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PAIN MEDICINE

Selective and Long-Lasting Neural Blockade with Resiniferatoxin Prevents Inflammatory Pain Hypersensitivity

Igor Kissin, MD PhD^*, Cheryl A. Bright, BS^*, and Edwin L. Bradley, Jr., PhD

*Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Biostatistics, University of Alabama at Birmingham

Address correspondence to Igor Kissin, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to kissin{at}zeus.bwh.harvard.edu

	Abstract

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Capsaicin can produce a selective and long-lasting neural blockade. Resiniferatoxin (RTX) is an ultrapotent vanilloid agonist with a unique spectrum of activities different from that of capsaicin. We sought to determine whether a single application of RTX to a peripheral nerve could completely prevent the long-lasting mechanical hyperalgesia caused by carrageenan injection. In rat experiments, RTX (0.001%) was administered percutaneously to the sciatic and saphenous nerves before the intraplantar injection of carrageenan. Responses to noxious mechanical (pressure on the paw) and thermal (hot plate) stimulations and changes in paw circumference were measured at various time intervals for 8 days after treatment. The administration of RTX resulted in mechanical and thermal hypoalgesia (for 2 and 8 days, respectively). Inflammatory hyperalgesia was completely prevented by the precarrageenan injection of RTX. Inflammatory enhancement of paw circumference was reduced by RTX (12.0 ± 2.4 mm versus 6.9 ± 3.4 mm, P < 0.005). We suggest that the selective nature of the effect of vanilloid agonists on nociception could provide an opportunity for prolonged neural blockade when early mobilization and/or preservation of protective sensation are required.

IMPLICATIONS: We report that an ultrapotent vanilloid agonist resiniferatoxin can provide a selective and long-lasting neural blockade. Applied to the sciatic and saphenous nerves, it completely prevented pain hypersensitivity caused by prolonged inflammatory process (injection of carrageenan into the paw).

	Introduction

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Peripheral neural blockade with local anesthetics is often used as a method of maintaining effective postoperative analgesia. Although neural blockade of nociception often results in pain relief well beyond the duration of the blockade, to provide reliable analgesia, it should last long enough to cover not only the surgery but also a significant part of the early postoperative period (inflammatory phase of surgical injury) (1). In the previous study, we observed in rats that the development of carrageenan (Car)-induced inflammatory hyperalgesia (usually present for several days) could be completely prevented by a long-term nerve block (tonicaine, 12 to 16 hours blockade duration) (2). Local anesthetic blockade is nonselective; therefore, prolongation of the effects of local anesthetics has significant limitations, especially when early mobilization or protective sensation is required.

Some vanilloid agonists can produce selective and long-lasting neural blockade (3). Vanilloid receptor (VR) is viewed as an integrator of nociceptive stimuli generated by inflammatory mediators; it is also activated by noxious heat (3). The cloning of VR heralded the rapid advances in VR pharmacology (4,5). This new development changed the view on the results of previous studies on capsaicin and its analogs. Several studies have reported that the application of capsaicin to a peripheral nerve results in an excitatory effect followed by a selective neuronal inactivation (6–9). Resiniferatoxin (RTX) is an ultrapotent capsaicin analog with a unique spectrum of activities (3). Its excitatory effects relative to its inactivating effects are far less pronounced compared with capsaicin. Some evidence suggests that the structure-activity relationships for the actions for capsaicin and its analogs leading to neuronal excitation and to inactivation are different (3). On this basis, it was suggested that excitation and inactivation correspond to different cellular events mediated by different subtypes of VR (10).

Kohane et al. (11) studied the initial phase of actions of capsaicin and RTX applied to the rat sciatic nerve and found that the interaction between tetrodotoxin (or saxitoxin) and capsaicin (or RTX) regarding suppression of thermal nociception is synergistic.

The question central to prospective use of vanilloid agonists for neural blockade in postoperative pain is their ability to inhibit mechanical hyperalgesia during inflammation. There are no studies on the effects of RTX applied to a peripheral nerve in inflammatory hyperalgesia. The reports on the effect of capsaicin nerve blockade in inflammatory hyperalgesia are usually limited to studies of the blockade of the responses to noxious heat stimuli. The studies regarding the effect of capsaicin (applied to a peripheral nerve) on responses to noxious mechanical stimuli are contradictory; Fitzgerald and Woolf (12) reported that noxious mechanical stimuli were unaffected by capsaicin, whereas Chung et al. (8) observed the inhibitory effect.

The main aim of this study was to determine if a single application of RTX to a peripheral nerve (selective blockade of noxious stimuli) could completely prevent the long-lasting Car-induced inflammatory hyperalgesia.

	Methods

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Experiments were performed on male Sprague-Dawley rats weighting 275–325 g. 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.

The responses to noxious mechanical stimulation were determined by measuring the threshold of motor response (coordinated struggle) to increasing pressure (13) with the use of an Analgesy-Meter (Ugo Basile, Milan, Italy). The threshold was measured by positioning the hind paws on a Teflon platform and directing the device’s 2-mm pressure cone on its dorsal surface. The cutoff pressure was 500 g.

The responses to noxious heat stimulation were determined with the hot-plate test modified as described by Wilder et al. (14). A hot plate (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 from placing the rat onto the hot plate to lifting of the foot was recorded. The cutoff time was 12 s.

Inflammation was induced by injection of 0.1 mL of 2% Car (Sigma Chemical, St Louis, MO) subcutaneously (30-gauge needle) in the plantar surface of the hind paw under halothane (2%) anesthesia. This is an accepted method for the assay of antiinflammatory drugs, and it was used in our previous study (2). To evaluate the development of edema, the plantar circumference of the injected paw was measured by a thread at the metatarsal level, as described by Fletcher et al. (15).

The blockade of the nociceptive input from the inflamed paw was achieved by percutaneous injections at two nerves, the sciatic and saphenous. Both injections were made simultaneously (under brief halothane anesthesia); the sciatic nerve was injected at the greater trochanter level and the saphenous nerve at the midthigh level.

To prevent the initial excitatory effect of RTX, its administration was preceded by bupivacaine (Bup) blockade. Bup (0.5%) was injected in a volume of 0.1 mL at the sciatic nerve and 0.05 mL at the saphenous nerve, providing the blockade for 1 to 2 h followed by hypoalgesia (see details in the results). Fifteen minutes after Bup, the injections at both nerves were repeated with the same volumes of the solutions of RTX or RTX vehicle (Veh; dimethyl sulfoxide in saline with Tween 80). RTX (Sigma) was dissolved in dimethyl sulfoxide (Sigma) to a concentration of 1 µg/µL and stored at -80°C under nitrogen. It was diluted to 0.001% before an experiment in 0.9% saline (Sal) with 0.3% Tween 80 (to avoid precipitation). With the Bup-RTX administration, there were no signs of behavior associated with pain (flinching or licking of the hind paw).

The rats were randomly assigned to one of four groups (n = 9 per group). In Group 1 (Bup-RTX + Car), after baseline measurements (behavioral variables and paw circumference), Bup was injected, and the completeness of sciatic and saphenous nerve blockade was confirmed (by first and fifth digits pinch). Fifteen minutes later, Bup was followed by RTX, and behavioral variables were measured at 1, 2, 4, and 6 h; immediately after this, Car was administered. These variables and paw circumference were again measured, 2 and 4 h after Car (8 and 10 h after RTX) and then 1, 2, 3, 6, and 8 days after the injections. All measurements were made on the injected and contralateral paw. In Group 2 (Bup-RTX), the administration of both drugs was not followed by the injection of Car, and the measurements were the same as in the first group. In Group 3 (Bup-Veh + Car), the injection of Bup was followed by the injections of Veh (for RTX) and Car. In Group 4 (Sal-Veh), Sal was used instead of Bup and Veh instead of RTX.

Raw data were expressed in grams for the motor reaction threshold to pressure and in millimeters for the paw circumference; results are presented as mean ± SD. They were analyzed using a two-way (group and time) analysis of variance, with time treated as a repeated-measures factor. Comparisons between group mean ± SD at each time were performed with one-way analysis of variance. Multiple comparisons among mean ± SD were made using Fisher’s protected least significant difference test. Comparisons between groups regarding the percentage of rats not responding to the stimulation over time were made with the asymptotic test of regression slopes from a least squares repeated-measures regression. The results were declared significant if P < 0.05.

	Results

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The effects of the percutaneous administration of RTX to the sciatic and saphenous nerves regarding mechanical hyperalgesia are presented in Figure 1. In the Bup-Veh + Car group (Car without RTX pretreatment), the motor reaction threshold to pressure was decreased by approximately half (from 163 ± 16 g to 79 ± 27 g 4 h after the Car injection, P < 0.001), and the process of the threshold recovery continued for 8 days. The effect of Car was identical to its effect observed in our previous study (2). In this group (Bup-Veh + Car), the effect of Bup was observed (without the addition of RTX) for 6 h before the administration of Car. One hour after the Bup injection, the response to noxious stimulation was blocked in all 9 rats of the group. At 2 h, the response was not completely blocked in 5 of 9 rats; however, the threshold of the response in these 5 rats was increased. Four hours after Bup, the threshold of the response to noxious stimulation was not significantly different from the control. In the Bup-RTX + Car group, motor response to noxious mechanical stimulation was completely blocked (with cutoff of 500 g) for 6 to 8 h. Twenty-four hours after the RTX injection, the pressure threshold was measurable but was greater than that at baseline (245 ± 61 g versus 156 ± 14 g, P < 0.001). The threshold declined by the second day; however, it still was significantly greater than the corresponding level in the Bup-Veh + Car group (167 ± 29 g versus 141 ± 19 g, P < 0.05). The pressure threshold changes in the Bup-RTX group were relatively similar to those in the Bup-RTX + Car group, although, in the former group, pressure threshold returned to the measurable values (below the cutoff level) later and had a tendency to be larger (Fig. 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. The effect of resiniferatoxin (RTX) on long-term mechanical hyperalgesia. RTX (0.001%) was applied percutaneously to both the sciatic (0.1 mL) and saphenous (0.05 mL) nerves. To prevent an initial excitatory effect of RTX, percutaneous bupivacaine (Bup) (0.5%) nerve blockades preceded (15 min) injections of RTX or RTX vehicle (Veh; dimethyl sulfoxide in saline (Sal) with Tween 80). Six hours after RTX, carrageenan (Car) was injected into the plantar surface of the ipsilateral paw (2%, 0.1 mL). Hyperalgesia was determined by measuring the threshold of motor response (coordinated struggle) to increasing pressure on the paw with an Analgesy-Meter (Ugo Basile). Four groups of adult male Sprague-Dawley rats (n = 9 per group) were used. Values are mean ± SD. The upward pointing arrows represent the time at which the drugs are administered. Statistical significance: a = P < 0.0001, b = P < 0.01, and c = P < 0.05, all versus the Bup-Veh + Car group. The results demonstrate that the percutaneous administration of RTX to the peripheral nerves suppresses motor responses to mechanical noxious stimulation, and the effect lasts for approximately 2 days (Bup-RTX group). The comparison of the Bup-RTX + Car and Bup-Veh + Car groups indicates that RTX completely prevents Car-induced hyperalgesia.

View larger version (22K): [in this window] [in a new window]   Figure 2. The effect of resiniferatoxin (RTX) on long-term thermal hyperalgesia. The rat’s foot was placed on the hot plate (56°C), and the latency of foot withdrawal was measured. See other details in Figure 1. Values in the upper block of the figure represent the percentage of rats (n = 9 per group) not responding to the thermal stimulation (with cutoff of 12 s). Statistical significance: a = P < 0.001 versus saline (Sal)-vehicle (Veh) group and b = P < 0.05 for the difference between curves for the duration of thermal blockade. The figure demonstrates that the RTX-induced complete blockade of the responses to thermal noxious stimulation lasts from 2 to 8 days (upper block). The thermal latency (lower block) does not completely recover even at Day 8. The comparison of the bupivacaine (Bup)-RTX + carrageenan (Car) and Bup-Veh + Car groups indicates that RTX completely prevents Car-induced hyperalgesia that lasts more than 8 days.

View larger version (15K): [in this window] [in a new window]   Figure 3. The effect of resiniferatoxin (RTX) on carrageenan (Car)-induced edema of the paw. The edema was measured as an increase of the paw circumference at the metatarsal level. Time scale indicates that from the moment of RTX administration, Car was injected at 6 h. See other details in Figure 1. Statistical significance: a = P < 0.002 and b = P < 0.005 versus bupivacaine (Bup)-vehicle (Veh) + Car group. The figure demonstrates that RTX suppresses the development of Car-induced edema.

	Discussion

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Fitzgerald and Woolf (12) reported that capsaicin (1.5%) applied locally to a peripheral nerve provided inhibition of responses to noxious heat stimuli for up to 16 days, but noxious mechanical stimuli were unaffected by this treatment. However, Chung et al. (8) found that capsaicin (1%) applied to the sciatic nerve, in addition to almost complete elimination of responses to noxious heat stimuli, decreased responses to noxious mechanical stimuli. At the same time, they observed that responses to innocuous mechanical stimuli were increased. Analysis of the studies with the systemic administration of capsaicin indicates that the drug does have a potential for the suppression of responses to noxious mechanical stimuli (18,19). Xu et al. (20) reported that the systemic administration of RTX (0.5 mg/kg subcutaneously) caused a marked thermal hypoalgesia that started to recover after two weeks and also caused mechanical hypoalgesia, which recovered a week after the injection. Kohane et al. (11) determined that RTX applied to the rat sciatic nerve suppressed responses to thermal noxious stimuli; they did not study responses to mechanical stimuli.

Our results demonstrated that a percutaneous application of RTX to peripheral nerves suppresses motor responses to mechanical noxious stimulation. Thus, RTX acts on responses to mechanical noxious stimuli in a manner similar to that observed by Chung et al. (8) with another vanilloid agonist, capsaicin.

The inhibitory effect of RTX on responses to noxious heat stimuli is much more pronounced than that on responses to noxious mechanical stimuli (Figs. 1 and 2). However, the effect of RTX on mechanical nociception can be sufficiently profound and long lasting. Experiments with Car-induced mechanical hyperalgesia demonstrated that its development was completely prevented by percutaneous injection of RTX to the sciatic and saphenous nerves (without RTX, hyperalgesia lasted for several days). However, the duration of the antihyperalgesic effect of RTX was only slightly more prolonged than that of reduced responsiveness to stimuli to the uninflamed paw (Bup-RTX versus Bup-RTX + Car).

The ability of vanilloid agonists to block the conduction of impulses was demonstrated in experiments with capsaicin in single-unit potential and compound-action potential recordings of whole peripheral nerve (7–9). These studies revealed that the application of capsaicin to a peripheral nerve produces changes in C-fiber afferent volleys that are caused by conduction blockade at the site of capsaicin application. A-fiber volleys were changed to a smaller degree, and Aß-fiber increases did not change at all. Because of the selective nature of neural blockade induced by vanilloid agonists, their antihyperalgesic effect is not associated with motor impairment.

We detected a significant effect of the RTX administration to the sciatic and saphenous nerves on the Car-induced paw edema (Fig. 3). Two recent studies in rats with prolonged local anesthetic blockade of peripheral nerves reported insignificant (2) or moderate (21) reduction of Car-induced edema. The VR is viewed as an integrator of nociceptive stimuli generated by inflammatory mediators (3). A greater degree of the antiinflammatory effect of RTX compared with that of local anesthetics might be related to this property.

RTX is an ultrapotent vanilloid agonist; its initial excitatory effects relative to its inactivating effects are far less pronounced compared with those of capsaicin (3). Nevertheless, to prevent the initial excitatory effect of RTX, its administration in our experiments was preceded by Bup (0.5%), which produced a blockade lasting from one to two hours. It was demonstrated previously in rat experiments that a local anesthetic blockade of such duration provides no noticeable effect on Car-induced hyperalgesia (2,21). The RTX-induced hypoalgesic effect lasted more than an order of magnitude longer than the effect of Bup (which in addition was nonselective).

Because of the constraints of humane treatment of experimental animals, we did not have an experimental group with RTX without the previous administration of Bup. Therefore, we cannot exclude a possibility that previous Bup was influencing the action of RTX. However, the profound difference in the duration of neural blockade induced by these drugs makes such a possibility, in our opinion, rather remote.

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. 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 (1,22). To lengthen the duration of the local anesthetic blockade, various continuous blockade techniques are used in clinical practice (23). The other avenue (still experimental) to prolong duration of the blockade is the development of sustained-release local anesthetics (24). However, the 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. Nevertheless, selective and long-duration analgesia has been reported after the epidural administration of a suspension preparation of the amino-ester local anesthetic butyl-aminobenzoate (butamben) in a study of nerve injury-induced allodynia in rats. Daily epidural butamben for five days resulted in dose-related attenuation of allodynia for at least seven days after the last epidural injection, with no change in motor function (25). The physicochemical properties of the suspension and selectivity for nontetrodotoxin sensitive sodium channels may have contributed to the selectivity of butamben (25). Unfortunately, a clinically useable formulation of butamben has not been produced despite anecdotal reports (25) of selective analgesic effects of butamben in patients with cancer pain. New developments in the area of VRs indicate that drugs for a selective and long-lasting nociceptive blockade can probably be found among vanilloid agonists. Selective nociceptive blockade would eliminate most serious problems associated with the long-lasting nonselective neural blockade with local anesthetics.

An important step for the clinical use of RTX was made by Cruz et al. (26) who successfully treated the irritable bladder syndrome by intravesical RTX. The important question regarding the clinical use of RTX for neural blockade is the duration of its effect and the completeness of the recovery after the drug wears off. Capsaicin applied locally to a peripheral nerve in large concentrations selectively and permanently damages sensory nerve fibers, resulting in sensory deficits that last for months (6). An intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers (27). In the present study, the effect of RTX on the responses to mechanical nociceptive stimulation lasted for several days and approximately one week for the responses to thermal stimulation. RTX shows a wide separation between dose-response curves for its various effects (3). Relatively small concentrations of RTX (0.001%) used in our experiments produced a spontaneously reversible neural blockade. Complete reversibility of the effects of small concentrations of RTX on the functions of different nerve fibers requires confirmation with the use of electrophysiological methods.

In conclusion, the experiments demonstrated that the percutaneous administration of RTX to peripheral nerves can provide long-lasting suppression, not only thermal but also mechanical nociception. Car-induced inflammatory hyperalgesia that usually lasts for several days can be completely prevented by a single injection of RTX to the sciatic and saphenous nerves. The selective nature of the effect of vanilloid agonists on nociception could provide an opportunity for neural blockade lasting for the entire period of residual injury-induced inflammation.

	Acknowledgments

 
The authors thank Dr. Gary Strichartz for helpful comments.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999