Therapeutic potential of spinal cord stimulation for gastrointestinal motility disorders a preliminary rodent study

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Published on March 6, 2014

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Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 377–384 doi: 10.1111/nmo.12273 Therapeutic potential of spinal cord stimulation for gastrointestinal motility disorders: a preliminary rodent study G.–Q. SONG ,*,† Y. SUN ,*,† R. D. FOREMAN ‡ & J. D. Z. CHEN *,§ *Veterans Research and Education Foundation, VA Medical Center, Oklahoma City, OK, USA †Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX, USA ‡Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA §Ningbo Pace Translational Medical Research Center, Beilun, Ningbo, China Key Messages • In this study, we found spinal cord stimulation • • • (SCS) improves gastric motility, probably by inhibiting the sympathetic activity and exciting the vagal activity. SCS may have therapeutic potential for treating GI motility disorders. The aim of this study was to investigate the effects and mechanisms of SCS on gastrointestinal (GI) motility in rats. Male rats chronically implanted with a unipolar electrode at T9/T10 were studied. The study included four experiments to assess the effects of SCS on (1) gastric tone; (2) gastric emptying of liquids and intestinal transit; (3) gastric emptying of solids; and (4) sympathovagal balance in healthy rats and/or in Streptozotocin (STZ)induced diabetic rat. SCS accelerates gastric emptying of liquids and solids, increases intestinal transit, and inhibits the sympathetic activity and excites the vagal activity. Abstract Background Spinal cord electrical stimulation (SCS) has been applied for the management of chronic pain. Most of studies have revealed a decrease in sympathetic activity with SCS. The aim of this study was to investigate the effects and mechanisms of SCS on gastrointestinal (GI) motility in healthy and diabetic rats. Methods Male rats chronically implanted with a unipolar electrode at T9/T10 were studied. The study included four experiments to assess the effects of SCS on (1) gastric tone; (2) gastric emptying of liquids and intestinal transit; (3) gastric emptying of solids; and (4) sympathovagal balance in healthy rats and/or in Streptozotocin (STZ)-induced diabetic rat. Key Results (1) Spinal cord stimulation intensity dependently increased gastric tone in healthy rats. The gastric volume was 0.97 Æ 0.15 mL at baseline, and decreased to 0.92 Æ 0.16 mL with SCS of the 30% motor threshold (MT; p = 0.13 vs baseline), 0.86 Æ 0.14 mL with 60% MT (p = 0.045 vs baseline), and 0.46 Æ 0.19 mL with 90% MT (p = 0.0050 vs baseline). (2) Spinal cord stimulation increased gastric emptying of liquids by about 17% and accelerated small intestinal transit by about 20% in healthy rats (p < 0.001). (3) Spinal cord stimulation accelerated gastric emptying of solids by about 24% in healthy rats and by about 78% in diabetic rats. (4) Spinal cord stimulation decreased sympathetic activity (1.13 Æ 0.18 vs 0.68 Æ 0.09, p < 0.04) and sympathovagal balance (0.51 Æ 0.036 vs 0.40 Æ 0.029, p = 0.028). Conclusions & Inferences Spinal cord stimulation Address for Correspondence Jiande Chen, Ningbo Pace Translational Medical Research Center, Beilun, Ningbo, China. Tel: 1-832-640-8111; fax: 86-574-86818262; e-mail: jiandedzchen@gmail.com Received: 13 September 2013 Accepted for publication: 8 November 2013 © 2013 John Wiley & Sons Ltd 377

G.–Q. Song et al. Neurogastroenterology and Motility accelerates gastric emptying of liquids and solids, and intestinal transit, probably by inhibiting the sympathetic activity. Spinal cord stimulation may have a therapeutic potential for treating GI motility disorders. Keywords gastric emptying, gastrointestinal motility, intestinal transit, spinal cord stimulation, sympathetic activity. INTRODUCTION Delayed gastric emptying or impaired gastric motility and visceral hypersensitivity to gastric distention are two major pathophysiological factors of functional dyspepsia or two major components of functional gastric disorders. Functional dyspepsia is a common disorder affecting about 25% of the general population.1 A proportion of patients meeting Rome symptom criteria for functional dyspepsia will be found, if studied, to have gastroparesis. Gastroparesis is reported in 30–50% of type I or type II diabetes and 25–40% of patients with functional dyspepsia.2–4 Common symptoms of functional dyspepsia and gastroparesis include epigastric pain or discomfort, early satiety, fullness, abdominal bloating, nausea, and vomiting. Medical treatment options for gastroparesis and functional dyspepsia are very limited. In addition to the intrinsic enteric nervous system, the extrinsic vagal and sympathetic nerves also play important roles in the regulation of gastric motility. It is well established that the activation of vagal cholinergic nerves enhances gastric motility, whereas the activation of sympathetic nerves inhibits gastric motility. In addition, vagal non-adrenergic non-cholinergic path contributes to inhibitory control of gastric motility.5 Spinal cord stimulation (SCS) has been widely applied for the treatment of pain.6–14 The main clinical applications of SCS consist of (i) chronic regional pain syndromes type I and II13; (ii) radicular pain: failed back surgery syndrome13; (iii) vascular pain: refractory angina and peripheral vascular diseases13; (iv) urological diseases: interstitial cystitis and urge incontinence; and (v) abdominal visceral pain.9,15 There have been few studies reporting potential applications of SCS for the treatment of gastrointestinal (GI) motility disorders.9,16,17 We hypothesized that SCS might improve GI motility by inhibiting sympathetic nerves or altering sympathovagal balance. The aim of this study was to investigate the effects of SCS on gastric emptying of liquids and solids, and small intestinal transit in regular and diabetic rats and possible mechanisms involving the extrinsic autonomic functions. Figure 1 A stimulation electrode was implanted into the epidural space (T9/T10) and a circular anode was placed subcutaneously with exposure of the contact made at the level of the neck. MATERIALS AND METHODS Animal preparation A total of 73 Sprague–Dawley rats (350–400 g) were used in this study. Before the surgical procedure, the rats were given ketamine (60 mg/kg, ip) together with Xylazine (5 mg/kg ip) to maintain a deep level of surgical anesthesia and muscle relaxation (disappearance of reflex with leg punch or toe pinch with a forceps). A laminectomy was performed to expose the lower thoracic and upper lumbar segments of the spinal cord. The caudal-most rib and the spinal nerve running immediately adjacent and caudal to that rib were located and followed to the spinal cord. That spinal segment was used as the ‘reference point’ for the T13 spinal level. A unipolar stimulation electrode (oval cathode 2 mm in length) was placed on the dorsal column immediately above the reference point, then moved to a predetermined spinal level of T9–T10, and chronically implanted into the epidural space (Fig. 1). The electrode connecting wire was fixed in the muscle layer of the back and brought out at the back of the neck. The circular anode (5 mm in diameter) was placed subcutaneously with exposure of the contact made at the level of the neck and also brought out at the back of the neck. The experiments were initiated when the rats were completely recovered (5–10 days) from the surgery. The electrode location was validated at the end of the study by visual examination. The experimental protocols were approved by the Institutional Animal Care and Use Committee of the VA Medical Center, Oklahoma City, OK, USA. In rats that were to be treated with Streptozotocin (STZ), the surgical procedure was performed before the induction of diabetes to ensure a complete recovery. Induction of diabetes After a complete recovery from the surgery, 18 of the animals were intraperitoneally injected with STZ (65 mg/ 378 © 2013 John Wiley & Sons Ltd

Volume 26, Number 3, March 2014 SCS for gastrointestinal motility disorders group, the experiment was the same as the sham group except that SCS with an intensity of 90% MT was applied during the 30 min postprandial period. kg, Sigma, St. Louis, MO, USA) dissolved in a 1.5 mL citrate buffer (pH 4.5, Sigma). The blood glucose level was measured weekly after the injection. Diabetes was defined as a blood glucose concentration of 350 mg/dL or higher. The animals (N = 2) that did not meet this criterion were excluded from the study. Experiment three Effects of SCS on gastric emptying of solids in healthy rats and diabetic rats chronically implanted with stimulation electrodes. This study included four groups of rats: eight healthy rats without SCS, eight healthy rats with SCS, eight diabetic rats without SCS, and eight diabetic rats with SCS. Diabetic rats were studied 6 weeks after the injection of STZ to ensure that gastric emptying was delayed according to our previous study,19 and healthy rats were age matched with the diabetic rats. Spinal cord stimulation The stimuli for SCS were delivered by a universal stimulator (Model A310; World Precision Instruments, Sarasota, FL, USA) and consisted of monophasic rectangular pulses (50 Hz; pulse width 0.2 ms; pulse train on/off time: 2 s/3 s) with an intensity of 30%, 60%, or 90% of the motor threshold (MT; tonic contractions of the abdominal muscles). These parameters were chosen based on pain control literature.9,16 However, in the application of SCS for pain control, stimuli are given continuously. In this application, we used trains of pulses, that is, the pulses were delivered for a certain period (2 s) and paused for another period (3 s). This concept was adopted from gastric electrical stimulation18 and was slightly different from the conventional method of SCS. Each of the four groups of rats was fasted for 24 h before the test and consumed 2.0 g of regular solid food during the study within 10 min (the composition of the solid meal: crude protein less than 23.0%, crude fat not less than 6.5%, crude fiber no more than 4.0%, ash no more than 8.0%, and added minerals no more than 2.5% [5008 Formulab Diet from Lab Diet in Missouri, USA]). Ninety minutes after feeding, the rat was killed and the stomach was removed. The content of the stomach was removed and left in open air to dry for a period of 48 h and the dried content was weighed.20 In the rats with SCS, SCS with an intensity of 90% MT was performed during the 90 min postprandial period. For the assessment of solid gastric emptying, 10 control samples of 2 g of the same solid food dissolved in 2 mL of saline were also air dried for 48 h. Gastric emptying was defined as the mean weight of the dried control samples minus the dried weight of the nonemptied food collected from the stomach times 100%. Experimental protocols A total of four experiments were performed after an overnight fast for Experiments 1 and 4, and 24-hour fast for Experiments 2 and 3 to investigate (i) the effects of SCS with different stimulation intensities on gastric tone; (ii) the effects of SCS on gastric emptying and intestinal transit in regular and diabetic rats; and (iii) mechanisms involving extrinsic autonomic functions. Experiment four Possible mechanism of SCS involving the extrinsic autonomic function. The effects of SCS on autonomic functions assessed by the spectral analysis of heart rate variability were studied in 16 healthy rats. Before the experiment, three cardiac pacing wires were placed (by suturing in the muscle under the skin) in the intercostal space below the first pair of nipples (two active electrodes) and the right rear leg (one reference electrode). The ECG was recorded from these wires in the fasting state for 20 min at baseline, 20 min during SCS of 90% MT, and 20 min after SCS. Experiment one Effects of SCS with different stimulation intensities on gastric tone. In addition to the SCS electrodes, a small intragastric balloon was chronically placed in the proximal stomach in seven healthy rats at the time when the SCS electrodes were implanted. The balloon bag was of a spherical shape with a maximal volume of about 5–7 mL and a nondistensible diameter of 2.0–2.5 cm. It was sutured to a flexible plastic tube with inside diameter of 1.67 mm and outside diameter of 2.42 mm. A 1- to 2-cm-long anterior epigastric incision was made, and the balloon was inserted into the stomach fundus, about 1 cm from the gastro-esophageal junction. The plastic tubing for air inflation of the balloon was exteriorized at the back of the neck along with the connecting wires of the electrodes. The abdomen was then closed by suturing with silk. Measurements and analyses Assessment of gastric tone Gastric tone was assessed by using a barostat machine, which is a recognized method.21 It is known that gastric tone is produced by sustained contractions of the stomach wall, and the variation in intraballoon volume is inversely correlated with the change in gastric tone.22 In this method, a catheter with one end attached to a non-compliant plastic balloon and the other end connected to an electronic barostat (G & J Electronics, North York, ON, Canada) was used to measure intraballoon volume. The minimal distending pressure (MDP) was determined by inflating the balloon in 1 mmHg steps until a pressure at which evident respiratory excursions were recorded and a proper balloon volume was achieved (>0.3 mL). The pressure that was 2 mmHg above MDP was defined as the operating pressure and used for recording gastric volume. Experimental protocol: The experiment included a 20-min baseline and three 20-min periods with SCS of three different intensities. The two consecutive SCS periods were separated with a period of 20 min or more in order for the gastric tone to recover to the baseline. Spinal cord stimulation was performed with an intensity of 30%, 60%, or 90% of the MT. Gastric tone was assessed by the measurement of gastric volume via the implanted gastric balloon using a computerized barostat throughout the experiment. Experiment two Effects of SCS on gastric emptying of liquids and intestinal transit. Sixteen healthy rats chronically implanted with stimulation electrodes were studied. After a complete recovery from the surgical procedure, they were evenly divided into sham SCS and SCS groups. In the sham group, the rats were gavage fed with 1.5 mL of methylcellulose mixed with phenol red. Thirty minutes after feeding, the rats were sacrificed, the stomach and the entire small bowl were removed, and gastric and small intestinal retention of phenol red were calculated. In the SCS © 2013 John Wiley & Sons Ltd Measurements of gastric emptying of liquids and intestinal transit Thirty minutes after the test meal of methylcellulose mixed with phenol red, the rats were killed under general anesthesia with 5% isoflurane inhalation, confirmed by chest 379

G.–Q. Song et al. Neurogastroenterology and Motility opening. For the assessment of gastric emptying, the entire stomach was carefully isolated, ligated just above the cardia and below the pylorus, and removed. For the intestinal transit, the entire small intestine was carefully harvested and divided into 10 equal segments. The phenol red contents of the stomach or each segment of the small intestine were measured using an established method described as follows23,24: Each segment was individually homogenized using a homogenizer (PowerGen 700 homogenizer; Fisher Scientific, Pittsburgh, PA, USA) with 100 mL of 0.1 N NaOH. The mixture was kept at room temperature for 1 h. The supernatant (5 mL) was added to 0.5 mL of a TCA solution (20% wt/vol) to precipitate proteins. After centrifugation (2500 g during 20 min), the supernatant was added to 4 mL of NaOH (0.5 N) to develop the maximum intensity of color. The solutions were read using a spectrophotometer (DU 650 spectrophotometer; Beckman Coulter Inc., Brea, CA, USA) at fixed wavelength of 560 nm. and the Student’s t-test was used to assess the effect of SCS in comparison with the baseline or control group. p < 0.05 was considered statistically significant. RESULTS Effects of SCS on gastric tone in healthy rats Spinal cord stimulation intensity dependently increased gastric tone. The gastric volume was 0.97 Æ 0.15 mL at baseline, and decreased to 0.92 Æ 0.16 mL with SCS of the 30% MT (p = 0.13 vs baseline), 0.86 Æ 0.14 mL with 60% MT (p = 0.045 vs baseline), and 0.46 Æ 0.08 mL with 90% MT (p = 0.0050 vs baseline; Fig. 2A). Fig. 2B presents a gastric tone tracing at baseline, during SCS and recovery periods. A decrease in gastric volume is indicative of increased gastric tone. Gastric emptying of liquids was determined as the total amount of phenol red mixed with the meal minus the amount of phenol red recovered from the stomach.23 Small intestinal transit was assessed using a parameter called geometric center (GC), calculated as follows: GC = sum of n 9 Pn for n = 1, 2,… 10. Where ‘n’ was the number of the intestinal segment and ‘Pn’ was the percentage of phenol red recovered from the corresponding segment.23 Effects of SCS on gastric emptying of liquids and small intestinal transit in healthy rats Assessment of autonomic functions The sympathetic and vagal activities were assessed from the ECG signal using the following method. Using a special software developed in our lab and validated in previous studies, R waves were identified from the ECG and R–R interval data were obtained; the R–R interval data were then interpolated and resampled to derive a heart rate variability signal. The smoothed spectral analysis method was then applied to compute the power spectrum of the heart rate variability signal.25 Spectral powers at three frequency ranges were averaged using a method published in the literature26,27: (a) a low-frequency band (LF; 0.3–0.8 Hz) reflecting mainly sympathetic activity; and (b) a high-frequency band (HF; 0.8–4.0 Hz) reflecting vagal efferent activity. The sympathovagal balance was defined as the ratio of LF/HF. Spinal cord stimulation accelerated gastric emptying of liquids and small intestinal transit. It was found that: SCS with an intensity of 90% MT accelerated gastric emptying of liquids by about 17% (91.6% Æ 2.3% vs 78.0% Æ 9%, p = 0.014). Spinal cord stimulation with an intensity of 90% MT increased small intestinal transit by about 20% (6.0 Æ 0.49 vs 4.9 Æ 0.28, p < 0.001) in healthy rats (Fig. 3). Effects of SCS on gastric emptying of solids in both healthy and diabetic rats Spinal cord stimulation accelerated gastric emptying of solids in both healthy and diabetic rats (Fig. 4). In the healthy rats, SCS increased gastric emptying of solids by about 24% (74.8% Æ 2.8% vs 60.0% Æ 3.7%, Statistical analysis The results are expressed as mean Æ SEM. ANOVA was used to compare the data among three or more different periods or groups 1.2 A *p = 0.045 or **p =0.005 vs. Baseline * Gastric volume (mL) 1 0.8 0.6 ** 0.4 0.2 0 Baseline 30%MT 60%MT 90%MT B Figure 2 (A) Effects of spinal cord stimulation (SCS) on gastric tone in regular rats. A significant decrease of gastric volume was noted with SCS of 60% or 90% motor threshold; (B) Tracing of gastric tone at the baseline, during SCS, and after SCS in a regular rat. 20-min SCS (0.2 ms, 50 Hz, 2s on, 3s off, 90% motor threshold) 380 © 2013 John Wiley & Sons Ltd

Volume 26, Number 3, March 2014 SCS for gastrointestinal motility disorders A 100% B *p = 0.014 * Geometric center Gastric emptying (%) Figure 3 Effects of spinal cord stimulation (SCS) on gastric emptying and small intestinal transit. SCS of the 90% motor threshold significantly accelerated gastric emptying and small intestinal transit. 7 *p < 0.001 * 6.5 90% 80% 70% 60% 50% 6 5.5 5 4.5 4 3.5 40% Sham 3 SCS Sham 1.5 SCS SCS Baseline Recovery *p = 0.037 or **p = 0.028 vs. the corresponding baseline 1.3 1.1 0.9 * 0.7 0.5 ** 0.3 Sympathetic activity Sympathovagal balance Figure 5 Effects of spinal cord stimulation (SCS) on sympathetic activity or sympathovagal balance in regular rats. SCS of the 90% motor threshold significantly decreased sympathetic activity and sympathovagal balance. Figure 4 Effects of spinal cord stimulation (SCS) on gastric emptying of solids. SCS accelerated gastric emptying of solids in both healthy and diabetic rats. In addition, gastric emptying of solids was delayed in diabetic rats. DISCUSSION p = 0.044). In the diabetic rats, SCS increased gastric emptying of solids by about 78.0% (71.9% Æ 6.4% vs 40.4% Æ 9.8%, p < 0.001) surpassing the gastric emptying in the healthy rats without SCS (71.9% vs 60.0%, p < 0.05). In addition, it can also be seen from Fig. 4 that the gastric emptying of solids in the untreated diabetic rats was delayed by about 32.7% in comparison with the untreated healthy rats (40.4% Æ 9.8% vs 60.0% Æ 3.7%, p = 0.005). In this study, it was found that SCS increased gastric tone in an intensity-dependent manner, accelerated gastric emptying of liquids and solids, improved intestinal transit, and decreased sympathetic activity and sympathovagal balance in rats. Gastroparesis is commonly seen in patients with diabetes in addition to its idiopathic and postoperative etiologies. However, limited treatment options are available for gastroparesis. Typically the medication therapy such as prokinetic agents is the first choice, including cisapride, tegaserod, domperidome, erythromycin, and metoclopramide. Cisapride and tegaserod have been dropped from the market due to their adverse effects, domperidome has not been available in USA, and erythromycin has been used with little effects in symptoms. In addition, metoclopramide is not potent in accelerating gastric emptying and has severe side effects. Surgical treatment is rarely used as it does not solve the problem. The use of jejunostomy tube feeding is one other option if the intestinal motility is normal. However, this only provides nutrition support, but does not solve the problem. In addition to directly improve muscle contractions of the stomach such as the prokinetics do, modulation of the extrinsic pathways is involved in the Mechanisms of SCS involving sympathetic/vagal activity Spinal cord stimulation decreased sympathetic activity and sympathovagal balance in healthy rats (Fig. 5). It was found that: SCS of 90% MT decreased sympathetic activity and sympathovagal balance from 1.13 Æ 0.18 and 0.51 Æ 0.036 at the baseline to 0.68 Æ 0.09 (p < 0.04, vs baseline) and 0.40 Æ 0.029 (p < 0.03, vs baseline) during SCS, respectively. After termination of SCS, the sympathetic activity and sympathovagal balance recovered to the baseline levels (0.94 Æ 0.16, p = 0.48. vs baseline and 0.47 Æ 0.04. p = 0.45 vs baseline). It was also noted that vagal activity was increased from 0.48 at the baseline to 0.60 with SCS (p = 0.029). © 2013 John Wiley & Sons Ltd 381

G.–Q. Song et al. Neurogastroenterology and Motility variability.35 The effects of SCS on sympathetic activity have also been reported in a number of other studies using different assessment methods: (i) in a rat model of mononeuropathy, SCS was reported to suppress pathological hyperexcitability of a wide dynamic of range spinal neurons after peripheral nerve lesions36; (ii) in a number of animal studies led by Linderoth, the peripheral vasodilatory effects of SCS were linked to the inhibition of efferent sympathetic activity as noted in the current.37–40 Improvement of GI motility resulting from the inhibition of the sympathetic activity has been reported in numerous previous studies. Epidural anesthesia was reported to increase GI motility and have a therapeutic potential for treating postoperative41; intraperitoneal administration of guanethidine in mice42 have been shown to increase gastric emptying. In addition to its prokinetic effects on GI motility, SCS has also been reported to attenuate visceromotor reflexes in rodent models of visceral hypersensitivity.9,33 As SCS has been and successfully and widely used for the treatment of various types of pain43–52 (e.g. neuropathetic pain), the treatment of visceral pain with SCS seems to be a natural extension of its applications. Indeed, a number of studies have demonstrated the therapeutic potential of SCS for the treatment of irritable bowel syndrome and various visceral pain.16,34,53,54 These studies, along with the two case report studies55,56 where SCS was associated with the relief from constipation and the adverse diarrhea symptoms, suggest that the increased GI transit following SCS may be associated with a release from sympathetic inhibition. Due to its minimally invasive nature, and the potentials of improving both GI motility and visceral hypersensitivity, SCS might play an important role in the management of other functional GI diseases such as functional dyspepsia, gastroparesis, and irritable bowel syndrome. The placement of stimulation electrode is considered as a simple procedure and is done under local anesthesia or a sedative. No hospitalization is required for the placement of stimulation electrodes and the stimulator. Similar to its application in treating pain, long-term treatment of motility disorders using an implantable stimulator can be determined after a temporary trial period using an external stimulator. This will greatly improve the outcome of the therapy. However, we acknowledge that our data were obtained with acute stimulation and the main findings were made with high stimulation intensities (mainly 90% MT). Therefore, more data will be needed to assess chronic effects of SCS and to study other stimulation parameters with low stimulation intensities in rats and regulation of gastric motility. Gastric motility is known to be enhanced with the augment of vagal activity and inhibition of sympathetic activity, and inhibited with the withdrawal of vagal activity and activation of sympathetic activity.28–32 Extrinsically, gastric motility is maintained by balancing the vagal and sympathetic activities. Our hypothesis was to break this balance by reducing the sympathetic contribution to the maintenance of gastric motility. Spinal cord stimulation that has been widely used in pain management is known to inhibit sympathetic activity9–11,13,33,34 and was therefore used in this study to test our hypothesis. To be able to visually and acutely observe the effect of SCS on gastric motility, a barostat device was first utilized to measure gastric tone. Using this measurement we were able to observe the prokinetic effect of SCS while adjusting the intensity of stimulation. As expected, an immediate increase in gastric tone (decrease in gastric volume) was noted in regular rats when SCS was applied and the prokinetic effect was intensity dependent. Therefore, further study was performed to investigate the prokinetic effects of SCS on gastric emptying in both regular and diabetic rats, and the hypothesized mechanism involving the autonomic function. It was found that SCS accelerated gastric empting of both liquids and solids and intestinal transit in regular rats, although the percentage of acceleration was not dramatic. Spinal cord stimulation was also found to accelerate gastric emptying of solids in STZ-induced diabetic rats and the increase was more dramatic than that observed in regular rats. While gastric emptying in the diabetic rats 6 weeks after the induction of diabetes was significantly delayed compared with regular rats, it was accelerated by the SCS to a level higher than that in the regular rats and comparable with that in the regular rats with SCS, suggesting that SCS is highly potent in improving gastric emptying in diabetic rats. In a rodent model of postoperative ileus, SCS was also found to normalize delayed gastric emptying in rats with postoperative ileus; however, no significant improvement in gastric emptying or intestinal transit was noted in regular rats.17 This difference might be attributed to the location of stimulation electrodes: T5–T8 in the previous study and T9–T10 in this study. The decrease in sympathetic activity and sympathovagal balance with SCS observed in this study suggests the involvement of the extrinsic autonomic pathway as we initially hypothesized. In patients with refractory angina, a similar decrease in sympathovagal balance was also reported with SCS, assessed by the same method of spectral analysis of the heart rate 382 © 2013 John Wiley & Sons Ltd

Volume 26, Number 3, March 2014 SCS for gastrointestinal motility disorders FUNDING other species as well. In addition, more basic and clinical research is needed in exploring therapeutic potentials of SCS in these areas. In conclusion, SCS accelerates gastric emptying of liquids and solids, and intestinal transit, probably by inhibiting the sympathetic activity. Spinal cord stimulation may have a therapeutic potential for treating GI motility disorders. This project was partially supported by a research grant from the Veterans Research and Education Foundation at VA Medical Center, Oklahoma City, OK. DISCLOSURE No conflicts of interest declared. ACKNOWLEDGEMENT This project was partially supported by a research grant from the Veterans Research and Education Foundation at VA Medical Center, Oklahoma City, OK. REFERENCES 1 Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, Whitehead WE, Janssens J et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993; 38: 1569–80. 2 Horowitz M, Edelbroek M, Fraser R, Maddox A, Wishart J. Disordered gastric motor function in diabetes mellitus. Recent insights into prevalence, pathophysiology, clinical relevance, and treatment. Scand J Gastroenterol 1991; 26: 673–84. 3 Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayner CK, Samsom M. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med 2002; 19: 177–94. 4 Park MI, Camilleri M. Gastroparesis: clinical update. Am J Gastroenterol 2006; 101: 1129–39. 5 Curro D, Ipavec V, Preziosi P. Neurotransmitters of the non-adrenergic non-cholinergic relaxation of proximal stomach. Eur Rev Med Pharmacol Sci 2008; 12(Suppl 1): 53–62. 6 Alo K. SCS for complex pain: initial experience with a dual electrode programmable, internal pulse generator. Pain Pract 2003; 3: 31–8. 7 Alo K, Mckay E. SNRS for the treatment of intractable pelvic pain and motor dysfunction: a case report. Neuromodulation 2001; 4: 19–23. 8 Doleys DM. Psychological factors in spinal cord stimulation therapy: brief review and discussion. Neurosurg Focus 2006; 21: E1. 9 Greenwood-Van Meerveld B, Johnson AC, Foreman RD, Linderoth B. © 2013 John Wiley & Sons Ltd 10 11 12 13 14 15 16 17 Spinal cord stimulation attenuates visceromotor reflexes in a rat model of post-inflammatory colonic hypersensitivity. Auton Neurosci 2005; 122: 69–76. Jessurun GA, Ten Vaarwerk IA, DeJongste MJ, Tio RA, Staal MJ. Sequelae of spinal cord stimulation for refractory angina pectoris. Reliability and safety profile of long-term clinical application. Coron Artery Dis 1997; 8: 33–8. Kemler MA, Reulen JP, Barendse GA, van Kleef M, de Vet HC, van den Wildenberg FA. Impact of spinal cord stimulation on sensory characteristics in complex regional pain syndrome type I: a randomized trial. Anesthesiology 2001; 95: 72–80. Kumar K, Malik S, Demeria D. Treatment of chronic pain with spinal cord stimulation versus alternative therapies: cost-effectiveness analysis. Neurosurgery 2002; 51: 106–15; discussion 115–6. Simpson BA. Spinal cord stimulation. Br J Neurosurg 1997; 11: 5–11. Van Buyten JP, Van Zundert J, Vueghs P, Vanduffel L. Efficacy of spinal cord stimulation: 10 years of experience in a pain centre in Belgium. Eur J Pain 2001; 5: 299–307. Tiede JM, Ghazi SM, Lamer TJ, Obray JB. The use of spinal cord stimulation in refractory abdominal visceral pain: case reports and literature review. Pain Pract 2006; 6: 197–202. Krames E, Mousad DG. Spinal cord stimulation reverses pain and diarrheal episodes of irritable bowel syndrome: a case report. Neuromodulation 2004; 7: 7. Maher J, Johnson AC, Newman R, Mendez S, Hoffmann TJ, Foreman R, 383 18 19 20 21 22 23 24 Greenwood-Van Meerveld B. Effect of spinal cord stimulation in a rodent model of post-operative ileus. Neurogastroenterol Motil 2009; 21: 672–7, e33–4. Zhang J, Chen JD. Systematic review: applications and future of gastric electrical stimulation. Aliment Pharmacol Ther 2006; 24: 991–1002. Liu J, Qiao X, Micci MA, Pasricha PJ, Chen JD. Improvement of gastric motility with gastric electrical stimulation in STZ-induced diabetic rats. Digestion 2004; 70: 159–66. Ariga H, Nakade Y, Tsukamoto K, Imai K, Chen C, Mantyh C, Pappas TN, Takahashi T. Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats. Regul Pept 2008; 146: 112–6. Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, Janssens J, Peeters T. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 2006; 55: 327–33. Tack J, Coulie B, Wilmer A, Andrioli A, Janssens J. Influence of sumatriptan on gastric fundus tone and on the perception of gastric distension in man. Gut 2000; 46: 468–73. Sallam HS, Oliveira HM, Gan HT, Herndon DN, Chen JD. Ghrelin improves burn-induced delayed gastrointestinal transit in rats. Am J Physiol Regul Integr Comp Physiol 2007; 292: R253–7. Scarpignato C, Capovilla T, Bertaccini G. Action of caerulein on gastric emptying of the conscious rat. Arch Int Pharmacodyn Ther 1980; 246: 286–94.

G.–Q. Song et al. 25 Wang ZS, Chen JD. Robust ECG R-R wave detection using evolutionaryprogramming-basedfuzzy inference system (EPFIS), and application to assessing brain-gutinteraction. IEE Proc Sci Meas Technol 2000; 147: 6. 26 Kruger C, Kalenka A, Haunstetter A, Schweizer M, Maier C, Ruhle U, Ehmke H, Kubler W et al. Baroreflex sensitivity and heart rate variability in conscious rats with myocardial infarction. Am J Physiol 1997; 273: H2240–7. 27 Liu J, Qiao X, Chen JD. Vagal afferent is involved in short-pulse gastric electrical stimulation in rats. Dig Dis Sci 2004; 49: 729–37. 28 Appenzeller O, Vinken P. Bruyn G. The Autonomic Nervous System. New York: Elsevier Health Sciences, 1999. 29 Costanzo L. Physiology, 4th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2006. 30 Goldstein D. The Autonomic Nervous System in Health and Disease. New York, NY: Informa Health Care, 2000. 31 J€nig W. The Integrative Action of a the Autonomic Nervous System: Neurobiology of Homeostasis. New York, NY: Cambridge University Press, 2006. 32 Robertson D. Primer on the Autonomic Nervous System, 2nd edn. Waltham, MA: Academic Press, 2004. 33 Greenwood-Van Meerveld B, Johnson AC, Foreman RD, Linderoth B. Attenuation by spinal cord stimulation of a nociceptive reflex generated by colorectal distention in a rat model. Auton Neurosci 2003; 104: 17–24. 34 Kapural L, Narouze SN, Janicki TI, Mekhail N. Spinal cord stimulation is an effective treatment for the chronic intractable visceral pelvic pain. Pain Med 2006; 7: 440–3. 35 Anselmino M, Ravera L, De Luca A, Capriolo M, Bordese R, Trevi GP, Grimaldi R. Spinal cord stimulation and 30-minute heart rate variability in refractory angina patients. Pacing Clin Electrophysiol 2009; 32: 37–42. 36 Yakhnitsa V, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates dorsal horn neuronal hyperexcitability in a rat model of mononeuropathy. Pain 1999; 79: 223– 33. 37 Linderoth B, Brodin E. Tachykinin release from rat spinal cord in vitro Neurogastroenterology and Motility 38 39 40 41 42 43 44 45 46 and in vivo in response to various stimuli. Regul Pept 1988; 21: 129–40. Linderoth B, Fedorcsak I, Meyerson BA. Peripheral vasodilatation after spinal cord stimulation: animal studies of putative effector mechanisms. Neurosurgery 1991; 28: 187–95. Linderoth B, Herregodts P, Meyerson BA. Sympathetic mediation of peripheral vasodilation induced by spinal cord stimulation: animal studies of the role of cholinergic and adrenergic receptor subtypes. Neurosurgery 1994; 35: 711–9. Wu M, Linderoth B, Foreman RD. Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies. Auton Neurosci 2008; 138: 9–23. Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth Analg 1998; 86: 837–44. de Jonge WJ, van den Wijngaard RM, The FO, ter Beek ML, Bennink RJ, Tytgat GN, Buijs RM, Reitsma PH et al. Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice. Gastroenterology 2003; 125: 1137–47. Deer TR, Skaribas IM, Haider N, Salmon J, Kim C, Nelson C, Tracy J, Espinet A et al. Effectiveness of cervical spinal cord stimulation for the management of chronic pain. Neuromodulation 2013 Sep 24. doi: 10. 1111/ner.12119. [Epub ahead of print]. PMID: 24112709. Lin WT, Chang CH, Cheng CY, Chen MC, Wen YR, Lin CT, Lin CW. Effects of low amplitude pulsed radiofrequency stimulation with different waveform in rats for neuropathic pain. Conf Proc IEEE Eng Med Biol Soc 2013; 2013: 3590–3. McAuley J, Aydin Y, Green C, van Groningen R. Patients’ experiences with spinal cord stimulation for lumbar spondylotic pain: comfort at the implantable programmable generator site. J Neurol Neurosurg Psychiatry 2013; 84: e2. Sumner L, Lofland K. Spinal cord stimulation: subjective pain intensity and presurgical correlates in chronic pain patients. Chronic Illn 2013 Sep 18. [Epub ahead of print]. PMID: 24048947. 384 47 Song Z, Ansah OB, Meyerson BA, Pertovaara A, Linderoth B. Exploration of supraspinal mechanisms in effects of spinal cord stimulation: role of the locus coeruleus. Neuroscience 2013; 253: 426–34. 48 Kamihara M, Nakano S, Fukunaga T, Ikeda K, Tsunetoh T, Tanada D, Murakawa K. Spinal cord stimulation for treatment of leg pain associated with lumbar spinal stenosis. Neuromodulation 2013. doi: 10.1111/ ner.12092. [Epub ahead of print]. PMID: 23919348. 49 Kumar K, Rizvi S. Cost-Effectiveness of spinal cord stimulation therapy in management of chronic pain. Pain Med 2013; 14: 1631–49. 50 Pluijms WA, van Kleef M, Honig WM, Janssen SP, Joosten EA. The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy. Eur J Pain 2013; 17: 1338–46. 51 Tiede J, Brown L, Gekht G, Vallejo R, Yearwood T, Morgan D. Novel spinal cord stimulation parameters in patients with predominant back pain. Neuromodulation 2013; 16: 370–5. 52 Perruchoud C, Eldabe S, Batterham AM, Madzinga G, Brookes M, Durrer A, Rosato M, Bovet N et al. Analgesic efficacy of high-frequency spinal cord stimulation: a randomized doubleblind placebo-controlled study. Neuromodulation 2013; 16: 363–9; discussion 369. 53 Kapural L, Rakic M. Spinal cord stimulation for chronic visceral pain secondary to chronic non-alcoholic pancreatitis. J Clin Gastroenterol 2008; 42: 750–1. 54 Kim JK, Hong SH, Kim MH, Lee JK. Spinal Cord Stimulation for Intractable Visceral Pain due to Chronic Pancreatitis. J Korean Neurosurg Soc 2009; 46: 165–7. 55 Pescatori M, Meglio M, Cioni B, Colagrande C. Colonic motility in two constipated neurological patients treated by spinal cord stimulation. In: Wienbeck M, ed. Motility of the Digestive Tract. New York, NY: Raven Press, 1982: 541–7. 56 Thakkar N, Connelly NR, Vieira P. Gastrointestinal symptoms secondary to implanted spinal cord stimulators. Anesth Analg 2003; 97: 547–9, table of contents. © 2013 John Wiley & Sons Ltd

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