Anesth Analg 2007; 105:1650-1656
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000287644.00420.49
ANESTHETIC PHARMACOLOGY
Secondary Hyperalgesia in the Postoperative Pain Model Is Dependent on Spinal Calcium/Calmodulin-Dependent Protein Kinase II
Activation
Toni L. Jones, PhD,
Adam C. Lustig, BS, and
Linda S. Sorkin, PhD
From the Department of Anesthesiology, University of California San Diego, La Jolla, California.
Address correspondence to Toni L. Jones, PhD, University of California San Diego, Anesthesiology, 9500 Gilman Drive, LA Jolla, CA 92093-0818. Address e-mail to tljones{at}ucsd.edu.
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Abstract
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BACKGROUND: Spinally administered non-N-methyl-d-aspartate (NMDA), but not NMDA, receptor antagonists block primary (1°) and secondary (2°) mechanical hyperalgesia and spontaneous pain after plantar incision. Hyperalgesia after thermal stimulation is also mediated by non-NMDA, but not NMDA, receptors. Although previous pain behavior studies in the thermal stimulus model demonstrated distinct protein kinase involvement downstream from spinal non-NMDA receptor activation, protein kinase signaling mechanisms have not been examined in the postoperative pain model. In the present study, we investigated whether spinal calcium/calmodulin-dependent protein kinase II
(CaMKII) mediates 1° and/or 2° hyperalgesia and spontaneous pain behavior after plantar incision.
METHODS: Catheterized rats received a 1 cm incision in the hindpaw and were tested over 2 days for responses to mechanical stimulation adjacent to or 1 cm away from the incision site. Some rats received intrathecal (IT) pretreatment with a CaMKII inhibitor (14, 34, or 104 nmol KN-93) or vehicle (5% dimethyl sulfoxide in sterile saline). Separate groups received IT 34 nmol or 104 nmol KN-93 and were tested for hindpaw weight bearing. Lumbar spinal cords were extracted 1 h after incision or sham treatment to measure phosphorylated CaMKII and -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid GLUR1-831 in Western immunoblots.
RESULTS: Incision increased spinal CaMKII and GLUR1-831 phosphorylation. Although pretreatment with all doses of IT KN-93 reduced the development of 2° hyperalgesia, only 34 nmol KN-93 appeared to have an effect on 1° hyperalgesia. IT KN-93 did not affect nonevoked pain.
CONCLUSION: Spinal sensitization underlying incision-evoked hyperalgesia involves spinal CaMKII activation and enhanced spinal -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) function.
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Introduction
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Despite current pharmacologic treatments, an alarming number of patients continue to report moderate to severe pain after surgery (1,2). This indicates that continued research in the mechanisms that mediate postoperative pain remains necessary. Interestingly, mechanisms involving neuronal plasticity in postoperative pain are only beginning to be investigated (3,4).
Plantar incision in the rat results in primary (1°) and secondary (2°) hyperalgesia, in addition to pain at rest (5,6), which parallel pain experienced by patients after surgery (7,8). Primary hyperalgesia is defined as an enhanced response to mechanical stimulation adjacent to the incision site and 2° hyperalgesia is an enhanced response to stimulation of uninjured tissue, away from the incision. Whereas incision-evoked 1° mechanical hyperalgesia is due to peripheral sensitization (i.e., spontaneous and increased nociceptor activity), 2° mechanical hyperalgesia is largely dependent on spinal sensitization (i.e., increased dorsal horn neuronal activity). Pain at rest is thought to be due to both peripheral and spinal sensitization (9,10).
Several receptor-mediated mechanisms that contribute to spinal sensitization also contribute to long-term potentiation (LTP), a neuroplasticity model for learning and memory (11,12). Both spinal sensitization and LTP involve enhanced synaptic activity requiring activation of ionotropic glutamate receptors, -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and N-methyl-d-aspartate (NMDA). Calcium-dependent signaling mechanisms also play an important role in spinal sensitization and LTP (12–17). Specifically, activated calcium/calmodulin-dependent protein kinase II (CaMKII), a serine-threonine protein kinase, is required for the induction of spinal LTP after noxious stimulation (13,17), as well as the development of spinal sensitization after tissue (15,18) or nerve injury (19,20). Increased phosphorylation of the AMPA GLUR1 receptor subunit (pGLUR1-831), an event that enhances AMPA receptor (AMPAr) channel conductance (21), often accompanies stimulus- and injury-evoked CaMKII activation. Accordingly, blockade of activated CaMKII reduces pain behaviors, spinal dorsal horn activity, and CaMKII-mediated increases in AMPAr channel function (13,17).
A previous study of pain behaviors after thermal stimulation, which also develop independent of spinal NMDA receptor activation, demonstrated distinct protein kinase activity downstream from activated spinal non-NMDA receptors (22). In the present set of experiments, we examined whether plantar incision in the postoperative pain model increases spinal dorsal horn CaMKII phosphorylation, a measure of activated CaMKII. In addition, phosphorylation of spinal AMPA GLUR1, an index of enhanced AMPAr channel function, was measured. We also determined if spinal pretreatment with a CaMKII inhibitor attenuated development of 1° and 2° hyperalgesia after surgical incision.
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METHODS
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Animals
Experiments using male Sprague–Dawley rats (300–350 g, Harlan Industries, Indianapolis, IN) were approved by the Institutional Animal Care and Use Committee of the University of California-San Diego. Rats for behavioral experiments were deeply anesthetized with 4%–5% isoflurane (50% oxygen: 50% room air) and maintained with 2%–3% isoflurane. Intrathecal (IT) catheters (8.0 cm-long, polyethylene (PE)-5 tubing with a 3 cm-long PE-10 tubing attachment) were inserted through the atlanto-occipital membrane at the foramen magnum. The PE-5 was guided down until it ended rostral to the lumbar enlargement (23). Each rat received 3 mL of intraperitoneal lactated Ringer's solution immediately and 1 day after catheter surgery. Thereafter, catheterized rats were individually housed and experiments occurred no less than 5 days after catheter implantation. In all behavioral experiments, the investigator was blinded with regard to the drug treatment administered to rats.
Plantar Hindpaw Incision
Catheterized rats were anesthetized as above. The right hindpaw was cleaned with povidone iodine and a sterile #11 scalpel blade was used to make a 1 cm-long incision through the skin and fascia of the plantar hindpaw, beginning 0.5 cm from the heel. The plantaris muscle was lifted and a 0.5 cm longitudinal incision was made. The skin was apposed and the wound was closed with two mattress sutures (sterile 5-0 mono-filament nylon). Triple antibiotic ointment was applied to the wound and rats were placed in a dedicated recovery area. Rats that received anesthesia without incision served as sham controls.
Experiment 1: Primary and Secondary Hyperalgesia Testing After Plantar Incision
Before incision, catheterized rats were acclimated to the testing room and testing apparatus (i.e., individual plexiglass compartments measuring 26 x 11 x 20 cm with 12 x 12 mm mesh floors) for 30 min on each of three sequential days. On the third day after acclimation, baseline mechanical withdrawal thresholds were measured using von Frey filaments applied to the plantar hindpaw, in order of ascending stiffness (6), for 4 s or until a withdrawal response occurred. The medial aspect of the paw, approximately 0.75 cm from the heel edge, was the 1° hyperalgesia test site (von Frey filaments 1–60 g = 10–522 mN). The medial area of the footpad, proximal to the toes, was the 2° hyperalgesia test site (von Frey filaments 1–26 g = 10–258 mN). Withdrawal thresholds were retested 1, 2, 4, 24, and 48 h after incision.
Experiment 2: Spinal CaMKII and AMPA GLUR1 Phosphorylation After Plantar Incision
One hour after sham treatment or incision, rats were re-anesthetized (4%–5% isoflurane) and their spinal cords were hydro-extruded with cold saline. Right dorsal lumbar (L2–6) enlargements were dissected, snap-frozen and homogenized by hand in cold lysis buffer (10 mM Tris-HCl, 1 mM EDTA, 300 mM sucrose with phosphatase and protease inhibitors, pH 7.5). Homogenates were centrifuged (8000 rpm, 10 min, 4°C) and the resulting supernatant was collected and recentrifuged (14,000 rpm, 60 min, 4°C). The protein concentration of the final supernatant was determined and equivalent amounts of protein (20 µg) were loaded for gel electrophoresis. Afterward, protein was transferred onto nitrocellulose membranes blocked with 5% low-fat milk in Tris-HCl buffer containing 0.1% Tween-20, pH 7.4, then incubated overnight (4°C) in 1° antibodies (mouse anti-CaMKII or mouse anti-phospho-CaMKII-threonine-286 (1:1000, Affinity Bioreagents, Golden, CO) and rabbit anti-phospho-GLUR1-Ser 831 (1:1000, Upstate Cell Signaling and Solutions, Lake Placid, NY)). Membranes were washed and incubated in 2° antibody (goat anti-mouse or goat anti-rabbit conjugated to horseradish peroxidase, Cell Signaling Technology, Danvers, MA). After radiographic film exposure, membranes were stripped and reprocessed for β-actin (mouse anti-β-actin; 1:10,000, Sigma, St. Louis, MO). Resulting immunoblots were scanned and densitometric analyses performed using ImageQuant (Amersham Biosciences, Piscataway, NJ). Immunoblot density was normalized to β-actin loading control. Normalized densities of spinal tissue from incised rats were compared to the appropriate sham control run on the same gel.
Experiment 3: Effect of Pretreatment with an IT CaMKII Inhibitor on Incision-Evoked Hyperalgesia
Catheterized rats were acclimated to the testing room and apparatus for 3 days. After baseline thresholds were measured on the third day, rats received a 10 µL IT injection of either vehicle (5% dimethyl sulfoxide in sterile saline) or CaMKII inhibitor (14 nmol, 34 nmol, or 104 nmol KN-93 in vehicle) (Calbiochem, La Jolla, CA), 30 min before incision. Injection was followed by a 10 µL saline flush. Withdrawal thresholds were retested 1, 2, 4, 24, and 48 h after incision.
Experiment 4: Effect of Pretreatment with an IT CaMKII Inhibitor on Nonevoked Pain Behavior After Incision
After acclimation to individual compartments with 8 x 8 mm mesh floors, catheterized rats received IT pretreatment with 34 nmol or 104 nmol KN-93 followed by a saline flush, 30 min before incision. Cumulative pain scores were used to measure the incidence of hindpaw weight bearing before and 2, 4, 24, and 48 h after incision (5). In this score, a numerical value is assigned to three different degrees of weight bearing. Briefly, 0 = full weight bearing, glabrous plantar skin is blanched due to pressure from the mesh floor; 1 = partial weight bearing, the glabrous plantar skin is partially blanched and; 2 = no weight bearing, the paw is held up and away from the mesh floor. This guarding behavior was assessed for each hindpaw over a 1-min period at 5-min intervals, for 60 min. Thus, each hindpaw was examined 12 times and the final cumulative pain score was determined as the sum of scores for the left hindpaw subtracted from that for the right hindpaw. Whereas 0 indicates absent nonevoked pain, an increasing value up to 24 indicates increasing nonevoked pain.
Data Analysis
The Friedman test (Dunn's post hoc) determined significant difference in within-group withdrawal thresholds and cumulative pain scores before and after incision, over time (P < 0.05 = hyperalgesia). A Student's t-test determined significant difference in protein expression after sham treatment versus incision. The Mann–Whitney U-test determined significant difference in between-group thresholds for IT vehicle and kinase inhibitor-treated groups, at individual time points. The areas under the curve (AUC) of withdrawal thresholds for each treatment group, over time, was also determined to calculate the percent maximum analgesic effect of the kinase inhibitor KN-93, relative to vehicle. (Percent maximum analgesic effect = Inhibitor AUC – Vehicle AUC/Maximum AUC – Vehicle AUC). P < 0.05 was considered significant. GraphPad Prism (San Diego, CA) was used to determine analyses and AUC.
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RESULTS
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Experiment 1: Plantar Incision Results in 1° and 2° Hyperalgesia
Previous studies demonstrated significant 1° and 2° hyperalgesia after plantar incision (6,24). As time-course and magnitude of pain behaviors vary from laboratory to laboratory, we replicated the plantar incision model and measured mechanical withdrawal thresholds of catheterized rats at 1° (Fig. 1A) and 2° (Fig. 1B) hyperalgesia test sites before and 1–48 h after plantar incision. These experiments were also conducted to determine an optimal time point at which to harvest spinal cord tissue for Experiment 2. Fig. 1 shows that baseline median withdrawal thresholds for each test site were 522 mN and 258 mN, respectively. Within 1 h postincision, median thresholds for both measures decreased below 30 mN and remained below 50 mN for the next 4 h indicating development of 1° and 2° hyperalgesia. Although withdrawal thresholds increased over time, medians did not reach 100 mN for the entire 2 days of testing.
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Figure 1. Plantar incision results in significant primary and secondary hyperalgesia. Illustrations of rat hindpaws show the sight of incision and placement of von Frey filaments for testing (A) primary and (B) secondary hyperalgesia, respectively. Box and whisker plots show the distribution of paw withdrawal thresholds corresponding to minimum, 25th, 50th (median), 75th and maximum percentile values, before (B) and 1–48 h after incision (arrow) in catheterized rats. Median thresholds decrease as low as 20 mN and 10 mN, for 1° and 2° hyperalgesia, respectively, 1–4 h after incision (Friedman test; P = 0.0005). (* = P < 0.05 and ** = P < 0.01, compared to baseline). n = 6/group. Hindpaw illustrations from Zahn PK and Brennan TJ, 1996, reproduced with permission from Lippincott Williams & Wilkins (Baltimore, MD).
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Experiment 2: Incision-Evoked Hyperalgesia Correlates with Increased Spinal pCaMKII and pGLUR1-831
Fig. 2 displays immunoblots processed for total CaMKII, pCaMKII, pGLUR1-831 and β-actin in dorsal lumbar segments, 1 h after sham treatment or incision. The graph shows relative immunoblot density from tissues of sham (S) and incised (I) rats, as a percent of sham. Although incision had no effect on total CaMKII, it significantly increased both pCaMKII and pGLUR1-831.
Experiment 3: Spinal Pretreatment with a CaMKII Inhibitor Significantly Reduces Development of 2° Hyperalgesia
The development of incision-evoked 1° and 2° hyperalgesia in rats that received pretreatment with vehicle or a CaMKII inhibitor (14, 34, or 104 nmol KN-93) was investigated. Fig. 3 shows that baseline median withdrawal thresholds at the 1° and 2° hyperalgesia test sites did not differ among treatment groups. Within 1 h postincision, vehicle-treated rats displayed substantially reduced median thresholds adjacent to and 1 cm away from the incision, indicating profound 1° and 2° hyperalgesia, respectively. Median thresholds at these sites decreased to as low as 20 mN during the first 4 h postincision and remained below 80 mN for up to 2 days. Rats that received 14 nmol, 34 nmol, or 104 nmol KN-93 continued to develop significant 1° hyperalgesia. In marked contrast, all doses of KN-93 reduced development of 2° hyperalgesia. In fact, inhibitor-treated rats displayed significantly increased thresholds from 1–4 h after incision, relative to vehicle (Mann–Whitney test). To demonstrate KN-93 reduction of 1° and 2° hyperalgesia during this time period, the percent maximum analgesic effect of the kinase inhibitor was determined. The first bar graph in Fig. 3 shows that, in the 1° hyperalgesia paradigm, 14 nmol and 104 nmol KN-93 produced minimal analgesia (21.4% ± 2.67% and 20.6% ± 4.05%, respectively), whereas the effect with 34 nmol KN-93 was more than twice (49.8% ± 14.37%) that achieved with either of the other doses. The second bar graph shows that analgesic effects of all three KN-93 doses were considerably stronger in the 2° hyperalgesia paradigm. Whereas 14 nmol and 104 nmol KN-93 increased withdrawal thresholds by 58.3% (±16.85) and 56.2% (±4.16), respectively, 34 nmol KN-93 increased thresholds by 78.6% (±17.12), relative to vehicle.
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Figure 3. Intrathecal pretreatment with a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor reduces development of incision-evoked 2° hyperalgesia. Box and whisker plots show the distribution of paw withdrawal thresholds for rats that received intrathecal (IT) vehicle (5% dimethyl sulfoxide), 14 nmol, 34 nmol or 104 nmol KN-93, 30 min before incision. Vehicle-treated rats display significantly reduced thresholds after incision indicating development of 1° and 2° hyperalgesia (P = 0.0001 and P = 0.0002, respectively). Pretreatments with 14 nmol KN-93, 34 nmol KN-93 and 104 nmol KN-93 do not block development of 1° hyperalgesia (P = 0.0017, P = 0.0122 and P = 0.0047, respectively). In the 2° hyperalgesia paradigm, all 3 doses of KN-93 result in increased withdrawal thresholds 1–4 h post-incision (Mann–Whitney test;  = P < 0.05 and = P < 0.01, compared to vehicle). (• = significantly lower than vehicle). (* = P < 0.05, ** = P < 0.01 and *** = P < 0.001, compared to baseline). n = 6/group. The bar graphs display the percent maximum analgesic effects of IT KN-93 in the 1° and 2° hyperalgesia paradigms, relative to vehicle.
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Experiment 4 Spinal Pretreatment with a CaMKII Inhibitor has no Effect on the Development of Nonevoked Pain
A previous postoperative pain study demonstrated that plantar incision results in spontaneous, or nonevoked, pain behaviors (25) that involve hindpaw lifting and some hindpaw licking and flinching (5,6). In the present study, we measured the cumulative pain score before and 2–48 h after incision for rats that received IT pretreatment with vehicle, 34 nmol KN-93 or 104 nmol KN-93. Fig. 4 shows that the baseline score (0) among the treatment groups did not differ. Vehicle-treated rats had increased scores postincision indicating occurrence of guarding and spontaneous pain. None of the KN-93 pretreatment doses had an effect on the development of these pain behaviors. In fact, median scores in all groups increased to at least 18 and remained elevated (10–15) for the entire 2 days of testing.
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Figure 4. Intrathecal pretreatment with a calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor does not reduce development of spontaneous, nonevoked pain behavior. Box and whisker plots show the distribution of cumulative pain scores corresponding to minimum, 25th, 50th (median), 75th, and maximum percentile values (0–24), before (B) and 2–48 h after incision (arrow). Rats received IT vehicle, 34 nmol KN-93 or 104 nmol KN-93, 30 min before incision. Vehicle-treated rats display significantly increased cumulative pain scores and thus, enhanced nonevoked pain behaviors (P = 0.0140). Pretreatment with 34 nmol or 104 nmol KN-93 has no effect on the development of nonevoked pain (34 nmol KN-93, P = 0.0012 and 104 nmol KN-93, P = 0.0208). (* = P < 0.05, ** = P < 0.01 and *** = P < 0.001, compared to baseline). n = 5/group.
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DISCUSSION
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The principle findings in this study are that: 1) incision increased spinal CaMKII and AMPA GLUR1-831 phosphorylation, 2) development of 2° hyperalgesia after incision required activated spinal CaMKII, and 3) inhibition of spinal CaMKII did not attenuate development of incision-evoked pain that is largely dependent on peripheral sensitization (i.e., 1° hyperalgesia and nonevoked pain behavior).
A previous study reported that spinal AMPA/KA (Kainate), but not NMDA, receptors mediate incision-evoked 1° and 2° hyperalgesia (24). This receptor pharmacology is similar to that observed in a thermal stimulus model. Importantly, 2° hyperalgesia in both models is mediated by spinal calcium-permeable AMPA/ KA (Ca2+-perm-AMPA/KA) receptors (24,26,27). We published that thermal stimulus-evoked 2° hyperalgesia requires spinal second-messenger systems that include activated protein kinase A and conventional protein kinase C (cPKC), but not CaMKII (22). For instance, thermal stimulation did not increase spinal CaMKII phosphorylation and IT pretreatment with 34 nmol KN-93 did not reduce development of thermal stimulus-evoked 2° hyperalgesia. This differs from results in the present study that demonstrate a role for spinal CaMKII, whereby IT pretreatment with KN-93 at even one-half log dose below 34 nmol significantly reduced development of incision-evoked 2° hyperalgesia.
It is likely that the extent of tissue injury contributes to differential spinal CaMKII involvement in the thermal stimulus and postoperative pain models. The thermal stimulus model involves brief hindpaw application of noxious heat that produces transient redness (27,28), whereas the postoperative pain model involves a 1 cm incision in hindpaw skin, fascia, and muscle (5). We previously hypothesized that nominal CaMKII activation after thermal stimulation reflected an insufficient level of calcium influx through Ca2+-perm-AMPA/KA receptors. Calcium influx through these receptors is reported to be less than that through NMDA receptors (29). Thus, increased CaMKII phosphorylation and reduced 2° hyperalgesia after IT KN-93 in the incision model suggests additional Ca2+-perm-AMPA/KA receptor activation and/or activation of NMDA receptors. Although previous postoperative pain studies demonstrated anti-hyperalgesic effects with conventional NMDA receptor antagonists only at doses that cause motor dysfunction (24,30), one study in mice reported that targeting a subset of spinal NMDA receptors containing the NR2B subunit (NR2B-NMDA) attenuates incision-evoked 1° hyperalgesia without disrupting motor performance on a rotating rod (31). Preliminary data from our own group using rats supports this finding. The extent to which CaMKII activation in the incision model occurs specifically downstream from spinal Ca2+-perm-AMPA and/or NR2B-NMDA receptors is now under study.
We also showed that development of incision-evoked hyperalgesia correlated with increased spinal AMPA GLUR1 receptor phosphorylation at serine 831 (pGLUR1–831). Incision-evoked CaMKII activation could very well mediate this increase, as the GLUR1 receptor subunit is a known substrate for CaMKII (21). However, activated cPKC can also phosphorylate GLUR1-831 (32) and might play a role in enhancing AMPAr function in the postoperative pain model. Regardless of cPKC action on GLUR1, our results support a requirement for spinal CaMKII activation and signaling during spinal sensitization after tissue injury (15,33).
It is worth mention that lower doses of KN-93 in 5% dimethyl sulfoxide vehicle are translucent and clear, whereas 104 nmol KN-93 is clouded. This possibly resulted in some KN-93 precipitation out of solution upon IT injection into cerebrospinal fluid. Thus, the actual amount of 104 nmol KN-93 available for diffusion into the dorsal horn is not known. However, this dose appeared to be sufficient in the 2° hyperalgesia paradigm, as it increased withdrawal thresholds relative to vehicle control and was analgesic.
In conclusion, hyperalgesia in the postoperative pain model correlated with increased spinal AMPAr phosphorylation and increased spinal CaMKII activation. Pretreatment with a CaMKII inhibitor attenuated development of 2° hyperalgesia more so than 1° hyperalgesia and nonevoked pain. Our findings indicate that targeting spinal CaMKII influences spinal sensitization after surgery and can help manage pain in the immediate postoperative period.
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Footnotes
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Accepted for publication August 8, 2007.
Supported by NIGMS grant GM07992 (to T.L.J.), the UNCF-Merck Science Initiative, and NINDS grant NS41580 (to L.S.S.).
Reprints will not be available from the author.
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Abstract
Introduction
