Anesth Analg 2007; 105:1152-1159
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000281435.58012.e3
ANALGESIA
Section Editor:
Tony L. Yaksh
Epidural Tezampanel, an AMPA/Kainate Receptor Antagonist, Produces Postoperative Analgesia in Rats
Hee Cheol Jin, MD, PhD,
Amber J. Keller, MD,
Jong Kwon Jung, MD,
Alberto Subieta, BS, and
Timothy J. Brennan, MD, PhD
From the Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa.
Address correspondence and reprint requests to Timothy J. Brennan, MD, PhD, Department of Anesthesia, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242-1079. Address e-mail to tim-brennan{at}uiowa.edu.
Abstract
BACKGROUND: We evaluated the epidural administration of tezampanel, a non-N-methyl-d-aspartate receptor antagonist, in a rat model for postoperative pain. We sought to determine if this drug affects nociception when administered epidurally by testing its effects on responses to heat in normal rats. The effects of epidural tezampanel on pain-related behaviors in rats that underwent plantar incision were also studied.
METHODS: Rats were anesthetized and epidural catheters were placed. One day after epidural catheterization, the baseline heat withdrawal latency was measured. Epidural tezampanel or morphine was tested for analgesia by examining their effects against heat withdrawal latency. Motor function was also tested. Comparisons to subcutaneous drug administration were made. Other rats underwent plantar incision after epidural catheterization to assess pain behavior caused by incision. The effects of epidural tezampanel on the cumulative pain scoring, based on guarding, the withdrawal threshold to von Frey filament application, and the withdrawal latency to heat, were measured. The effects of epidural tezampanel on arterial blood pressure and heart rate were also tested.
RESULTS: Both epidural morphine and epidural tezampanel increased withdrawal latency to heat. Only subcutaneous morphine affected heat withdrawal latency. After plantar incision, epidural tezampanel decreased the median guarding pain score, increased the heat withdrawal latency and increased the mechanical withdrawal threshold indicating analgesic effects. Arterial blood pressure and heart rate did not change after epidural drug administration.
CONCLUSION: These experiments demonstrate that epidural administration of tezampanel produces analgesia to heat, motor side effects in some rats, and reduces pain behaviors caused by incision. No systemic analgesia was apparent using the largest dose.
Glutamate activates both N-methyl-d-aspartate (NMDA) as well as non-N-methyl-d-aspartate excitatory ionotropic amino acid receptors (1). It has been suggested that drugs blocking the non-N-methyl-d-aspartate,  -amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate, receptor system may be useful for the treatment of a variety of diseases; yet, clinical anesthesia has not taken advantage of drugs blocking the non-N-methyl-d-aspartate receptor system (2).
Previously, we demonstrated that intrathecal injection of a non-N-methyl-d-aspartate receptor antagonist, LY293558 (NGX424, tezampanel), blocked both sensory and motor responses in the hindquarter of the rat sufficient to produce spinal anesthesia (3). This study suggested that drugs like tezampanel that block AMPA/kainate receptors may be alternatives to local anesthetics for spinal anesthesia and spinal analgesia by producing synaptic blockade, rather than conduction blockade of sensory and motor transmission (2,4–10).
In a previous study, intrathecal tezampanel reduced the exaggerated responses to mechanical stimuli after plantar incision (3). However, motor side effects were prominent. Epidural administration is an alternative to intrathecal administration for postoperative analgesia. In this study, we sought to determine if tezampanel affects nociception when administered epidurally by testing its effects on responses to heat in normal rats. A comparison to morphine is made. Because this drug may be an alternative to local anesthetics for spinal anesthesia, it is logical that it may also be an alternative to currently available epidural analgesics for postoperative pain management. Thus, we evaluated the epidural administration of tezampanel, an AMPA/kainate receptor antagonist, in a rat model for postoperative pain. We tested epidural tezampanel against a variety of incision-induced, pain-related behaviors in our model.
METHODS
The Animal Care and Use Committee at the University of Iowa, IA, approved these experiments, and the animals were treated in accordance with the Ethical Guidelines for Investigations of Experimental Pain in Conscious Animals. Male Sprague-Dawley rats, 250–300 g (Harlan, Indianapolis, IN), were housed in pairs before surgery and were housed individually afterward. Food and water were available ad libitum. At the end of protocol, rats were killed using CO2.
Surgery
Epidural Catheterization
A polyethylene (PE10) catheter (length, 15 cm; OD, 0.61 mm; ID, 0.28 mm) was prepared and cold-sterilized before insertion. Rats were anesthetized with 2%–3% halothane in oxygen delivered via a nose cone. The lumbar region was shaved, prepared with 10% povidone–iodine, made kyphotic, and incised 2–2.5 cm longitudinally in the midline at the level of the iliac crests. The paraspinal musculature was dissected bluntly from vertebra. The sixth spinous process was removed to facilitate epidural catheter insertion. After making a small hole between L5 and L6 intervertebral space with an electrical drill, the epidural catheter was inserted approximately 4 cm with the aid of a dissecting microscope. The catheter was sutured to the fascia, tunneled under the skin to the cervical region, flushed with saline, and sealed with electrocautery. The skin was closed with 3-0 silk suture. After the experiments, rats were killed, and the catheter was injected with 60 µL of Evan’s blue dye and flushed with 30 µL of saline. The spine was dissected to confirm dye in the epidural space. Of 67 rats with catheters placed, 7 were intrathecal and 60 were epidural; the data from rats with intrathecal catheters were excluded. The rat epidural space quickly develops adhesions after cannulation (11,12). Because previous studies showed that epidural fibrosis was a problem (11,12), rats were studied 1 and 2 days after epidural cannulation. This requires two consecutive days of surgery, first the epidural procedure followed by the plantar incision.
Plantar Incision
The day after epidural catheterization, rats are anesthetized for plantar incision using the same method as described earlier. As described previously (13), the plantar aspect of the right hindpaw was sterilized with 10% povidone-iodine and the paw was placed through a sterile drape. A 1-cm longitudinal incision was made with a number 11 blade, through skin and fascia of the plantar aspect of the foot, starting 0.5 cm from the proximal edge of the heel and extending toward the toes. The underlying flexor muscle was elevated and incised longitudinally. The muscle origin and insertion remained intact. After hemostasis with gentle pressure, the skin was apposed with two mattress sutures of 5-0 nylon on an FS-2 needle. The wound site was covered with a mixture of polymixin B, neomycin, and bacitracin ointment. After surgery, the rats were allowed to recover in their cages.
Behavioral Testing
Rats were acclimated 2 days before testing began. Five tests were used. To assess pain behavior, we measured the cumulative pain scoring based on guarding, the withdrawal threshold to von Frey filament application, and the withdrawal latency to heat. For motor function, we measured the placing reflex and the ambulation score (3,5).
Withdrawal Threshold to Mechanical Stimulation
Unrestrained rats were placed beneath a clear plastic chamber (21 x 27 x 15 cm) on an elevated plastic mesh floor and allowed to acclimate. Withdrawal threshold to mechanical stimulation were determined using calibrated von Frey filaments applied from underneath the cage through openings in the plastic mesh floor (grid 12 x 12 mm) to an area adjacent to the wound near the medial heel. Each von Frey filament was applied once starting with 10 mN (1.0 g) and continuing until a withdrawal threshold occurred or the 250 mN (25.5 g) filament was tested. After 5 min test-free period, each filament was again applied once beginning with 10 mN until a withdrawal threshold was elicited. This was repeated a third time 5 min later. The lowest force from the three tests producing a response was considered the withdrawal threshold. If there was no withdrawal response to 250 mN, the next filament, 586 mN, was recorded.
Cumulative Pain Score
The unrestrained animals were placed on an elevated plastic mesh floor (grid 8 x 8 mm) under a clear plastic chamber (21 x 27 x 15 cm) and allowed to acclimate for 25 min. By using an angled magnifying mirror, the incised foot could be viewed. Each animal was closely observed during a 1-min period repeated every 5 min for 1 h. Depending on the position in which the foot was found during the scoring period, a 0, 1, or 2 was given. Full weight bearing of the foot (score = 0) was present if the plantar aspect of the hindpaw was blanched or distorted by the mesh. If the foot was completely off the mesh, a score of two was recorded. If the plantar aspect of the hindpaw touched the mesh without blanching or distorting, a one was given. The sum of the 12 scores (0–24) of each side was calculated and the value that the sum of right side minus the sum of left side was recorded as the cumulative pain score.
Withdrawal Latency to Heat
Heat withdrawal was measured by applying a focused radiant heat source from underneath a glass floor (3 mm thick) to the plantar aspect of the paw. The heat stimulus was light from a 50-W projector lamp, with an aperture diameter of 6 mm. At the beginning of the study, the intensity of the heat was adjusted so that the baseline was approximately 15 s. The maximum time of exposure was set at 25.1 s to prevent possible heat injury. The latency to an abrupt withdrawal of the hindpaw from the heat was recorded. Heat withdrawal latency was measured in two groups; in unincised rats, latency was measured in each paw and averaged. In incised rats, latency of the incised paw was measured three times and averaged.
Motor Testing
Ambulation (walking) was observed for approximately 1 min and scored (2 = normal; 1 = limping; 0 = paralyzed). Then, the placing reflex was tested. Rats were placed on a table, and the dorsum of each hindpaw was drawn across the edge of the table. This elicits a lifting of the paw onto the surface of the table (2 = normal; 1 = delay of 1 to 2 s; 0 = more than 2 s).
Experimental Protocols
Epidural Drug Administration in Unincised Rats
One day after epidural catheterization, the baseline heat withdrawal latency was measured. Preservative-free saline (n = 5), preservative-free 5% dextrose in water (n = 5), morphine 215 nmol (n = 7), tezampanel 24 nmol (n = 7), tezampanel 72 nmol (n = 7), or tezampanel 125 nmol (n = 7) was injected via the epidural catheter. Thirty, 60, 120, 180, and 240 min after injection, heat withdrawal latency, placing reflex, and ambulation score were measured. The next day, heat withdrawal latency was measured again. There was no residual effect of the previous day’s injection. Drug or vehicle was injected and responses to heat were measured as described above. No rat received the same dose of drug or vehicle. Twenty-four rats were used for testing epidural drug administration; 10 rats were tested once and 14 rats were tested twice. The injection volume for all epidural drug injection was 60 µL. All epidural drug injections were followed by a flush of 30 µL preservative-free saline. In our preliminary trials, small injection volumes of 20 µL, similar to those used by Nishiyama and Hanaoka (12) produced inconsistent analgesia after tezampanel injection. In some cases, sensory tests revealed only one limb was affected.
Subcutaneous Drug Administration in Unincised Rats
After acclimation, the preinjection heat withdrawal latency was measured. Saline (n = 6), 5% dextrose in water (n = 6), morphine 215 nmol (n = 6), tezampanel 72 nmol (n = 6), or tezampanel 125 nmol (n = 6) was injected subcutaneously. Thirty, 60, 120, 180, and 240 min after injection, heat withdrawal latency, placing reflex, and ambulation score were measured. The next day, heat withdrawal was measured again. There was no residual effect of the previous day’s injection. Drug or vehicle was injected and responses to heat were measured. Twelve rats were used for testing subcutaneous drugs; six were tested four times and six were used once. The injection volume was 0.3 mL for subcutaneous administration.
Epidural Drug Injection After Plantar Incision
Rats underwent epidural cannulation. The next day, before plantar incision, the baseline pain behaviors cumulative pain score was measured. Then plantar incision was made, and 2 h later, the cumulative pain score was again measured. Five percent dextrose water (n = 6), tezampanel 24 nmol (n = 6), tezampanel 72 nmol (n = 6), or tezampanel 125 nmol (n = 6) was injected via the epidural catheter. Twenty-five minutes later, the cumulative pain score was measured for 1 h.
The next day, postincision day one, the heat withdrawal latency and mechanical withdrawal threshold were measured. Vehicle (n = 6), tezampanel 24 nmol (n = 6), tezampanel 72 nmol (n = 6), or tezampanel 125 nmol (n = 6) was injected via the epidural catheter. Twenty-five minutes after the injection, withdrawal threshold to mechanical stimulation and the withdrawal latency to heat were measured. The time to perform these tests was approximately 1 h. Thirty-six rats were used to obtain the data; 24 rats were tested on both days; resting pain on the day of incision followed by heat and mechanical testing on postincision day 1. Twelve rats were tested only the day of incision for resting pain.
Arterial Blood Pressure and Hear Rate Measurements
For arterial blood pressure measurement, the paratracheal region was shaved, prepared with povidone–iodine, and incised 1.5–2 cm longitudinally lateral to the midline. The carotid artery was isolated and cannulated with PE-50 tubing that had been stretched by exposing the distal end to heat. The secured catheter was tunneled subcutaneously to the posterior neck region. The skin was closed with 4-0 silk, and the rat recovered for 2–3 days before measurements were made. Mean arterial blood pressure and heart rate were measured before epidural injection and 15, 30, 60, 90, 120, and 180 min after injection. The carotid artery catheter was attached to a pressure transducer and relayed to a polygraph and preamplifier (Grass Instruments, Quincy, MA; model 7P511J). Heart rate was intermittently measured by counting the arterial pulse wave for 30 s.
Drugs
Preservative-free saline, preservative-free 5% dextrose in water were used for vehicle injections. Morphine (Sigma, St. Louis, MO) 215 nmol was dissolved in saline. Tezampanel, a gift from TorreyPines Therapeutics (San Diego, CA), was dissolved in 5% dextrose in water. Drugs were made fresh each week. The person evaluating the behavior was blinded to which drug or vehicle was injected.
Statistical Analysis
All drug effects were compared versus baseline, predrug responses. Heat withdrawal latency was analyzed using repeated measure of ANOVA. Post hoc Dunnett’s test was used for comparison of drug effect versus baseline in nonincised rats. A paired t-test was used to determine significance of drug effect versus preinjection values in incised rats. For withdrawal threshold to mechanical stimulation and the cumulative pain score, nonparametric statistics were used (14). Wilcoxon’s signed rank test was used to determine significance of drug effect versus preinjection values in incised rats. For nonincised rats, motor tests after epidural injection were analyzed with Friedman test and post hoc Dunn’s test for comparison of drug effect versus baseline. The results are expressed as median or mean ± sd (sd) when appropriate. P < 0.05 was considered significant.
RESULTS
Epidural administration of saline, 5% dextrose, and tezampanel 24 nmol did not change withdrawal latency to heat in unincised rats (Figs. 1A and B). Epidural morphine (215 nmol) increased withdrawal latency to heat 30 and 60 min (P < 0.05 versus pre) after injection. Epidural tezampanel 72 nmol increased withdrawal latency to heat 30, 60, and 120 min (P < 0.05 versus pre) after injection, and the largest dose, 125 nmol, increased withdrawal latency through 180 min (P < 0.05 versus pre). Subcutaneous administration of saline, 5% dextrose, tezampanel 72 nmol, and tezampanel 125 nmol had no effect (Figs. 1C and D). Subcutaneous administration of morphine 215 nmol increased withdrawal latency to heat 30, 60, 120, and 180 min after injection (P < 0.05 versus pre).
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Figure 1. Time course of withdrawal latency to heat before and after epidural and subcutaneous drug injection in normal, unincised rats. Withdrawal latency to heat was measured before and 30, 60, 120, 180, and 240 min after epidural injection of saline, morphine 215 nmol (A), epidural injection of 5% dextrose in water, tezampanel 24 nmol, tezampanel 72 nmol, and tezampanel 125 nmol (B), after subcutaneous injection of saline, morphine 215 nmol (C), after subcutaneous injection of 5% dextrose in water, tezampanel 72 nmol, and tezampanel 125 nmol (D). Data are expressed as the mean ± sd *P < 0.05 versus preinjection; **P < 0.01 versus preinjection; ***P < 0.001 versus preinjection.
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Epidural injection of tezampanel caused transient motor deficits in a few rats; we could detect changes in 2 rats after 24 nmol, 2 rats after 72 nmol, and 3 rats after 125 nmol using the placing reflex (Fig. 2), and in 2 rats after 72 nmol and 2 rats after 125 nmol using the ambulation test (Fig. 3). There was no statistical difference in the placing reflex or ambulation test before versus after injection. There were no motor deficits after subcutaneous drug administration (data not shown).
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Figure 2. Time course of placing reflex before and after epidural drug injection in unincised rats. Placing reflex was measured before and 30, 60, 120, 180, and 240 min after epidural injection of saline (A), morphine 215 nmol (B), 5% dextrose (C), tezampanel 24 nmol (D), tezampanel 72 nmol (E), and tezampanel 125 nmol (F). Solid lines are the medians for the filled circles (left hindpaw) placing reflex. Broken lines are the medians for the open circles (right hindpaw) placing reflex.
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Figure 3. Time course of ambulation score before and after epidural drug injection in unincised rats. Ambulation score was measured before and 30, 60, 120, 180, and 240 min after epidural injection saline (A), morphine 215 nmol (B), 5% dextrose (C), tezampanel 24 nmol (D), tezampanel 72 nmol (E), and tezampanel 125 nmol (F). Solid lines are the medians for the filled circles which are each rat’s score. n = 5 in saline and 5% dextrose in water group; n = 7 in other groups.
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In all rats, incision increased the median cumulative pain score from 0.0 to 16.5 on the day of incision. Epidural injection of 5% dextrose and tezampanel 24 nmol did not change the cumulative pain score (Fig. 4A). Epidural injection of tezampanel 72 nmol and 125 nmol decreased the cumulative pain score from 15.5 and 16.0 to 5.0 and 2.0, respectively (P < 0.05 versus postincision). On postoperative day 1, the heat withdrawal threshold had decreased from 16.7 ± 1.5 to 4.3 ± 1.0 s and the median withdrawal threshold had decreased from 250 to 31 mN in all rats. Epidural injection of vehicle had no effect, but tezampanel 24 nmol, 72 nmol, and 125 nmol increased the heat withdrawal latency to 5.2 ± 1.4, 8.6 ± 2.5, 13.2 ± 6.8 s, respectively (P < 0.05 versus postincision; Fig. 4B). Neither vehicle nor 24 nmol of tezampanel affected mechanical threshold after incision, but 72 and 125 nmol increased the median withdrawal threshold to 114 and 340 mN, respectively (P < 0.05 versus postincision; Fig. 4C). Epidural tezampanel, 125 nmol, did not affect arterial blood pressure or heart rate similar to our results for intrathecal injection (3). The average mean arterial blood pressure was 120 ± 10 mm Hg, and the lowest reading in the next 3 h was 120 ± 15 mm Hg (data not shown).
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Figure 4. Pain behaviors before and after epidural drug injection in incised rats. Cumulative pain score (A), withdrawal latency to heat (B), and mechanical withdrawal threshold (C) were measured before plantar incision, after plantar incision, and after epidural injection of 5% dextrose in water, tezampanel 24 nmol, tezampanel 72 nmol, tezampanel 125 nmol. PreInc: preincision; PostInc: postincision; PostDrug: after epidural drug injection. Von Frey threshold and cumulative pain score are expressed as the median and range. Withdrawal latency is expressed as the mean ± sd *P < 0.05 versus PostInc. n = 6 per group.
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DISCUSSION
These experiments demonstrate that epidural administration of tezampanel produces analgesia to heat, motor side effects in some rats, and reduces pain behaviors caused by incision. No systemic analgesia was apparent using the largest dose of tezampanel that was administered epidurally. Arterial blood pressure was not affected by epidural tezampanel. In previous studies, we examined intrathecal tezampanel only against mechanical responses after incision. In this study, epidural injection was used and a variety of pain behaviors were examined.
We compared the analgesic effects produced by epidural and subcutaneous tezampanel to epidural and subcutaneous morphine using withdrawal to noxious radiant heat. In rats, both subcutaneous and epidural morphine, 215 nmol, increased the withdrawal latency to heat and affected the responses to a similar degree. Other authors have demonstrated analgesic effects of epidural morphine in doses ranging from 2.5 to 100 µg (approximately 9–360 nmol) in other nociceptive models in rats (15–18). We chose the 215 nmol dose of morphine because it produced consistent, bilateral effects on heat withdrawal responses and with a similar magnitude to the 72 nmol dose of tezampanel. It was surprising that the subcutaneous route of morphine administration had virtually the same effect as the epidural dose. This may have been related to the volume of injection or the nociceptive test, hindpaw withdrawal to heat. Neither route of morphine administration produced detectable motor effects.
Epidural tezampanel increased the heat withdrawal latency in normal, unincised rats, demonstrating an antinociceptive effect. This is not surprising, since primary afferent nociceptors and dorsal horn interneurons release glutamate onto AMPA/kainate receptors of the spinal cord (19–23). Because systemically administered tezampanel in doses up to 125 nmol showed no effect on heat withdrawal latency, the effect of epidural administration was likely a spinal action of the drug. In agreement, intrathecal non-N-methyl-d-aspartate receptor antagonists were antinociceptive in normal animals (3,24). In previous studies, spinal dorsal horn cells activated by noxious stimuli are inhibited by non-N-methyl-d-aspartate receptor antagonists (20). These studies are in agreement with a spinal action of epidural tezampanel to inhibit heat responses.
No hemodynamic effects were observed after epidural tezampanel. Previous studies showed that intrathecal tezampanel, administered in doses that produced complete spinal anesthesia, did not affect arterial blood pressure (3). Thus, we did not anticipate hypotension or compensatory tachycardia after epidural administration of tezampanel because the magnitude of the motor and sensory effects was less than intrathecal administration. Thus, a potential advantage of epidural administration of tezampanel over epidural local anesthetics may be fewer hemodynamic effects.
Epidural tezampanel affected all exaggerated pain-related behaviors caused by plantar incision as observed with intrathecal tezampanel and other non-N-methyl-d-aspartate receptor antagonists administered intrathecally in this model (25). In agreement, dorsal horn neurons sensitized by incision were inhibited by a spinal non-N-methyl-d-aspartate receptor antagonists (26). It is tempting to speculate on the role of the non-N-methyl-d-aspartate receptor system and central sensitization after surgery, since this class of receptors has been implicated in plasticity of other systems (27,28). Clearly, epidural doses that are antihyperalgesic after incision are antinociceptive to heat in the normal condition.
Epidural tezampanel, on occasion, affected motor function, but, as opposed to the analgesic effect, the motor responses were inconsistently decreased. The motor deficits after epidural injection of tezampanel were less than motor deficits caused by antihyperalgesic doses administered intrathecally in rats (25). For example, intrathecal administration of 0.5 nmol significantly decreased mechanical responsiveness after incision but also significantly slowed the placing reflex, a greater effect than observed after epidural administration.
Subcutaneously administered tezampanel, in doses injected epidurally, were not evaluated in incised rats. Previous studies showed very little effect of subcutaneous administration of much larger doses, 17 µmol/kg (approximately 50 µmol per rat) on mechanical withdrawal threshold (25). Thus, the largest epidural dose in the present study, 125 nmol, is unlikely to have a systemic effect on pain behaviors. Hopefully, doses that may be effective when administered epidurally to humans may not produce side effects if accidentally administered parenterally.
Thus far, no formal toxicity studies on spinal administration of tezampanel have been undertaken; therefore, this drug cannot be tested epidurally or intrathecally in human studies. Since few new drugs have been added to our armamentarium for postoperative epidural analgesia beyond opioids and local anesthetics, further studies of drugs like tezampanel are warranted. Our results indicate that such drugs may be a good alternative to local anesthetics and opioids for postoperative pain management when administered epidurally.
Footnotes
Accepted for publication June 18, 2007.
Supported by the National Institutes of Health, Bethesda, Maryland, Grant GM 55831 and GM 067762 (to T.J.B.).
Presented at the Annual meeting of the American Pain Society, San Antonio, Texas, May 3–6, 2006.
Dr. Brennan has received a patent no. 10/033,632 for Tezampanel for spinal anesthesia.
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