Behavioral Neuroscience 2014, Vol. 128, No. 5, 625– 632
© 2014 American Psychological Association 0735-7044/14/$12.00 http://dx.doi.org/10.1037/bne0000004
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Spinal Cord Stimulation (SCS) Improves Decreased Physical Activity Induced by Nerve Injury Karina L. Sato
Lisa M. Johanek
Universidade Federal de Sergipe and University of Iowa
Medtronic, Minneapolis, Minnesota
Luciana S. Sanada
Kathleen A. Sluka
Universidade Federal do Triângulo Mineiro and University of Iowa
University of Iowa
Spinal cord stimulation (SCS) is used to manage treatment of neuropathic pain to reduce pain and hyperalgesia and to improve activity. Prior studies using animal models of neuropathic pain have shown that SCS reduces hyperalgesia; however, it is unclear whether SCS affects physical activity. Therefore, we tested whether nerve injury (spared nerve injury [SNI] model) reduced physical activity levels, and whether SCS could restore these decreased activity levels. We tested whether SCS given over a long duration (6 hr daily for 3 months) remained effective. We compared SNI with uninjured controls over 4 weeks, and SNI with sham SCS with SNI with active SCS (4 or 60 Hz at 90% motor threshold). We confirmed the presence of mechanical hyperalgesia by examining mechanical thresholds of the paw with von Frey filaments. Physical activity levels were monitored over 30 min in an automated activity chamber as follows: overall activity, distance traveled, grooming behaviors, and rearing. Measures were taken during SCS every 1–2 weeks for 3 months. Animals with SNI (and no or sham SCS) showed decreased withdrawal thresholds ipsilaterally and reduced physical activity (rearing, distance, lines crossed) for 3 months. Both 4- and 60-Hz SCS increased paw withdrawal threshold during and immediately after SCS through 3 months. Both 4- and 60-Hz SCS increased the overall activity (lines crossed), distance traveled, and rearing, but not grooming behaviors for 3 months. This effect remained similar across the 3 months. Thus, measurement of spontaneous physical activity could be useful to examine nocifensive behaviors after nerve injury and is sensitive to SCS. Keywords: pain, hyperalgesia, open field, neuropathic, nerve injury
injury (SNI) model produces heat hyperalgesia and mechanical and cold allodynia that persist for at least 6 months (Decosterd & Woolf, 2000). However, the effects of nerve injury on spontaneous physical activity levels over a long duration are unclear. Using the chronic constriction injury model in mice, Basbaum et al. were unable to show long-term changes in home cage activity or open field tests— deficits were eliminated within 2 weeks after injury (Urban, Scherrer, Goulding, Tecott, & Basbaum, 2011). Prior studies in animals with inflammatory hyperalgesia have shown reductions in running wheel activity, and in activity when placed in a novel environment, that is, an open field test (Cobos et al., 2012; LaBuda & Fuchs, 2001; Pratt, Fuchs, & Sluka, 2013; Sluka & Rasmussen, 2010). Similarly, in animals with nerve injury produced by spinal nerve ligation or chronic constriction injury, there were decreases in activity levels (number of crossings) that last for at least 21 days (Grégoire, Michaud, Chapuy, Eschalier, & Ardid, 2012; Kontinen, Kauppila, Paananen, Pertovaara, & Kalso, 1999; Mendes et al., 2013); longer durations have not been tested. This decrease in overall activity could reflect an increase in movement-related pain as a result of the nerve injury. Thus, it is unclear whether the reductions in physical activity occur after SNI, whether they persist beyond 3 weeks, and whether they are sensitive to treatments like spinal cord stimulation (SCS).
Neuropathic pain is associated with diseases that affect the peripheral or central nervous system, including trauma, metabolic diseases, compression injuries, neurotoxins, infection, immune diseases, vitamin deficiencies, and cancer (Woolf & Mannion, 1999). Neuropathic pain can be difficult to diagnose and manage, and it significantly interferes with quality of life (Dworkin, 2002; Harden & Cohen, 2003; Magrinelli, Zanette, & Tamburin, 2013; Rowbotham, 2002; Woolf & Mannion, 1999). Experimental models of peripheral neuropathic pain in animals have been developed to mimic human neuropathic pain syndromes. The spared nerve
This article was published Online First June 9, 2014. Karina L. Sato, Department of Physical Therapy, Universidade Federal de Sergipe, and Department of Physical Therapy and Rehabilitation Science, University of Iowa; Lisa M. Johanek, Medtronic, Minneapolis, Minnesota; Luciana S. Sanada, Department of Biology, Universidade Federal do Triângulo Mineiro, and Department of Physical Therapy and Rehabilitation Science, University of Iowa; and Kathleen A. Sluka, Department of Physical Therapy and Rehabilitation Science, University of Iowa. Correspondence concerning this article should be addressed to Kathleen A. Sluka, Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242. E-mail: kathleen-sluka@ uiowa.edu 625
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SCS is used to treat chronic neuropathic pain that is resistant to conservative management (Shrivastav & Musley, 2009; Smits, van Kleef, Holsheimer, & Joosten, 2013). SCS delivers electric current to the dorsal columns through implanted electrodes. Clinical studies in patients with neuropathic pain, complex regional pain syndrome, cancer pain, and chronic low back pain have showed that SCS reduces allodynia and pain, and improves return to work (Schlaier et al., 2007; Wolter, Fauler, & Kieselbach, 2013; Wolter & Kieselbach, 2012; Kemler et al., 2000; Kumar et al., 2007; North, Kidd, Farrokhi, & Piantadosi, 2005; Yakovlev & Ellias, 2008). In animals with nerve ligation, SCS reduces mechanical hyperalgesia with frequencies ranging from 10 – 60 Hz and durations as short as 5 min and as long as 6 hr (El-Khoury et al., 2002; Li, Yang, Meyerson, & Linderoth, 2006; Meyerson, Ren, Herregodts, & Linderoth, 1995; Sato, King, Johanek, & Sluka, 2013; Yakhnitsa, Linderoth, & Meyerson, 1999; Maeda, Ikeuchi, Wacnik, & Sluka, 2009). Our lab has performed the longest reported duration of treatment in animals where rats with 6 hr of SCS had better analgesia than rats with 30 min of stimulation (Sato, Johanek, Sanada, & Sluka, 2014). Further, these prior studies used external neurostimulators that required rats to be anesthetized, restrained, or tethered for delivery of current and, thus, stress could have interfered with testing effectiveness. Clinically, if SCS is used for many months to years, patients report reductions in spontaneous pain and improvement in ability to perform activities of daily living. Thus, the aims of this study were as follows: (a) to examine the effects of SNI on physical activity levels, (b) to examine the effects of SCS on reduced physical activity levels in SNI, and (c) to examine effects of long-term delivery (3 months) of SCS on neuropathic pain behaviors (e.g., mechanical hyperalgesia, reduced physical activity) using an internal neurostimulator.
Method Animals The experiments were performed on adult male Sprague– Dawley rats when they reached 6 – 8 weeks old (250 –350 g). Rats were housed in transparent plastic cages with free access to food and water on a 12h light⫺dark cycle. All experimental procedures were approved by the Animal Care and Use Committee at the University of Iowa and followed National Institutes of Health guidelines for use of animals in laboratory research.
Nerve Injury Model In the group with nerve injury, all rats were anesthetized with 2–3% isoflurane. The tibial and common peroneal nerves on one limb were tightly ligated with 4 – 0 silk and the sural nerve was kept intact, as previously described (Decosterd & Woolf, 2000). The overlying muscle was sutured with 4 – 0 silk, and tissue was sutured with 3– 0 silk.
direction. The lead was fixed to the muscle with sutures and the proximal end of the lead was tunneled inside the animal for connection to a neurostimulator (InterStim II Neurostimulator, model no. 3058; Medtronic Inc., Minneapolis, MN). This neurostimulator was placed between the muscle and the skin on the left flank. This allowed us to program the stimulator (model no. 8840; Medtronic Inc., Minneapolis, MN) externally and allowed animals to remain in their home cages for treatment.
SCS Parameters SCS was applied at each frequency (0 Hz [sham], 4 Hz, and 60 Hz) at an intensity of 90% motor threshold (MT) and a pulse width of 0.25 ms for 6 hr a day over 3 months. The intensity was adjusted, increased in a 0.05-mV increments (the minimal unit for the neurostimulator) until the animal showed a motor response. The 90% MT was then calculated and used to deliver SCS during all treatments. All SCS parameters were programmed into the stimulator and delivered at the same time each day with 6 hr on and 18 hr off. We previously showed analgesic effects with both 4and 60-Hz SCS (Maeda et al., 2009; Sato et al., 2013; Sato et al., 2014), that 6 hr of SCS was more effective than 30 min (Sato et al., 2014), and that 90% MT was more effective than 75% or 50% MT (Sato et al., 2014).
Behavior Tests Mechanical withdrawal thresholds. Before surgery, rats were acclimated to the room for 30 min and to transparent plastic testing cages on an elevated, wire mesh floor for 15 min. To test for mechanical withdrawal thresholds of the paw, calibrated von Frey filaments with bending forces ranging from 1⫺402 mN were applied to the lateral surface of both the ipsilateral and contralateral paw in the area innervated by the sural nerve, as previously described (Maeda et al., 2009). The lowest withdrawal force that produced a withdrawal was recorded as the threshold. A decrease in mechanical withdrawal threshold of the paw was interpreted as cutaneous hyperalgesia of the paw in this study. Activity box. Physical activity was measured using a novel open field activity box that was automated (LimeLight program; Actimetrics, Wilmette, IL). Animals were placed in the box for 30 min, and their activity was videotaped and stored for later analysis. The examiner left the room for the videotaping session. The computerized system reported a variety of automated measures based on a point on the animal’s back located half-way between its nose and tail base. The box measured 40 ⫻ 40 cm and was divided into 10 squares, with the area of each box being 16 cm2. The following measures were assessed: crossings as a measure of overall activity: the number of times the rat crossed into each subregion (square); distance: the total distance traveled in centimeters; grooming: the time (in seconds) spent grooming; and rearing: the number of times the animal reared. The computer program analyzed the number of crossings and distance traveled. Grooming and rearing were scored manually from the stored digital files.
Implantation of the Electrode After nerve injury, a small laminectomy was performed at the T13 spinal level, which corresponds to the upper lumbar spinal cord region, and a lead was inserted epidurally in the rostral
Experimental Design Experiment 1. Animals received SNI and lead implantation with an implantable stimulator. This group was compared with
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naive animals to examine the effects of the implantable stimulator and SNI on weight and withdrawal thresholds of the paw. No stimulation was given to the animals. For 4 weeks after surgery, weight and mechanical withdrawal thresholds were measured weekly (n ⫽ 5/group). Experiment 2. Animals received SNI and lead implantation with the implantable stimulator. The mechanical withdrawal threshold was assessed before SNI, before SCS, and during SCS once a week for the first month, and every other week for months 2 and 3. Withdrawal thresholds and activity box measurements were made in the last 30 min of the 6-hr SCS period. We also tested mechanical withdrawal thresholds 1 hr after the electrode was turned off. Sham SCS (n ⫽ 9) was compared with 4-Hz SCS (n ⫽ 9) and 60-Hz SCS (n ⫽ 9).
Statistical Analysis Analysis of the data was performed using SPSS, Version 19. Data for mechanical withdrawal thresholds of the paw were presented as mean ⫾ SEM. For mechanical withdrawal thresholds and activity levels, we examined these differences across time and between groups using repeated-measures analysis of variance. Post hoc testing between different groups was performed using the Tukey’s test. A p value ⬍ 0.05 was considered significant.
Results No Effect of Internal Stimulator on Hyperalgesia and Weight To test whether the implantation of an internal stimulator caused adverse effects, we examined weight and paw withdrawal thresholds in SNI animals implanted with an internal stimulator. All rats implanted with the neurostimulator and given an SNI gained weight over the 4-week period (p ⬍ .001 for Weeks 1– 4 vs. baseline, paired t test), with before surgery averaging 311 g (SEM ⫽ 3) and increasing to 382 g (SEM ⫽ 1) by Week 4 (see Figure 1a). Before SNI, baseline withdrawal thresholds averaged 197 mN (SEM ⫽ 54) in the SNI group and were similar to a control group without SNI or the internal stimulator (M ⫽ 171 mN, SEM ⫽ 16). Seven days later, all rats with SNI showed a significant decrease in withdrawal threshold ipsilaterally, with an average of 8.6 mN (SEM ⫽ 4.6; p ⫽ .008) when compared with uninjured controls; this decrease remained significant through 28 days after SNI (p ⫽ .007, Weeks 2⫺4), F(1, 8) ⫽ 8.7, p ⫽ .02 (see Figure 1b). The uninjured control group remained unchanged throughout the 28-day testing period (see Figure 1b).
SNI Decreased Physical Activity Levels To test whether nerve injury resulted in a decrease in physical activity levels, we videotaped rats with SNI in an activity box for 30 min and compared them with rats without injury every week for 1 month. Significant decreases in the number of crossings (see Figure 2a), F(1, 8) ⫽ 45.6, p ⫽ .001, distance traveled (see Figure 2b), F(1, 8) ⫽ 10.9, p ⫽ .01, and rearing (see Figure 2c), F(1, 8) ⫽ 13.0, p ⫽ .007, occurred after SNI
Figure 1. Average weight before and after implantation of the internal stimulator over 4 weeks (a). Average withdrawal thresholds ipsilateral to nerve injury over 4 weeks in animals with spared nerve injury (SNI) plus an implanted neurostimulator compared with uninjured controls (b). ⴱ Significant difference from controls.
when compared with uninjured controls. Significant decreases occurred for Weeks 1– 4 for the number of crossings (p range: ⬍ .005 to ⬍ .001), distance traveled (p range: .01–.002), and for Weeks 1–3 for number of times reared (p range: .03–.002). Grooming behavior, measured as total number of behaviors or time spent grooming, was unchanged after SNI (see Figure 2d), F(1, 8) ⫽ 0.13, p ⫽ .73.
Long-Term Repetitive SCS Reverses Mechanical Hyperalgesia Induced by SNI Both 4- and 60-Hz SCS delivered daily for 6 hr significantly increased withdrawal thresholds of the paw when compared with sham SCS, F(2, 24) ⫽ 13.0, p ⫽ .001. Withdrawal thresholds in animals receiving 4- (p ⫽ .043) and 60-Hz SCS (p ⫽ .0001) were significantly greater than those receiving sham SCS. When comparing results during SCS, F(2, 24) ⫽ 27.3, p ⫽ .001, both 4- and 60-Hz SCS were significantly greater than sham SCS (p ⫽ .001), and 60 Hz produced a greater reduction
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Figure 2. Average number of crossings in the activity box over 30 min before (baseline) and up to 4 weeks after spared nerve injury (SNI) (a). Average distance (in centimeters) traveled in the activity box before (baseline) and up to 4 weeks after SNI (b). Average of number of times the animal reared before (baseline) and up to 4 weeks after SNI (c). Average of number of times the rat groomed before (baseline) and up to 4 weeks after SNI (d). ⴱ Significant difference between baseline.
than 4 Hz (p ⫽ .02). When comparing responses immediately after SCS, F(2, 24) ⫽ 14.1, p ⫽ .001, both 4 (p ⫽ .014) and 60 Hz (p ⫽ .001) similarly increased withdrawal thresholds when compared with sham SCS; however, there was no difference between 4- and 60-Hz SCS (p ⫽ .08; see Figure 3). The ability of SCS to reverse the reduced mechanical withdrawal of the paw remained consistent and significant throughout the 3-month testing period. Nonresponders were calculated based on a change in withdrawal threshold of the paw; nonresponders showed less than 10% change in withdrawal threshold. This constituted 15% of those that received SCS.
Long-Term Repetitive SCS Reverses the Decreased Activity Levels Induced by SNI Physical activity levels were tested every 1–2 weeks over 3 months to examine the long-term effects on SCS on spontaneous, nonreflexive behaviors. During both 4- and 60-Hz SCS, there was a significant overall difference in the number of crossings, F(2, 24) ⫽ 16.75, p ⫽ .001 (see Figure 4a), distance traveled, F(2, 24) ⫽ 25.21, p ⫽ .001 (see Figure 4b), and rearing, F(2, 24) ⫽ 21.4, p ⫽ .001 (see Figure 4c), when compared with sham SCS. Animals that received either 4- or 60-Hz SCS showed a significantly greater number of crossings, greater distance traveled, and more time spent rearing when compared with animals that received sham SCS (ps ⫽ .001). Figure 4 shows differences between groups at each time point. A significant improvement in crossings, distance traveled, and
rearing occurred with a single treatment with SCS as observed on Day 1, and these improvements with SCS remained effective for nearly 3 months. However, after 3 months of 4- or 60-Hz SCS, some measures no longer differed from sham SCS (rearing: 4 Hz vs. sham at 11 and 13 weeks; distance: 4 Hz vs. sham at 11 and 13 weeks, 60 Hz vs. sham at 13 weeks; crossings: 60 Hz vs. sham at 13 weeks).
Discussion The current study showed significant decreases in spontaneous physical activity levels in animals with SNI. This is in agreement with other studies that have shown SNI decreases activity in open field tests, including reductions in the total number of crossings and distance traveled (Grégoire et al., 2012; Kontinen et al., 1999; Leite-Almeida et al., 2009; Mendes et al., 2013). These behaviors were sensitive to treatments commonly used for neuropathic pain, including duloxetine and gabapentin (Grégoire et al., 2012), suggesting the decreases are related to nocifensive behaviors. The current study extends these prior findings by showing that this loss in activity levels persists for several months after nerve injury. On the other hand, in mice with nerve injury, home cage monitoring showed a short-lived decrease in activity returning to normal by 2 weeks after injury (Urban et al., 2011). Novel exploratory activity is uniquely different from home cage activity and may be affected differently by the nerve injury.
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Figure 3. Average withdrawal thresholds before (baseline) spared nerve injury (SNI) and lead implantation, during (D) spinal cord stimulation (SCS) and immediately after (A) SCS. Animals received sham, 4-Hz, or 60-Hz SCS beginning 2 weeks after SNI for 3 months daily. Measures were taken during the first treatment (Week 2), weekly during the first month of SCS (Weeks 3⫺5), and every 2 weeks for the last 2 months of SCS (Weeks 7, 9, 11, and 13). Testing was performed during (D) SCS and 1 hr after (A) SCS. ⴱ There were significant increases in withdrawal threshold during and after SCS over the 3-month period for the groups that received 4- and 60-Hz SCS when compared with sham SCS.
Alternatively, differences in the activity levels between studies could be related to differences between rats and mice. In the current study, daily SCS for 3 months reduced mechanical hyperalgesia and restored physical activity levels. The reduction in mechanical hyperalgesia parallels the increases in physical activity levels. This is the first study to show the long-term effectiveness of SCS with repeated treatment and to show improvements in physical activity. Prior studies have shown that a single treatment or treatment for 4 –5 days reduces mechanical hyperalgesia of the paw after nerve injury in multiple models (Guan et al., 2010; Maeda et al., 2009; Smits et al., 2006; Song, Ansah, Meyerson, Pertovaara, & Linderoth, 2013; Truin et al., 2011; Sato et al., 2013; Sato et al., 2014). The magnitude of the reduction varies considerably between studies, with some reports showing nearly complete reversal and others showing a smaller reversal. The effects in the current study with the internal stimulator were similar to those observed using the same electrode with an external stimulator; differences between study may represent differences in experimental set-up (Sato et al., 2013; Sato et al., 2014). The effects of SCS use a number of neurotransmitters and their receptors, including serotonin, opioids, ␥-aminobutyric acid, and acetylcholine (Cui, Meyerson, Sollevi, & Linderoth, 1998; Cui, O’Connor, Ungerstedt, Linderoth, & Meyerson, 1997; Linderoth, Gazelius, Franck, & Brodin, 1992; Sato et al., 2013; Schechtmann, Song, Ultenius, Meyerson, & Linderoth, 2008; Song, Meyerson, & Linderoth, 2011; Ultenius, Song, Lin, Meyerson, & Linderoth, 2013). Further, SCS inhibits C-fiber⫺mediated responses of dorsal horn wide-dynamic-range neurons in both nerve-injured and sham-operated rats (Guan et al., 2010), and inhibits release of glutamate and aspartate (Cui et al., 1998; Cui et al., 1997; Stiller et al., 1996). It has been hypothesized that repetitive SCS given daily over several months may lead to prolonged
Figure 4. Physical activity levels before (baseline) spared nerve injury (SNI) and lead implantation, and during the last 30 min of spinal cord stimulation (SCS). Animals received sham, 4-Hz, or 60-Hz SCS beginning 2 weeks after SNI for 3 months daily. Measures were taken during the first treatment (Week 2), weekly during the first month of SCS (Weeks 3⫺5), and every 2 weeks for the last 2 months of SCS (Weeks 7, 9, 11, 13). A. Number of crossings in activity box B. Distance (in centimeters) traveled C. Number of times reared. ⴱ Significantly different from sham.
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inhibition of nociceptive transmission through a progressive resolution of the underlying pathophysiologic mechanism of neuropathic pain, in particular, the reversal of central sensitization. We recently showed that 4 days of SCS, both 4 and 60 Hz, reduces SNI-induced glial cell activation (Sato et al., 2014). SCS has been used for more than 30 years to treat chronic pain, particularly neuropathic pain (Gybels & Sweet, 1989). People with neuropathic pain have used SCS for many years (1⫺7 year; Flagg, McGreevy, & Williams, 2012; Kumar, Rizvi, & Bnurs, 2011; Pluijms et al., 2012; Sarubbo et al., 2012; Wolter & Kieselbach, 2012). Recently, Dimarco, Kowalski, Hromyak, and Geertman (2013) showed that patients with chronic pain who applied daily SCS over a 2-year period continued to derive significant clinical benefits. The current study confirmed the continued effectiveness of SCS over a long duration. Further, prior studies in human subjects have shown that SCS reduces pain, improves ability to perform daily activities, and improves quality of life (Deer et al., 2014; Kumar, Toth, & Nath, 1996; Pluijms et al., 2012). Further, Meier et al. (2014) showed in patients with neuropathic pain that the main impact of SCS on quality of life is reduced pain intensity. The improvements in physical activity that occurred during SCS in the current study are likely the result of a reduction in pain-like behaviors. The current study developed a rat SCS model using an implanted internal neurostimulator, allowing us to test physical activity levels during stimulation and to give daily SCS over a long duration. Animals continued to gain weight, eat, drink, and groom normally, indicating no adverse events due to the implanted device. A prior study by our laboratory also used animals with the internal stimulator in a chronic muscle pain model. In this model, decreases only occurred with the distance traveled, and the magnitude of these changes was much less than the current study (Gong et al., 2014), suggesting that the implantable device does not affect activity levels alone. Using this stimulator, we showed the long-term effectiveness of SCS on hyperalgesia and activity levels. The effects of SCS may last for some period of time after stimulation is turned off. However, with the current design, we were unable to show whether these effects were long-lasting as we applied SCS daily, and we tested while SCS was on. Near the end of 3 months, the effects of SCS on activity levels appeared to be less pronounced. This could be explained by either reduced effectiveness of the SCS, or a learning effect with repetitive testing in the activity box. A noninjured control group was not included, but would have provided insight into the effects of repetitive activity box testing.
Conclusion This study pioneered the long-term use of an internal neurostimulator and enabled the use of activity box testing to evaluate the behavior of animals with SNI and SCS. We showed that activity decreased in rats with SNI. Long-term treatment with SCS decreased hyperalgesia and increased activity levels. Thus, SCS may not only have effects in reducing mechanical hyperalgesia, but it could also help restore normal function that is reduced as a result of the pain itself.
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Received February 21, 2014 Revision received April 22, 2014 Accepted April 23, 2014 䡲
© 2014 American Psychological Association 0735-7044/14/$12.00 http://dx.doi.org/10.1037/bne0000004
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Spinal Cord Stimulation (SCS) Improves Decreased Physical Activity Induced by Nerve Injury Karina L. Sato
Lisa M. Johanek
Universidade Federal de Sergipe and University of Iowa
Medtronic, Minneapolis, Minnesota
Luciana S. Sanada
Kathleen A. Sluka
Universidade Federal do Triângulo Mineiro and University of Iowa
University of Iowa
Spinal cord stimulation (SCS) is used to manage treatment of neuropathic pain to reduce pain and hyperalgesia and to improve activity. Prior studies using animal models of neuropathic pain have shown that SCS reduces hyperalgesia; however, it is unclear whether SCS affects physical activity. Therefore, we tested whether nerve injury (spared nerve injury [SNI] model) reduced physical activity levels, and whether SCS could restore these decreased activity levels. We tested whether SCS given over a long duration (6 hr daily for 3 months) remained effective. We compared SNI with uninjured controls over 4 weeks, and SNI with sham SCS with SNI with active SCS (4 or 60 Hz at 90% motor threshold). We confirmed the presence of mechanical hyperalgesia by examining mechanical thresholds of the paw with von Frey filaments. Physical activity levels were monitored over 30 min in an automated activity chamber as follows: overall activity, distance traveled, grooming behaviors, and rearing. Measures were taken during SCS every 1–2 weeks for 3 months. Animals with SNI (and no or sham SCS) showed decreased withdrawal thresholds ipsilaterally and reduced physical activity (rearing, distance, lines crossed) for 3 months. Both 4- and 60-Hz SCS increased paw withdrawal threshold during and immediately after SCS through 3 months. Both 4- and 60-Hz SCS increased the overall activity (lines crossed), distance traveled, and rearing, but not grooming behaviors for 3 months. This effect remained similar across the 3 months. Thus, measurement of spontaneous physical activity could be useful to examine nocifensive behaviors after nerve injury and is sensitive to SCS. Keywords: pain, hyperalgesia, open field, neuropathic, nerve injury
injury (SNI) model produces heat hyperalgesia and mechanical and cold allodynia that persist for at least 6 months (Decosterd & Woolf, 2000). However, the effects of nerve injury on spontaneous physical activity levels over a long duration are unclear. Using the chronic constriction injury model in mice, Basbaum et al. were unable to show long-term changes in home cage activity or open field tests— deficits were eliminated within 2 weeks after injury (Urban, Scherrer, Goulding, Tecott, & Basbaum, 2011). Prior studies in animals with inflammatory hyperalgesia have shown reductions in running wheel activity, and in activity when placed in a novel environment, that is, an open field test (Cobos et al., 2012; LaBuda & Fuchs, 2001; Pratt, Fuchs, & Sluka, 2013; Sluka & Rasmussen, 2010). Similarly, in animals with nerve injury produced by spinal nerve ligation or chronic constriction injury, there were decreases in activity levels (number of crossings) that last for at least 21 days (Grégoire, Michaud, Chapuy, Eschalier, & Ardid, 2012; Kontinen, Kauppila, Paananen, Pertovaara, & Kalso, 1999; Mendes et al., 2013); longer durations have not been tested. This decrease in overall activity could reflect an increase in movement-related pain as a result of the nerve injury. Thus, it is unclear whether the reductions in physical activity occur after SNI, whether they persist beyond 3 weeks, and whether they are sensitive to treatments like spinal cord stimulation (SCS).
Neuropathic pain is associated with diseases that affect the peripheral or central nervous system, including trauma, metabolic diseases, compression injuries, neurotoxins, infection, immune diseases, vitamin deficiencies, and cancer (Woolf & Mannion, 1999). Neuropathic pain can be difficult to diagnose and manage, and it significantly interferes with quality of life (Dworkin, 2002; Harden & Cohen, 2003; Magrinelli, Zanette, & Tamburin, 2013; Rowbotham, 2002; Woolf & Mannion, 1999). Experimental models of peripheral neuropathic pain in animals have been developed to mimic human neuropathic pain syndromes. The spared nerve
This article was published Online First June 9, 2014. Karina L. Sato, Department of Physical Therapy, Universidade Federal de Sergipe, and Department of Physical Therapy and Rehabilitation Science, University of Iowa; Lisa M. Johanek, Medtronic, Minneapolis, Minnesota; Luciana S. Sanada, Department of Biology, Universidade Federal do Triângulo Mineiro, and Department of Physical Therapy and Rehabilitation Science, University of Iowa; and Kathleen A. Sluka, Department of Physical Therapy and Rehabilitation Science, University of Iowa. Correspondence concerning this article should be addressed to Kathleen A. Sluka, Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA 52242. E-mail: kathleen-sluka@ uiowa.edu 625
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SCS is used to treat chronic neuropathic pain that is resistant to conservative management (Shrivastav & Musley, 2009; Smits, van Kleef, Holsheimer, & Joosten, 2013). SCS delivers electric current to the dorsal columns through implanted electrodes. Clinical studies in patients with neuropathic pain, complex regional pain syndrome, cancer pain, and chronic low back pain have showed that SCS reduces allodynia and pain, and improves return to work (Schlaier et al., 2007; Wolter, Fauler, & Kieselbach, 2013; Wolter & Kieselbach, 2012; Kemler et al., 2000; Kumar et al., 2007; North, Kidd, Farrokhi, & Piantadosi, 2005; Yakovlev & Ellias, 2008). In animals with nerve ligation, SCS reduces mechanical hyperalgesia with frequencies ranging from 10 – 60 Hz and durations as short as 5 min and as long as 6 hr (El-Khoury et al., 2002; Li, Yang, Meyerson, & Linderoth, 2006; Meyerson, Ren, Herregodts, & Linderoth, 1995; Sato, King, Johanek, & Sluka, 2013; Yakhnitsa, Linderoth, & Meyerson, 1999; Maeda, Ikeuchi, Wacnik, & Sluka, 2009). Our lab has performed the longest reported duration of treatment in animals where rats with 6 hr of SCS had better analgesia than rats with 30 min of stimulation (Sato, Johanek, Sanada, & Sluka, 2014). Further, these prior studies used external neurostimulators that required rats to be anesthetized, restrained, or tethered for delivery of current and, thus, stress could have interfered with testing effectiveness. Clinically, if SCS is used for many months to years, patients report reductions in spontaneous pain and improvement in ability to perform activities of daily living. Thus, the aims of this study were as follows: (a) to examine the effects of SNI on physical activity levels, (b) to examine the effects of SCS on reduced physical activity levels in SNI, and (c) to examine effects of long-term delivery (3 months) of SCS on neuropathic pain behaviors (e.g., mechanical hyperalgesia, reduced physical activity) using an internal neurostimulator.
Method Animals The experiments were performed on adult male Sprague– Dawley rats when they reached 6 – 8 weeks old (250 –350 g). Rats were housed in transparent plastic cages with free access to food and water on a 12h light⫺dark cycle. All experimental procedures were approved by the Animal Care and Use Committee at the University of Iowa and followed National Institutes of Health guidelines for use of animals in laboratory research.
Nerve Injury Model In the group with nerve injury, all rats were anesthetized with 2–3% isoflurane. The tibial and common peroneal nerves on one limb were tightly ligated with 4 – 0 silk and the sural nerve was kept intact, as previously described (Decosterd & Woolf, 2000). The overlying muscle was sutured with 4 – 0 silk, and tissue was sutured with 3– 0 silk.
direction. The lead was fixed to the muscle with sutures and the proximal end of the lead was tunneled inside the animal for connection to a neurostimulator (InterStim II Neurostimulator, model no. 3058; Medtronic Inc., Minneapolis, MN). This neurostimulator was placed between the muscle and the skin on the left flank. This allowed us to program the stimulator (model no. 8840; Medtronic Inc., Minneapolis, MN) externally and allowed animals to remain in their home cages for treatment.
SCS Parameters SCS was applied at each frequency (0 Hz [sham], 4 Hz, and 60 Hz) at an intensity of 90% motor threshold (MT) and a pulse width of 0.25 ms for 6 hr a day over 3 months. The intensity was adjusted, increased in a 0.05-mV increments (the minimal unit for the neurostimulator) until the animal showed a motor response. The 90% MT was then calculated and used to deliver SCS during all treatments. All SCS parameters were programmed into the stimulator and delivered at the same time each day with 6 hr on and 18 hr off. We previously showed analgesic effects with both 4and 60-Hz SCS (Maeda et al., 2009; Sato et al., 2013; Sato et al., 2014), that 6 hr of SCS was more effective than 30 min (Sato et al., 2014), and that 90% MT was more effective than 75% or 50% MT (Sato et al., 2014).
Behavior Tests Mechanical withdrawal thresholds. Before surgery, rats were acclimated to the room for 30 min and to transparent plastic testing cages on an elevated, wire mesh floor for 15 min. To test for mechanical withdrawal thresholds of the paw, calibrated von Frey filaments with bending forces ranging from 1⫺402 mN were applied to the lateral surface of both the ipsilateral and contralateral paw in the area innervated by the sural nerve, as previously described (Maeda et al., 2009). The lowest withdrawal force that produced a withdrawal was recorded as the threshold. A decrease in mechanical withdrawal threshold of the paw was interpreted as cutaneous hyperalgesia of the paw in this study. Activity box. Physical activity was measured using a novel open field activity box that was automated (LimeLight program; Actimetrics, Wilmette, IL). Animals were placed in the box for 30 min, and their activity was videotaped and stored for later analysis. The examiner left the room for the videotaping session. The computerized system reported a variety of automated measures based on a point on the animal’s back located half-way between its nose and tail base. The box measured 40 ⫻ 40 cm and was divided into 10 squares, with the area of each box being 16 cm2. The following measures were assessed: crossings as a measure of overall activity: the number of times the rat crossed into each subregion (square); distance: the total distance traveled in centimeters; grooming: the time (in seconds) spent grooming; and rearing: the number of times the animal reared. The computer program analyzed the number of crossings and distance traveled. Grooming and rearing were scored manually from the stored digital files.
Implantation of the Electrode After nerve injury, a small laminectomy was performed at the T13 spinal level, which corresponds to the upper lumbar spinal cord region, and a lead was inserted epidurally in the rostral
Experimental Design Experiment 1. Animals received SNI and lead implantation with an implantable stimulator. This group was compared with
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naive animals to examine the effects of the implantable stimulator and SNI on weight and withdrawal thresholds of the paw. No stimulation was given to the animals. For 4 weeks after surgery, weight and mechanical withdrawal thresholds were measured weekly (n ⫽ 5/group). Experiment 2. Animals received SNI and lead implantation with the implantable stimulator. The mechanical withdrawal threshold was assessed before SNI, before SCS, and during SCS once a week for the first month, and every other week for months 2 and 3. Withdrawal thresholds and activity box measurements were made in the last 30 min of the 6-hr SCS period. We also tested mechanical withdrawal thresholds 1 hr after the electrode was turned off. Sham SCS (n ⫽ 9) was compared with 4-Hz SCS (n ⫽ 9) and 60-Hz SCS (n ⫽ 9).
Statistical Analysis Analysis of the data was performed using SPSS, Version 19. Data for mechanical withdrawal thresholds of the paw were presented as mean ⫾ SEM. For mechanical withdrawal thresholds and activity levels, we examined these differences across time and between groups using repeated-measures analysis of variance. Post hoc testing between different groups was performed using the Tukey’s test. A p value ⬍ 0.05 was considered significant.
Results No Effect of Internal Stimulator on Hyperalgesia and Weight To test whether the implantation of an internal stimulator caused adverse effects, we examined weight and paw withdrawal thresholds in SNI animals implanted with an internal stimulator. All rats implanted with the neurostimulator and given an SNI gained weight over the 4-week period (p ⬍ .001 for Weeks 1– 4 vs. baseline, paired t test), with before surgery averaging 311 g (SEM ⫽ 3) and increasing to 382 g (SEM ⫽ 1) by Week 4 (see Figure 1a). Before SNI, baseline withdrawal thresholds averaged 197 mN (SEM ⫽ 54) in the SNI group and were similar to a control group without SNI or the internal stimulator (M ⫽ 171 mN, SEM ⫽ 16). Seven days later, all rats with SNI showed a significant decrease in withdrawal threshold ipsilaterally, with an average of 8.6 mN (SEM ⫽ 4.6; p ⫽ .008) when compared with uninjured controls; this decrease remained significant through 28 days after SNI (p ⫽ .007, Weeks 2⫺4), F(1, 8) ⫽ 8.7, p ⫽ .02 (see Figure 1b). The uninjured control group remained unchanged throughout the 28-day testing period (see Figure 1b).
SNI Decreased Physical Activity Levels To test whether nerve injury resulted in a decrease in physical activity levels, we videotaped rats with SNI in an activity box for 30 min and compared them with rats without injury every week for 1 month. Significant decreases in the number of crossings (see Figure 2a), F(1, 8) ⫽ 45.6, p ⫽ .001, distance traveled (see Figure 2b), F(1, 8) ⫽ 10.9, p ⫽ .01, and rearing (see Figure 2c), F(1, 8) ⫽ 13.0, p ⫽ .007, occurred after SNI
Figure 1. Average weight before and after implantation of the internal stimulator over 4 weeks (a). Average withdrawal thresholds ipsilateral to nerve injury over 4 weeks in animals with spared nerve injury (SNI) plus an implanted neurostimulator compared with uninjured controls (b). ⴱ Significant difference from controls.
when compared with uninjured controls. Significant decreases occurred for Weeks 1– 4 for the number of crossings (p range: ⬍ .005 to ⬍ .001), distance traveled (p range: .01–.002), and for Weeks 1–3 for number of times reared (p range: .03–.002). Grooming behavior, measured as total number of behaviors or time spent grooming, was unchanged after SNI (see Figure 2d), F(1, 8) ⫽ 0.13, p ⫽ .73.
Long-Term Repetitive SCS Reverses Mechanical Hyperalgesia Induced by SNI Both 4- and 60-Hz SCS delivered daily for 6 hr significantly increased withdrawal thresholds of the paw when compared with sham SCS, F(2, 24) ⫽ 13.0, p ⫽ .001. Withdrawal thresholds in animals receiving 4- (p ⫽ .043) and 60-Hz SCS (p ⫽ .0001) were significantly greater than those receiving sham SCS. When comparing results during SCS, F(2, 24) ⫽ 27.3, p ⫽ .001, both 4- and 60-Hz SCS were significantly greater than sham SCS (p ⫽ .001), and 60 Hz produced a greater reduction
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Figure 2. Average number of crossings in the activity box over 30 min before (baseline) and up to 4 weeks after spared nerve injury (SNI) (a). Average distance (in centimeters) traveled in the activity box before (baseline) and up to 4 weeks after SNI (b). Average of number of times the animal reared before (baseline) and up to 4 weeks after SNI (c). Average of number of times the rat groomed before (baseline) and up to 4 weeks after SNI (d). ⴱ Significant difference between baseline.
than 4 Hz (p ⫽ .02). When comparing responses immediately after SCS, F(2, 24) ⫽ 14.1, p ⫽ .001, both 4 (p ⫽ .014) and 60 Hz (p ⫽ .001) similarly increased withdrawal thresholds when compared with sham SCS; however, there was no difference between 4- and 60-Hz SCS (p ⫽ .08; see Figure 3). The ability of SCS to reverse the reduced mechanical withdrawal of the paw remained consistent and significant throughout the 3-month testing period. Nonresponders were calculated based on a change in withdrawal threshold of the paw; nonresponders showed less than 10% change in withdrawal threshold. This constituted 15% of those that received SCS.
Long-Term Repetitive SCS Reverses the Decreased Activity Levels Induced by SNI Physical activity levels were tested every 1–2 weeks over 3 months to examine the long-term effects on SCS on spontaneous, nonreflexive behaviors. During both 4- and 60-Hz SCS, there was a significant overall difference in the number of crossings, F(2, 24) ⫽ 16.75, p ⫽ .001 (see Figure 4a), distance traveled, F(2, 24) ⫽ 25.21, p ⫽ .001 (see Figure 4b), and rearing, F(2, 24) ⫽ 21.4, p ⫽ .001 (see Figure 4c), when compared with sham SCS. Animals that received either 4- or 60-Hz SCS showed a significantly greater number of crossings, greater distance traveled, and more time spent rearing when compared with animals that received sham SCS (ps ⫽ .001). Figure 4 shows differences between groups at each time point. A significant improvement in crossings, distance traveled, and
rearing occurred with a single treatment with SCS as observed on Day 1, and these improvements with SCS remained effective for nearly 3 months. However, after 3 months of 4- or 60-Hz SCS, some measures no longer differed from sham SCS (rearing: 4 Hz vs. sham at 11 and 13 weeks; distance: 4 Hz vs. sham at 11 and 13 weeks, 60 Hz vs. sham at 13 weeks; crossings: 60 Hz vs. sham at 13 weeks).
Discussion The current study showed significant decreases in spontaneous physical activity levels in animals with SNI. This is in agreement with other studies that have shown SNI decreases activity in open field tests, including reductions in the total number of crossings and distance traveled (Grégoire et al., 2012; Kontinen et al., 1999; Leite-Almeida et al., 2009; Mendes et al., 2013). These behaviors were sensitive to treatments commonly used for neuropathic pain, including duloxetine and gabapentin (Grégoire et al., 2012), suggesting the decreases are related to nocifensive behaviors. The current study extends these prior findings by showing that this loss in activity levels persists for several months after nerve injury. On the other hand, in mice with nerve injury, home cage monitoring showed a short-lived decrease in activity returning to normal by 2 weeks after injury (Urban et al., 2011). Novel exploratory activity is uniquely different from home cage activity and may be affected differently by the nerve injury.
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Figure 3. Average withdrawal thresholds before (baseline) spared nerve injury (SNI) and lead implantation, during (D) spinal cord stimulation (SCS) and immediately after (A) SCS. Animals received sham, 4-Hz, or 60-Hz SCS beginning 2 weeks after SNI for 3 months daily. Measures were taken during the first treatment (Week 2), weekly during the first month of SCS (Weeks 3⫺5), and every 2 weeks for the last 2 months of SCS (Weeks 7, 9, 11, and 13). Testing was performed during (D) SCS and 1 hr after (A) SCS. ⴱ There were significant increases in withdrawal threshold during and after SCS over the 3-month period for the groups that received 4- and 60-Hz SCS when compared with sham SCS.
Alternatively, differences in the activity levels between studies could be related to differences between rats and mice. In the current study, daily SCS for 3 months reduced mechanical hyperalgesia and restored physical activity levels. The reduction in mechanical hyperalgesia parallels the increases in physical activity levels. This is the first study to show the long-term effectiveness of SCS with repeated treatment and to show improvements in physical activity. Prior studies have shown that a single treatment or treatment for 4 –5 days reduces mechanical hyperalgesia of the paw after nerve injury in multiple models (Guan et al., 2010; Maeda et al., 2009; Smits et al., 2006; Song, Ansah, Meyerson, Pertovaara, & Linderoth, 2013; Truin et al., 2011; Sato et al., 2013; Sato et al., 2014). The magnitude of the reduction varies considerably between studies, with some reports showing nearly complete reversal and others showing a smaller reversal. The effects in the current study with the internal stimulator were similar to those observed using the same electrode with an external stimulator; differences between study may represent differences in experimental set-up (Sato et al., 2013; Sato et al., 2014). The effects of SCS use a number of neurotransmitters and their receptors, including serotonin, opioids, ␥-aminobutyric acid, and acetylcholine (Cui, Meyerson, Sollevi, & Linderoth, 1998; Cui, O’Connor, Ungerstedt, Linderoth, & Meyerson, 1997; Linderoth, Gazelius, Franck, & Brodin, 1992; Sato et al., 2013; Schechtmann, Song, Ultenius, Meyerson, & Linderoth, 2008; Song, Meyerson, & Linderoth, 2011; Ultenius, Song, Lin, Meyerson, & Linderoth, 2013). Further, SCS inhibits C-fiber⫺mediated responses of dorsal horn wide-dynamic-range neurons in both nerve-injured and sham-operated rats (Guan et al., 2010), and inhibits release of glutamate and aspartate (Cui et al., 1998; Cui et al., 1997; Stiller et al., 1996). It has been hypothesized that repetitive SCS given daily over several months may lead to prolonged
Figure 4. Physical activity levels before (baseline) spared nerve injury (SNI) and lead implantation, and during the last 30 min of spinal cord stimulation (SCS). Animals received sham, 4-Hz, or 60-Hz SCS beginning 2 weeks after SNI for 3 months daily. Measures were taken during the first treatment (Week 2), weekly during the first month of SCS (Weeks 3⫺5), and every 2 weeks for the last 2 months of SCS (Weeks 7, 9, 11, 13). A. Number of crossings in activity box B. Distance (in centimeters) traveled C. Number of times reared. ⴱ Significantly different from sham.
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inhibition of nociceptive transmission through a progressive resolution of the underlying pathophysiologic mechanism of neuropathic pain, in particular, the reversal of central sensitization. We recently showed that 4 days of SCS, both 4 and 60 Hz, reduces SNI-induced glial cell activation (Sato et al., 2014). SCS has been used for more than 30 years to treat chronic pain, particularly neuropathic pain (Gybels & Sweet, 1989). People with neuropathic pain have used SCS for many years (1⫺7 year; Flagg, McGreevy, & Williams, 2012; Kumar, Rizvi, & Bnurs, 2011; Pluijms et al., 2012; Sarubbo et al., 2012; Wolter & Kieselbach, 2012). Recently, Dimarco, Kowalski, Hromyak, and Geertman (2013) showed that patients with chronic pain who applied daily SCS over a 2-year period continued to derive significant clinical benefits. The current study confirmed the continued effectiveness of SCS over a long duration. Further, prior studies in human subjects have shown that SCS reduces pain, improves ability to perform daily activities, and improves quality of life (Deer et al., 2014; Kumar, Toth, & Nath, 1996; Pluijms et al., 2012). Further, Meier et al. (2014) showed in patients with neuropathic pain that the main impact of SCS on quality of life is reduced pain intensity. The improvements in physical activity that occurred during SCS in the current study are likely the result of a reduction in pain-like behaviors. The current study developed a rat SCS model using an implanted internal neurostimulator, allowing us to test physical activity levels during stimulation and to give daily SCS over a long duration. Animals continued to gain weight, eat, drink, and groom normally, indicating no adverse events due to the implanted device. A prior study by our laboratory also used animals with the internal stimulator in a chronic muscle pain model. In this model, decreases only occurred with the distance traveled, and the magnitude of these changes was much less than the current study (Gong et al., 2014), suggesting that the implantable device does not affect activity levels alone. Using this stimulator, we showed the long-term effectiveness of SCS on hyperalgesia and activity levels. The effects of SCS may last for some period of time after stimulation is turned off. However, with the current design, we were unable to show whether these effects were long-lasting as we applied SCS daily, and we tested while SCS was on. Near the end of 3 months, the effects of SCS on activity levels appeared to be less pronounced. This could be explained by either reduced effectiveness of the SCS, or a learning effect with repetitive testing in the activity box. A noninjured control group was not included, but would have provided insight into the effects of repetitive activity box testing.
Conclusion This study pioneered the long-term use of an internal neurostimulator and enabled the use of activity box testing to evaluate the behavior of animals with SNI and SCS. We showed that activity decreased in rats with SNI. Long-term treatment with SCS decreased hyperalgesia and increased activity levels. Thus, SCS may not only have effects in reducing mechanical hyperalgesia, but it could also help restore normal function that is reduced as a result of the pain itself.
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Received February 21, 2014 Revision received April 22, 2014 Accepted April 23, 2014 䡲
