (P < 0.0005).
RTX completely prevented the incision-induced pain behavior associated with weight bearing. On the day of surgery, the cumulative pain score was 16.2 ± 3.0 (mean ± se) in the Bup-Veh + Inc group and was 0.1 ± 0.1 in the Bup-RTX + Inc group (P < 0.0001 for the difference).
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Discussion |
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Our results demonstrated that perineural RTX inhibits responses to noxious mechanical stimuli in a dose-dependent fashion. A dose of 0.03 µg (0.00003%; 0.1 mL) increased the threshold to noxious pressure for 24 hours. This dose is approximately 3000 times smaller than the dose that produces mechanical hypoalgesia after systemic administration of RTX (13). Complete, but reliably reversible (three weeks or less), block of all nociceptive responses (including the response to noxious heat) was observed with an RTX dose of 1 µg (0.001%; 0.1 mL). With RTX doses of 3 µg (0.003%; 0.1 mL) and 10 µg (0.01%; 0.1mL), in 2 of 10 animals responses to noxious heat did not recover in three weeks. It is possible to suggest that the recovery in these two cases might have occurred by nerve fiber regeneration. If so, the process could have lasted up to eight weeks (14).
Comparison of the responses to noxious pressure and heat revealed that the predominance of the RTX effect on thermal responses was especially prominent with the large concentrations. For example, when the RTX concentration was larger than 0.0003%, blockade of the pressure response did not last longer than 48 hours, even with the largest RTX concentration (0.01%), whereas the blockade of response to heat after this dose could last longer than 3 weeks. At the same time, with the small concentrations of RTX, there were no pronounced differences between the effects on responses to heat and pressure. For example, at an RTX concentration of 0.00003%, both effects lasted 24 hours.
The three-week duration of observations on the RTX-induced blockade in this study was based on the results of studies in rats on the recovery of nociceptive functions of sciatic nerve fibers damaged by different methods. Whether the damage was from a neurolytic block by a local anesthetic (14) or from mechanical nerve injury (15), regeneration of sciatic nerve fibers began to contribute to nociception no earlier than three weeks after the destruction of the fibers. Thus, restoration of nociceptive responses beyond the three-week period is not necessarily due to a reversible nature of the effect of vanilloids on the fiber but may be the result of nerve regeneration with the growth of new fibers. However, the restoration of nociceptive responses before this time speaks against fiber degeneration as an underlying mechanism.
The separation between doses of RTX that produce hypoalgesia and those that produce nociceptive blockade that may last longer than three weeks is rather wide—approximately two orders of magnitude (Fig. 5). The effects of RTX that last longer than three weeks are related to the controversial question about the mechanism underlying this effect: is it a result of the degeneration of afferent fibers or of a long-lasting but reversible loss of their function (16,17)? Avelino and Cruz (18) have commented on this controversy and suggested that the outcomes of the studies that use immunohistochemical methods and those that use electron microscopy are contradictory because immunoreactivity could be lost due to vanilloid-induced axonal transport blockade that slows the arrival of protein gene product (or another marker) to peripheral axons—a process that occurs without nerve degeneration. Almost all published studies on the toxicity of vanilloids after their perineural administration have been performed with capsaicin. At the same time, the spectrum of actions of RTX and capsaicin differ. Whereas capsaicin acts on vanilloid receptors and other targets in overlapping concentration ranges, the various effects of RTX show a profound separation (1). Even if large concentrations of RTX could cause nerve fiber degeneration, these concentrations are far larger than the concentrations that produce hypoalgesia (Fig. 5).
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= concentration that provided an increase in the latency of the withdrawal response to heat by at least 100%; • = minimal concentration that induced blockade of the responses to noxious heat lasting >3 wk in 1 out of 5 rats. Restoration of nociceptive responses beyond the 3-wk period was regarded as a possibility for irreversible damage of the nerve fibers. The figure indicates that the separation is rather wide between doses that produce hypoalgesia and those that produce blockade of the responses to noxious heat and last >3 wk (which can potentially cause fiber degeneration).As we observed in our previous study (7), RTX does not inhibit motor function. This was also clearly demonstrated in the present study when the withdrawal responses to von Frey filaments were measured. Figure 4 illustrates that there was no increase in withdrawal thresholds after RTX administration; indeed, 24 hours after RTX the threshold even had a tendency for decrease.
This study also found that a single percutaneous injection of RTX to the sciatic and saphenous nerves can completely prevent the mechanical hyperalgesia caused by a surgical incision. This outcome is compatible with the results of our previous study, which demonstrated that perineural RTX prevents carrageenan-induced inflammatory hyperalgesia (7). It should be noted that although the concentration of RTX used in experiments with incision-induced hyperalgesia (0.0003%) was smaller than that used with carrageenan-induced hyperalgesia, incisional hyperalgesia was completely prevented.
Brennan et al. (19) reported results of a study with perineural administration of capsaicin in the incisional model of postoperative pain. They applied 1% cap-saicin (in cotton pledgets) on the nerves of the hindlimb, and 4 days later made a plantar incision. One finding of this study was that capsaicin profoundly reduced the cumulative pain score based on weight-bearing at a time when withdrawal latency to heat was not blocked; latency only increased from 11 ± 1s to 17 ± 3s. This result suggests that a valuable therapeutic effect is achievable at the concentrations of a vanilloid that are smaller than those causing complete blockade of sensitivity to noxious heat (which is an extremely sensitive indicator of the antinociceptive effect of vanilloid).
Neubert et al. (20) recently reported the ability of peripherally administered RTX to prevent carrageenan-induced hyperalgesia. They demonstrated that intraplantar injection of RTX blocked both inflammation-induced hyperalgesia and spinal c-Fos induction and hypothesized that the localized, selective, and reversible inactivation of the nerves caused by RTX infiltration could be used for prevention of postoperative pain.
Peripheral neural blockade with local anesthetics is often used as a method of maintaining effective postoperative analgesia. It often provides a postoperative analgesic effect well beyond the duration of the blockade (21). This effect can be explained by the suppression of central sensitization. To provide significant benefits, the regional blockade should last long enough to cover not only the surgery, but also the initial inflammatory phase of injury that extends into the postoperative period and contributes substantially to the process of central sensitization (22,23). To lengthen the duration of the local anesthetic blockade, various continuous blockade techniques are used in clinical practice (24). The other avenue (still experimental) to prolonging the duration of the blockade is sustained-release local anesthetics (25). However, extension of the local anesthetic blockade well into the postoperative period presents a problem for early mobilization (rehabilitation) after surgery and when protective sensation is required. The selective nature of nociceptive blockade with vanilloids would eliminate most serious problems associated with the long-lasting nonselective neural blockade with local anesthetics.
In conclusion, this series of experiments demonstrated that perineural RTX inhibits responses to noxious mechanical stimuli in a dose-dependent manner. This effect is long lasting but reversible. Incisional hyperalgesia that usually lasts for several days can be completely prevented by a single percutaneous injection of RTX to the sciatic and saphenous nerves.
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