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Anesth Analg 2006;103:334-343
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000223674.52364.5c

ANESTHETIC PHARMACOLOGY

Section Editor:
James G. Bovill

Upregulation of Cerebrospinal Fluid and Peripheral Prostaglandin E2 in a Rat Postoperative Pain Model

Jeffrey S. Kroin, PhD, Asokumar Buvanendran, MD, Daniel E. Watts, BS, Chiranjeev Saha, MD, and Kenneth J. Tuman, MD

From the Department of Anesthesiology, Rush Medical College, Chicago, Illinois.

Address correspondence and reprint requests to Jeffrey S. Kroin, PhD, Department of Anesthesiology, Rush Medical College, 1653 W. Congress Parkway, Chicago, IL 60612. Address e-mail to jkroin{at}rush.edu.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 
Analgesic management of postoperative pain associated with thoracic surgery remains a difficult clinical challenge. In the present study we used a thoracic muscle incision model to characterize pain-related behavior and changes in prostaglandin E2 (PGE2) in both thoracic cerebrospinal fluid (CSF) and incision site tissues. A deep muscle incision was made in the left thoracic region of rats anesthetized with isoflurane, propofol, or spinal bupivacaine. Thoracic CSF and incision site tissue concentrations of PGE2 were monitored for 6 h using microdialysis loop catheters. Postoperative pain-related behavior was assessed by recording exploratory locomotive activity. Thoracic muscle surgery decreased rearing and ambulation. Oral ketorolac or rofecoxib 3 mg/kg restored normal rearing and ambulation. Postoperative CSF PGE2 concentration increased most (threefold) with spinal anesthesia, and not at all with propofol. With surgery under isoflurane or spinal bupivacaine, presurgical oral administration of ketorolac or rofecoxib 3 mg/kg reduced postsurgical CSF PGE2 levels and tissue PGE2 levels. Intrathecal ketorolac (4 µg) reduced CSF PGE2 after surgery without affecting tissue PGE2 levels, whereas intrathecal L-745,337 (80 µg) did not reduce CSF PGE2. Thoracic surgical wounds increase pain-related behavior and CSF and tissue PGE2 levels, all of which can be attenuated by oral cyclooxygenase inhibitors.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 
Modulation of postoperative pain with cyclooxygenase (COX) inhibitors is increasingly common. Preoperative oral administration of a COX-2 selective inhibitor in patients decreases both postoperative pain and surgical site and cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2) after hip replacement surgery (1). PGE2 is the predominant eicosanoid released from endothelial cells after surgical trauma (2). IV administration of a COX-2 selective inhibitor is more effective in reducing CSF PGE2 and pain after vascular surgery in patients than a mixed COX-1/COX-2 inhibitor (3). In humans, after tooth extraction, implanted microdialysis probes have recorded an increase in PGE2 at the surgical site, and both mixed COX-1/COX-2 inhibitors and a COX-2 selective inhibitor can reduce tissue PGE2 (4–6). Still, the link between reduced postoperative pain and COX inhibitors remains to be clarified (7).

After plantar hindpaw incision in rats, there is postoperative hyperalgesia and upregulation of spinal COX-2 protein (8) and COX-1 immunochemistry (9). However, the change in spinal PGE2 after surgery in the rat has not been characterized. Increases in spinal PGE2 postsurgically may be important clinically because animal studies have shown that increases in spinal PGE2 are associated with pain (10), spinal hyperexcitability (11), and fever (12).

Evaluation of central nervous system biochemical changes during surgery must consider the effect(s) of anesthesia. CSF PGE2 concentration is decreased in pentobarbital-anesthetized cats compared with conscious animals (13). Isoflurane anesthesia decreases PGE2 in the rat hypothalamus (14). However, no animal studies have examined the effects of anesthetics on surgery-induced changes in central nervous system PGE2. These studies would be difficult to perform in humans.

Behavioral tests have been used to assess postoperative pain after abdominal incisions in rats (15–18). The present study used a thoracic surgery model to characterize changes in pain-related behavior and PGE2 at the wound site and in thoracic CSF. We tested the hypothesis that presurgical administration of oral or intrathecal COX inhibitors can attenuate these central and peripheral PGE2 responses to a thoracic muscle incision, along with reducing pain-related behavior. We also tested the hypothesis that general anesthesia (isoflurane or propofol) and spinal anesthesia (intrathecal bupivacaine) would have different effects on the central and/or peripheral PGE2 response to surgery.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 
Experiments were performed on 300–350 g male Sprague-Dawley rats (Charles River, Wilmington, MA) and were approved by the Institutional Animal Care and Use Committee. Under isoflurane anesthesia and sterile conditions, a combined microdialysis/injection catheter was implanted in the thoracic CSF space via the cisterna magna (19,20). The active dialysis membrane was adjacent to the upper thoracic spinal cord and the lower cervical spinal cord. The microdialysis loop catheter was tested immediately after implantation for leaks by measuring the volume delivered at the outlet end when the inlet was perfused at 2.5 µL/min with artificial CSF (Ringer's solution). The inlet and the outlet of the microdialysis catheter and the inlet of the intrathecal injection catheter were externalized through the skin and plugged with stylets.

After a 7-day recovery, during which time any animal showing neurological impairment was euthanized, the inlet of the microdialysis catheter was connected to a microinfusion pump (Bee syringe pump, BAS, West Lafayette, IN). Initially, 2.5 µL/min of artificial CSF perfusate was infused over a 30-min period. After this washout interval, dialysate was collected over the next 30-min epoch to be used as the CSF PGE2 baseline value. Preliminary experiments showed no difference in baseline CSF PGE2 concentration in rats when a 60-min washout was used rather than a 30-min washout. All dialysate samples were frozen on dry ice immediately after collection and stored at –80°C until assayed.

Microdialysis loop catheters for measurement of PGE2 were constructed using the techniques of Marsala et al. (19). For CSF measurement, the intrathecal portion of the loop catheter was 4 cm long, with the active dialysis membrane (10 kDa cutoff) covering the 2 cm nearest the tip. An additional polyethylene catheter (0.6 mm outer diameter) was attached to the microdialysis loop catheter for intrathecal injection or infusion (20). For tissue PGE2 measurement, the implanted portion of the loop catheter was 2 cm of active dialysis membrane. We measured the in vitro recovery of PGE2 as 95% when infused at 2.5 µL/min. In vivo recovery of PGE2 will be less than the in vitro recovery (19), and because it would be difficult to correctly compensate for in vivo recovery over the 7-h measurement period of these experiments, the PGE2 values in the CSF dialysate are presented as percentage of presurgery baseline and not as the actual CSF concentration. For the tissue site measurements, there is no comparable presurgery baseline, and so the postsurgical PGE2 values in the tissue dialysate are presented as percent of the dialysate PGE2 level at the end of surgery.

To examine the effect of anesthesia on surgery-induced PGE2 production, animals were randomly divided into to 3 anesthetic groups (12 rats/group) after baseline CSF PGE2 collection. Details of anesthetic delivery and selection of doses are given in the Appendix. Half of the animals in each anesthetic group were sham-control animals that received a 3-cm long skin incision over the left lateral thoracic region and insertion of a tissue microdialysis catheter adjacent to the muscle, under sterile conditions. The tissue microdialysis catheter had been connected to a syringe pump and had completed a washout period (2.5 µL/min, 30 min) before insertion. The other 6 animals in each group received the same thoracic skin incision, but in addition both superficial and deep chest wall muscles were incised by creating 3-cm long lateral cuts over the 3rd, 5th, and 7th ribs. The intercostal muscles were spared. A tissue microdialysis catheter was placed in the muscle wound for PGE2 sampling. After securing the tissue catheter, the skin and muscle incisions in all animals were closed with sutures. After the 30-min surgery, animals were allowed to recover from anesthesia and both CSF and tissue dialysate were collected from awake rats at 30-min intervals for the next 360 min.

To examine the effects of COX inhibitors on CSF and tissue PGE2 response to surgery, animals with previously implanted CSF microdialysis sampling/injection catheters were assigned to 5 drug groups (n = 6/group) and administered: COX-1/COX-2 inhibitor ketorolac tromethamine (Abbott Laboratories, North Chicago, IL) 3 mg/kg by oral gavage (0.5 mL) in a drug-suspending vehicle (Ora-Plus; Paddock Labs, Minneapolis, MN); COX-2 selective inhibitor rofecoxib (oral suspension, Merck, West Point, PA) 3 mg/kg by oral gavage; ketorolac tromethamine 80 µg intrathecal (8 µL injection followed by 8 µL saline flush); ketorolac tromethamine 4 µg intrathecal; water soluble COX-2 selective inhibitor L-745,337 (Merck Frosst, Kirkland, Quebec) 80 µg intrathecal. The vehicle for all intrathecal injections was 0.9% sodium chloride injection. Two min after drug administration, animals were given an intrathecal infusion of 0.75% hyperbaric (8.25% dextrose) bupivacaine at 5 µL/min for 20 min, with head elevated 10° to minimize brain exposure. This anesthetic dose is sufficient to eliminate incisional pain, as evaluated by lack of any evasive responses (muscle flinching, vocalization) to pinprick testing over the thoracic dermatome (see Appendix). Animals then received muscle and skin incisions as in the Anesthesia experiments and a tissue microdialysis catheter was placed in the muscle wound for PGE2 sampling. Another group of 6 animals underwent spinal anesthesia and thoracic skin and muscle surgery, without COX inhibitors. In addition, there was a group of 6 sham-operated control rats that underwent spinal anesthesia but had only a thoracic skin incision and subcutaneous microdialysis catheter placement. After the 30-min surgery, animals were allowed to recover from anesthesia and both CSF and tissue dialysate were collected from awake rats at 30 min intervals for the next 360 min.

A second set of experiments was performed in a similar manner with 4 groups of animals (n = 6/group), except that the thoracic incisions were performed under 1.5% isoflurane. The animal groups were as follows: thoracic skin and muscle surgery without COX inhibitors, administration of ketorolac 3 mg/kg or rofecoxib 3 mg/kg by oral gavage before thoracic skin and muscle surgery, and a sham-operated control group. Because preliminary experiments had demonstrated that general anesthetics suppress the CSF PGE2 increase after surgery, intrathecal COX inhibitor administration was evaluated only under spinal anesthesia to increase our ability to detect statistical differences among the COX modulation groups.

PGE2 in samples of CSF or tissue dialysate were measured by enzyme-linked immunosorbent assay in 96-well microtitration plates following the manufacturer's protocols (Assay Designs, Ann Arbor, MI). The detection limit for the assay was 13 pg/mL. The intra-day and inter-day coefficients of variation were both <10%.

Exploratory locomotive activity was assessed after thoracic surgery using the same method used to evaluate postoperative pain in a rat laparotomy model (15,16). Animals were tested in clear vivarium plastic cages (42 x 25 x 20 cm) surrounded by a cage rack Photobeam Activity System (San Diego Instruments, San Diego, CA) in which beam interruptions are automatically recorded. Adjacent beams were 5 cm apart, with a lower set at foot level and an upper set 11 cm above ground. The lower set of photobeams measured ambulation (movement from one beam to another). The upper set measured rearing (beam brakes in the vertical direction).

In the first set of experiments, rats underwent thoracic muscle surgery (n = 12) or sham skin incision surgery (n = 12) under 1.5% isoflurane as before but with no catheters implanted. Rearing and ambulation were then recorded from 1–6 h after surgery. In the second set of experiments, 40 rats were implanted with thoracic intrathecal catheters similar to the CSF microdialysis experiments and 7 days later were divided into 4 groups (n = 10/group). Three groups underwent thoracic skin and muscle surgery under 1.5% isoflurane, with oral administration of ketorolac 3 mg/kg, rofecoxib 3 mg/kg, or vehicle before surgery, and the fourth group was a skin incision sham with oral vehicle. Intrathecal catheters were included in these experiments because behavioral assessment of a rat laparotomy model showed that intrathecal catheterization alone reduces exploratory activity in rats (16).

Behavioral data comparing muscle incision versus sham skin incision were analyzed over a 6-h postoperative period (collected in 1-h bins) using a repeated-measures general linear model (SPSS 11.5, SPSS, Chicago, IL) with post hoc analysis using the Bonferroni-corrected Student's t-test at each time period (P < 0.05). Total counts over 6 h were compared between the 2 groups with Student's t-test. For the COX inhibitor experiments, behavioral data were compared for the total number of counts (beam breaks) over 6 h among 4 groups using analysis of variance with the Tukey-B post hoc test. PGE2 responses were compared between groups (no more than 3) over time using a repeated-measures general linear model with post hoc Fisher's least significant difference test (P < 0.05). PGE2 dialysate concentrations in CSF presurgery or in tissue at end of surgery were compared among all groups in each figure using analysis of variance with the Tukey-B post hoc test. Within each group, the PGE2 concentration for each animal was averaged over all postsurgical times (up to 6 h) and then compared with the initial sample with the Wilcoxon's signed rank test (P < 0.05). Statistical power was not sufficient to compare the initial PGE2 sample (e.g., presurgery CSF) to the PGE2 level at each 30 min sample over 6 h. Data are displayed as mean ± sem.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 
Exploratory locomotive behavior showed a decrease in both measures of activity for 6 h after thoracic muscle incision versus skin incision alone (Fig. 1). Rearing was the most sensitive indicator, with a significant group by time interaction (F = 7.11; P = 0.001) and group main effect (F = 26.7; P < 0.001). Overall 6-h rearing counts decreased by 56.1% (98.3 ± 13.5 versus 224.2 ± 20.2; P < 0.001) after thoracic muscle incisions relative to sham-skin incision. Ambulation did not have a significant group by time interaction (F = 2.4; P = 0.078), but there was a group main effect (F = 9.84; P = 0.005). Overall ambulatory counts decreased by 36.0% (1140 ± 82 versus 1780 ± 187; P = 0.005).


Figure 115
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  		Figure 1. Effects of thoracic muscle incisions on rearing (A) and ambulation (B) over time and between groups in rats (n = 12/group) (mean ± sem). *P < 0.05 compared with sham skin incision.

 

The effect of COX inhibition on rearing was significant (F = 5.82; P = 0.003), with both ketorolac and rofecoxib 3 mg/kg increasing total 6-h counts compared with muscle surgery (Fig. 2A). There was no difference between surgery with preinjection of COX inhibitor and sham surgery. Ambulatory activity was also different among groups (F = 4.03; P = 0.015), with both COX inhibitors reversing the effects of surgery (Fig. 2B).


Figure 215
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  		Figure 2. Rearing (A) and ambulation (B) total counts over 6 h in rats after thoracic surgery (with oral vehicle) or with preinjection of the oral cyclooxygenase (COX) inhibitors ketorolac 3 mg/kg or rofecoxib 3 mg/kg (mean ± sem). Sham group is thoracic skin incision with oral vehicle. Both COX inhibitors reversed the effect of surgery on rearing and ambulatory behavior. All 40 rats (n = 10/group) had thoracic intrathecal catheters. *P < 0.05 compared with thoracic muscle incisions.

 

CSF PGE2 concentration after thoracic muscle surgery differed among anesthetic groups, with a significant group by time interaction (F = 6.95; P = 0.004) and group main effect (F = 7.62; P = 0.006). Post hoc analysis showed that CSF PGE2 was greater with spinal bupivacaine anesthesia compared with isoflurane or propofol (Fig. 3). With spinal bupivacaine, CSF PGE2 also increased in surgery animals compared with the sham-operated control animals under the same anesthesia (P = 0.038). With isoflurane anesthesia, postsurgical CSF PGE2 concentration increased compared with sham animals with the same anesthesia (P = 0.017). With propofol anesthesia, there was no difference in postsurgical CSF PGE2 between surgery and sham animals. When averaged over the 6-h postsurgical period, CSF PGE2 concentration increased in surgery animals compared with presurgery baseline in both the spinal bupivacaine and isoflurane groups and decreased compared with baseline for both the surgery and sham animals with propofol. Before surgery, baseline dialysate CSF PGE2 concentrations did not differ among the 6 experimental groups displayed in Figure 3.


Figure 315
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  		Figure 3. CSF PGE2: isoflurane, propofol, or spinal bupivacaine. Time course of prostaglandin E2 (PGE) concentration in spinal cerebrospinal fluid (CSF) dialysate after thoracic muscle surgery or skin sham incision performed under different anesthetics (mean ± sem): 1.5% isoflurane, 80 mg/kg propofol, thoracic intrathecal hyperbaric bupivacaine 0.75% (5 µL/min, 20 min). Dialysate concentrations as percentage of presurgical baseline (time 0). Baseline values in pg/mL: sham, isoflurane = 1566 ± 310; surgery, isoflurane = 2034 ± 488; sham, spinal bupivacaine = 3186 ± 996; surgery, spinal bupivacaine = 2979 ± 575; sham, propofol = 2762 ± 1047; surgery, propofol = 3186 ± 764. Statistical differences (P < 0.05) among curves over a 360-min period: *compared with sham, spinal bupivacaine; {dagger}compared with surgery, isoflurane or surgery, propofol; {ddagger}compared with sham, isoflurane. n = 6 rats per group.

 

Postoperative surgical site tissue dialysate PGE2 concentration did not differ among surgical anesthetic groups (Fig. 4). With spinal bupivacaine, tissue PGE2 increased in surgery animals compared with the sham-operated control animals under the same anesthesia (P = 0.005). Tissue PGE2 also increased in surgery animals compared with the corresponding sham operations for isoflurane (P < 0.001) and propofol (P = 0.008). When averaged over the 6-h postsurgical period, tissue PGE2 increased in surgery animals compared with the initial sample (end of surgery) in the spinal bupivacaine group and decreased compared with the initial sample for both the spinal bupivacaine and propofol sham animals. However, initial dialysate tissue PGE2 concentrations differed among the 6 experimental groups (F = 3.05; P = 0.026) displayed in Figure 4. The values in the legend below the figure show that immediately after surgery, tissue PGE2 in surgery animals is already 2–3 times that of sham animals (although only statistically significant for the isoflurane group). It should be noted that the 30 min tissue dialysate data (end of surgery) may also be influenced by the reduced sampling interval for PGE2 (compared with CSF) because the microdialysis catheter was inserted into the tissue at approximately 20 min after the start of surgery, unlike the CSF microdialysis catheter that was in place during the entire 30-min surgical period.


Figure 415
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  		Figure 4. Tissue PGE2: isoflurane, propofol, or spinal bupivacaine. Time course of prostaglandin E2 (PGE2) concentration in local tissue dialysate after thoracic muscle surgery or skin sham incision performed under different anesthetics (mean ± sem). Dialysate concentrations as percent of initial sample obtained at end of surgery (time 30). Initial values in pg/mL: sham, isoflurane = 2457 ± 907; surgery, isoflurane = 8885 ± 2835; sham, spinal bupivacaine = 2625 ± 856; surgery, spinal bupivacaine = 5361 ± 1652; sham, propofol = 1811 ± 810; surgery, propofol = 5278 ± 972. Statistical differences (P < 0.05) among curves over a 360-min period: *compared with sham, spinal bupivacaine; {dagger}compared with sham, propofol; {ddagger}compared with sham, isoflurane; n = 6 rats per group.

 

Because surgery under spinal bupivacaine anesthesia produced the largest increase in CSF PGE2 concentration among anesthetic choices (Fig. 3), most of the COX inhibitor experiments were done with that mode of anesthesia. There was a difference among groups in the 6-h postoperative time course of CSF PGE2 when comparing surgery with oral ketorolac preinjection at 3 mg/kg, surgery with oral rofecoxib 3 mg/kg, and surgery alone (F = 8.38; P = 0.005). Post hoc testing showed a reduced postsurgical CSF PGE2 concentration with either oral COX inhibitor compared with surgery alone (Fig. 5). There was a difference in CSF PGE2 among groups when comparing surgery with intrathecal ketorolac preinjection at 4 or 80 µg and surgery alone (F = 4.43; P = 0.031). Post hoc testing demonstrated that intrathecal ketorolac at 4 or 80 µg before surgery reduced CSF PGE2 compared with surgery alone (Fig. 5). However, there was no difference in postsurgical CSF PGE2 between surgery with preinjection of COX-2 selective inhibitor L-745,337 at 80 µg and surgery alone. It was not possible to test even larger doses of L-745,337 because its maximum water solubility is 10 mg/mL. When averaged over the 6-h postsurgical period, CSF PGE2 concentration decreased in surgery animals with oral ketorolac 3 mg/kg compared with the presurgery baseline and increased compared with baseline in surgery-alone animals. Before surgery, baseline dialysate CSF PGE2 concentrations did not differ among the 7 experimental groups displayed in Figure 5.


Figure 515
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  		Figure 5. CSF PGE2: spinal bupivacaine, effect of COX inhibitors. Time course of prostaglandin E2 (PGE2) concentration in spinal cerebrospinal fluid (CSF) dialysate after thoracic surgery performed under spinal bupivacaine (0.75%, hyperbaric, 5 µL/min, 20 min) with prior COX inhibitor administration (mean ± sem). Dialysate concentrations as percentage of presurgical baseline (time 0). Baseline values in pg/mL: sham = 3159 ± 996; surgery = 2979 ± 575; surgery, 3 mg/kg rofecoxib = 3786 ± 800; surgery, 3 mg/kg ketorolac = 4763 ± 1247; surgery, 80 µg intrathecal (IT) L-745,337 = 2832 ± 759; 80 µg IT ketorolac = 3646 ± 1061; 4 µg IT ketorolac = 4189 ± 1006. Statistical differences (P < 0.05) among curves over a 360-min period: *compared with sham; {dagger}compared with surgery {ddagger}compared with surgery. n = 6 rats per group.

 

There was a difference in the 6-h postoperative time course of tissue PGE2 when comparing surgery under spinal bupivacaine among groups with oral ketorolac preinjection at 3 mg/kg, oral rofecoxib at 3 mg/kg, and surgery alone, with a significant group by time interaction (F = 4.57; P = 0.033) and group main effect (F = 10.7; P = 0.002). Post hoc testing showed a reduced postsurgical tissue PGE2 with either oral COX inhibitor compared with surgery alone (Fig. 6). There was a difference in tissue PGE2 among groups when comparing surgery with intrathecal ketorolac preinjection at 4 or 80 µg, and surgery alone, with a significant group by time interaction (F = 3.91; P = 0.015) and group main effect (F = 4.82; P = 0.024). Post hoc testing showed a reduced postsurgical tissue PGE2 with intrathecal ketorolac 80 µg compared with surgery alone, but the 4 µg dose was not different from surgery alone. Tissue PGE2 did not differ between surgery with intrathecal L-745,337 at 80 µg and surgery alone. When averaged over the 6-h postsurgical period, tissue PGE2 decreased in surgery animals compared with the initial sample (end of surgery) in the oral ketorolac and rofecoxib groups and the sham group and increased compared with the initial sample for both the intrathecal ketorolac 4 µg group and the surgery-alone group. Initial dialysate tissue PGE2 concentrations differed among the 7 experimental groups (F = 2.66; P = 0.033) displayed in Figure 6.


Figure 615
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  		Figure 6. Tissue PGE2: spinal bupivacaine, effect of COX inhibitors. Time course of prostaglandin E2 (PGE2) concentration in local tissue dialysate after thoracic surgery performed under spinal bupivacaine, with prior cyclooxygenase (COX) inhibitor administration (mean ± sem). Dialysate concentrations as percent of initial sample obtained at end of surgery (time 30). Initial values in pg/mL: sham = 2625 ± 856; surgery = 5361 ± 1652; surgery, 3 mg/kg rofecoxib = 6432 ± 1038; surgery, 3 mg/kg ketorolac = 3766 ± 556; surgery, 80 µg intrathecal (IT) L-745,337 = 7860 ± 677; 80 µg IT ketorolac = 8274 ± 1474; 4 µg IT ketorolac = 5560 ± 1393. Statistical differences (P < 0.05) among curves over a 360-min period: *compared with sham; {dagger}compared with surgery; {ddagger}compared with surgery or surgery with 4 µg IT ketorolac. n = 6 rats per group.

 

With surgery under 1.5% isoflurane (similar conditions to the behavioral data in Fig. 2), there was a difference among groups in the 6-h postoperative time course of CSF PGE2 when comparing surgery with oral ketorolac preinjection at 3 mg/kg, surgery with oral rofecoxib 3 mg/kg, and surgery alone (F = 14.9; P < 0.001). Post hoc testing showed a reduced postsurgical CSF PGE2 concentration with either oral COX inhibitor compared with surgery alone (Fig. 7). When averaged over the 6-h postsurgical period, CSF PGE2 concentration decreased in surgery animals with oral ketorolac 3 mg/kg compared with the presurgery baseline and increased compared with baseline in surgery-alone animals. Before surgery, baseline dialysate CSF PGE2 concentrations did not differ among the 4 experimental groups displayed in Figure 7.


Figure 715
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  		Figure 7. CSF PGE2: isoflurane, effect of COX inhibitors. Time course of PGE2 concentration in spinal cerebrospinal fluid (CSF) dialysate after thoracic surgery performed under isoflurane (1.5%), with prior cyclooxygenase (COX) inhibitor administration (mean ± sem). Dialysate concentrations as percent of presurgical baseline (time 0). Baseline values in pg/mL: sham = 1567 ± 310; surgery = 2034 ± 488; surgery, 3 mg/kg rofecoxib = 1838 ± 381; surgery, 3 mg/kg ketorolac = 3068 ± 997. Statistical differences (P < 0.05) among curves over a 360 min period: *compared with sham; {dagger}compared with surgery. n = 6 rats per group.

 

There was a difference in the 6-h postoperative time course of tissue PGE2 when comparing surgery under isoflurane among groups with oral ketorolac preinjection at 3 mg/kg, oral rofecoxib at 3 mg/kg, and surgery alone, with a significant group by time interaction (F = 7.71; P = 0.003) and group main effect (F = 26.3; P < 0.001). Post hoc testing showed a reduced postsurgical tissue PGE2 with either oral COX inhibitor compared with surgery alone and also a lower value for ketorolac than rofecoxib (Fig. 8). When averaged over the 6-h postsurgical period, tissue PGE2 decreased in surgery animals compared with the initial sample (end of surgery) in the oral ketorolac and rofecoxib groups. Initial dialysate tissue PGE2 concentrations differed among the 4 experimental groups (F = 4.29; P = 0.019) displayed in Figure 8.


Figure 815
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  		Figure 8. Tissue PGE2: isoflurane, effect of COX inhibitors. Time course of PGE2 concentration in local tissue dialysate after thoracic surgery performed under isoflurane, with prior cyclooxygenase (COX) inhibitor administration (mean ± sem). Dialysate concentrations as percentage of initial sample obtained at end of surgery (time 30). Initial values in pg/mL: sham = 2457 ± 910; surgery = 8886 ± 2835; surgery, 3 mg/kg rofecoxib = 7927 ± 2032; surgery, 3 mg/kg ketorolac = 2468 ± 394. Statistical differences (P < 0.05) among curves over a 360-min period: *compared with sham; {dagger}compared with surgery; {ddagger}compared with surgery, 3 mg/kg rofecoxib. n = 6 rats per group.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 
Laparotomy in rats produces pain-related behaviors that can be attenuated with analgesics (15–18). This animal model is of clinical relevance because it mimics aspects of postoperative pain-related behavior in humans (e.g., decreased locomotor activity), and drugs that are effective in reducing postoperative pain in patients, such as opioids and nonsteroidal antiinflammatory drugs, produce behavioral improvement in these rats (15–18). Thoracic muscle incisions reduced spontaneous exploratory activity over a 6-hour postoperative period (Fig. 1), with rearing behavior showing the greatest effect. In the laparotomy model, using the same behavioral measures, there was also a decrease in all variables of exploratory activity at 24 hours after surgery with rearing being the most sensitive indicator (15). In another laparotomy study, using different behavioral measures (writhing, staggering, back arching), pain-related behavior lasted for 270–390 minutes postsurgery (17,18). In our study, the effect of muscle incision on locomotor behavior was only significant at 1- to 4-hour time points, with no difference at 5 hours and 6 hours. This may be an adaptation of all groups of animals to the testing environment, so the motivation to explore the chamber decreases, and it becomes difficult to detect differences among experimental groups when rates of behavior decrease (15).

Thoracic muscle incisions produced an increase of PGE2 in both CSF and tissue in the postoperative period compared with sham surgery, with isoflurane or spinal bupivacaine anesthesia (Figs. 3 and 4). There is evidence from other studies that increased tissue or CSF PGE2 is associated with pain. After local inflammation in the rat footpad there is hyperalgesia and an increase in peripheral tissue site PGE2 (21,22). Rats injected in the hindpaw with the nociceptive stimulus formalin show pain-related behavior and an increase in lumbar CSF PGE2 (twofold) that matches the time course of the pain (23). PGE2 in dorsal horn tissue also reaches its peak value at 30 minutes and returns to baseline approximately 1–2 hours after hindpaw formalin injection, which is the same as the time course for flinching behavior (24). In addition, intrathecal injection of PGE2 produces nociceptive effects in mice (10), and PGE2 applied to rat spinal cord slices depolarizes deep dorsal horn neurons (11). Although the above studies suggest that increased tissue or CSF PGE2 is related to pain, more conclusive evidence comes from studies in which PGE2 is reduced, i.e., COX inhibition experiments.

Preinjection of either oral ketorolac or rofecoxib at 3 mg/kg had an analgesic effect in the thoracic incision model, performed under isoflurane anesthesia, as evidenced by reversal of the surgery-induced deficit in rearing and ambulatory behavior over the initial 6-hour postsurgical period (Fig. 2). In one laparotomy study, when administered 24 hours after surgery, IP ketorolac (5 mg/kg) appeared to produce a slight reversal of rearing behavior from surgery alone, although it did not reverse reduced ambulation (15). In addition, ketorolac greatly enhanced the efficacy of morphine in reversing the surgery-induced effect on rearing behavior. In another group of laparotomy studies, subcutaneous administration of COX inhibitors, ketoprofen, or carboprofen at 5 mg/kg before surgery reduced pain-related behavior over the next 4–5 hours (17,18). Therefore, the results demonstrating analgesic effects of systemically administered COX inhibitors in the thoracic incision model have similarities to the studies with the laparotomy model.

Similar to the alleviation of rearing and ambulation deficits by oral ketorolac or rofecoxib at 3 mg/kg, there was a reduction of both CSF and tissue PGE2 over the 6 hours after thoracic muscle incisions compared with sham incisions, with either isoflurane or spinal bupivacaine surgical anesthesia (Figs. 5–8). Both drugs at that dose produce more than a 50% inhibition of carrageenan-induced paw hyperalgesia, although ketorolac has a smaller ED50 (25,26). This suggests that postsurgical increases in tissue PGE2 may be both COX-1 and COX-2 dependent. Ketorolac has high selectivity for COX-1 over COX-2 in some assays (25,27,28), but it is also a potent COX-2 inhibitor (27), and so for in vivo studies, ketorolac should be considered a mixed COX-1/COX-2 inhibitor. Rofecoxib and L-745,337 are among the most COX-2 selective compounds (26,27,29), and so for in vivo studies, rofecoxib and L-745,337 can be considered selective COX-2 inhibitors.

After foot incision surgery in the rat there is an increase in spinal cord COX-2 protein beginning at 3 hours and lasting through 12 hours (8). However, a plantar hindpaw incision also produces a later increase in COX-1 immunoreactivity in the dorsal horn (9). In a preliminary study, we determined that both COX-1 and COX-2 protein are increased in the rat ipsilateral thoracic cord at 4 hours after thoracic muscle surgery (30). Therefore, postsurgical increases in CSF PGE2 may also be both COX-1 and COX-2 dependent.

Intrathecally, ketorolac at both the 4 and 80 µg dose reduced CSF PGE2 (Fig. 5). However, the 80 µg intrathecal dose also reduced tissue PGE2 (Fig. 6), making it unclear whether that larger ketorolac dose was inhibiting CSF PGE2 via direct spinal action or indirectly by suppressing peripheral inflammation. However, the 4 µg intrathecal dose did not reduce the upregulation of tissue PGE2, indicating that the reduction of CSF PGE2 at the smaller dose was most likely attributable to direct inhibition of COX-1 at the spinal level. In Figure 6 it appears that the increase in tissue PGE2 was delayed by the 4 µg intrathecal dose, although more extensive statistical modeling would be required to prove this point. Intrathecal injection of the COX-2 selective inhibitor L-745,337 had no overall effect in reducing CSF PGE2. That same intrathecal dose of L-745,337 administered alone did not reduce hyperalgesia in a rat postoperative pain model (31), although oral L-745,337 at 3 mg/kg reduces carrageenan-induced hyperalgesia by 90% (32). Considering the results in aggregate, our data suggest that at small doses, intrathecal ketorolac blocks upregulation of CSF PGE2 by inhibiting a COX-1, but not COX-2, pathway.

Although the original purpose of this study was to examine central and peripheral PGE2 responses after thoracic surgery and whether presurgical administration of oral or intrathecal COX inhibitors can attenuate PGE2, it soon became evident that under isoflurane anesthesia, CSF PGE2 did not increase as much as we expected. This was the impetus for us to compare the effect on postsurgical CSF PGE2 upregulation of different types of anesthesia. The inspired isoflurane concentration was set at 1.5%, which approximates the published minimum alveolar concentration of isoflurane in rats (33,34). The 80 mg/kg IP propofol dose has been shown to produce a mean duration of 43 minutes of anesthesia in rats (35). Lumbar intrathecal injection of bupivacaine (0.75% in 8.25% dextrose) at 40 µL volume has been demonstrated to inhibit foot withdrawal to pinch or pinprick for 15 minutes (36), and to extend our anesthesia time to 30 minutes to allow completion of surgery we infused at 5 µL/min for 20 minutes, delivering a total of 100 µL. Although our doses of the 3 anesthetics may not have been equivalent in all aspects of anesthesia, we tried to match induction times, duration, and recovery from anesthesia as closely as possible. There is not a standard criterion for depth of anesthesia in the rat, so we did attempt to match depth among the 3 anesthetics.

The observational nature of our study does not provide explanation for the mechanisms by which spinal bupivacaine produced the largest postsurgical CSF PGE2 upregulation and isoflurane a moderate increase, whereas propofol did not allow any increase in CSF PGE2. Propofol is thought to produce sedation and anesthesia primarily by enhancing gamma-aminobutyric acid (GABA)-A receptors (37); however, the exact mechanism of action has not been fully elucidated. A cannabinoid receptor (CP1) antagonist reduced the number of mice that lost their righting reflex in response to propofol, suggesting that cannabinoid receptor activity contributes to the sedative properties of propofol (38). Isoflurane also enhances the function of GABA-A channels (39), possibly by altering channel gating characteristics (40,41). In general, there does not seem to be an obvious link between GABA-A channels and PGE2 production, except in thermogenic studies in which injections of the GABA-A receptor agonist muscimol into the preoptic area of the hypothalamus attenuates CNS PGE2 production (42) and blocks fever (43). The primary action of spinal bupivacaine is blockade of conduction via spinal nerve roots (36), although there may be direct effects within the spinal cord (44). Although it has been suggested that intrathecal lidocaine may inhibit spinal prostaglandin production (45), we did not observe any decrease in CSF PGE2 in sham-operated rats with spinal bupivacaine. Because intrathecal bupivacaine directly blocks primary afferent fibers, it would be predicted that CSF PGE2 should be depressed by this mode of anesthesia. However, in a rat peripheral inflammation model, local anesthetic blockade of the sciatic nerve of the inflamed hindlimb did not eliminate COX-2 mRNA induction in the lumbar spinal cord or CSF PGE2 upregulation (46).

In conclusion, postoperative pain, and CSF and tissue PGE2 concentrations can be reduced by oral administration of either a mixed COX-1/COX-2 inhibitor or a COX-2 selective inhibitor. Intrathecal administration of a COX-1/COX-2 inhibitor reduces CSF PGE2 concentration but a COX-2 selective inhibitor does not, suggesting a direct spinal action involving COX-1. Future experiments will be needed to examine the mechanisms by which surgical anesthesia influences postoperative CSF PGE2 and possibly other postsurgical outcomes.


   APPENDIX: ANESTHETIC DOSE-FINDING EXPERIMENTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
REFERENCES
 
Methods

Preliminary dose-finding experiments were performed to determine the dose of each of the 3 anesthetics used in this study required to provide surgical anesthesia for a duration of 30 min and full recovery within the next 30 min. Induction time was evaluated by recording loss of evasive responses (muscle flinching, vocalization) using pinprick testing over the thoracic dermatome. For spinal bupivacaine anesthesia, where there was concern about the animal feeling pain, but not being able to respond, facial dermatomes were also interrogated by pin, as well as measurement of heart rate. Starting at 30 min from the start of surgical anesthesia, recovery from anesthesia was evaluated as the time required for return of the righting response. One group of animals was sedated by 30-s exposure to 4% isoflurane in an enclosed chamber and then anesthetized with 1.0%, 1.5%, or 2.0% isoflurane in oxygen delivered at 1 L/min by mask from a veterinary vaporizer over a 30-min period beyond induction time. Another group received a single intraperitoneal injection of 30, 50, or 80 mg/kg propofol (Diprivan, AstraZenica, Wilmington, DE). The final group was infused intrathecally with hyperbaric 0.75% bupivacaine hydrochloride in 8.25% dextrose at 1, 2, 3, 5, or 10 µL/min for 5–25 min (head elevated 10° to minimize brain exposure). The outcome of these dose-finding experiments is presented below.

Results

The 1.0% isoflurane concentration did not abolish the animals' response to nociceptive pinprick stimulation. At 1.5% isoflurane (n = 6), induction time was 4.0 ± 1.0 min (including the initial 30-s period with 4% isoflurane in a chamber), and the pinprick response returned 34.7 ± 0.7 min later (mean ± sem). The righting response returned in another 1.3 ± 0.2 min, which is 6 min from the termination of the 30-min anesthesia. The 30 mg/kg and 50 mg/kg doses of propofol yielded <10 min of anesthesia. At 80 mg/kg propofol (n = 6), induction time was 6.4 ± 0.4 min, duration of pinprick anesthesia 32.4 ± 1.9 min, and the righting reflex returned 4.8 ± 1.7 min later (achieving the criteria for 30 min of anesthesia, with recovery 7 min later). At 3 µL/min or less of hyperbaric 0.75% bupivacaine, the animals were still responsive to thoracic pinprick testing. At 5 µL/min (n = 6), the animals became analgesic after 7.8 ± 0.8 min, and with a total volume of 100 µL delivered (20 min of total infusion), the animals were unresponsive to thoracic testing for a total of 37.2 ± 1.2 min. The righting response returned in another 6.6 ± 1.8 min, which is 13.8 min beyond 30-min anesthesia. The animals appeared relaxed during the 30-min anesthesia period (decreased head movements) but would still vocalize to pinprick testing near the nose. During the actual surgery under spinal bupivacaine, there was no increase in heart rate during the 30-min anesthetic period: baseline = 430 bpm, 15 min of anesthesia = 390 bpm, 30 min of anesthesia = 420 bpm, and 30 min later = 430 bpm. During the actual skin and muscle incisions, the 3 anesthetic regimens all allowed completion of surgery without animal movement.


   Footnotes
 
Accepted for publication April 11, 2006.

Supported, in part, by University Anesthesiologists S.C., Chicago, Illinois.


   REFERENCES
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 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 APPENDIX: ANESTHETIC DOSE...
 REFERENCES
 

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