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Research Report
Effects of spinal cord stimulation with “standard clinical” andhigher frequencies on peripheral blood flow in rats
Jie Gaoa,b,1,2, Mingyuan Wua,c,⁎,1, Linggen Lib, Chao Qina, Jay P. Farbera,Bengt Linderotha,d, Robert D. Foremana,⁎aDepartment of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USAbDepartment of Peripheral Vascular Diseases, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine,Harbin, PR China, 150040cHarold Hamm Oklahoma Diabetes Center & Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center,Oklahoma City, OK 73190, USAdDepartment of Neurosurgery, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
A R T I C L E I N F O
⁎ Corresponding authors. M. Wu is to be contaUniversity of Oklahoma Health Sciences Cen3181. R.D. Foreman, Department of PhysioloOklahoma City, OK 73104, USA. Fax: +1 405 2
Article history:Accepted 24 November 2009Available online 3 December 2009
Background: It is unclear whether spinal cord stimulation (SCS) at higher frequenciesinduces further increases in vasodilation and enhances clinical efficacy. Objectives: Thisstudy investigated effects of SCS at both a normal frequency (as used clinically) and twohigher frequencies on peripheral vasodilation. Methods: A unipolar ball electrode wasplaced on the left dorsal column at the lumbar 2–3 spinal cord segments (L2–L3) in sodiumpentobarbital anesthetized, paralyzed, and artificially ventilated rats. Cutaneous blood flowrecordings from both ipsilateral (left) and contralateral (right) hind foot pads weremeasuredwith laser Doppler flow perfusion monitors. SCS at frequencies of 50, 200, or 500 Hz wasapplied at 30%, 60%, and 90% of motor threshold (MT) using standard square waves.Resiniferatoxin (RTX: an ultrapotent analog of capsaicin) and a calcitonin gene-relatedpeptide (CGRP) receptor blocker (CGRP8–37) was also used to elucidate mechanisms of SCSvasodilation at these higher frequencies. Results: SCS applied with the three frequenciesproduced similar MT (n=22). SCS at 500 Hz significantly increased cutaneous blood flow anddecreased vascular resistance compared to changes induced by frequencies of 50 and 200 Hz(P<0.05, n=8). RTX (2 μg/kg, i.v.) as well as CGRP8–37 (2.37 mg/kg, i.v.) significantly reducedSCS-induced vasodilation at 500 Hz (P<0.05, n=6) as compared to responses prior toadministrations of these drugs. Conclusion: SCS at 500 Hz significantly increased SCS-
cted at Harold Hamm Oklahoma Diabetes Center & Section of Endocrinology and Diabetes,ter, 941 S.L. Young Blvd., Room BSEB 330A, Oklahoma City, OK 73104, USA. Fax: +1 405 271gy, University of Oklahoma Health Sciences Center, 940 S.L. Young Blvd., Room BMSB 653,71 3181.du (M. Wu), [email protected] (R.D. Foreman).d peptide; MT, motor threshold; PVD, peripheral vascular disease; RTX, resiniferatoxin; SCS,
in Harbin Medical University and her postdoctoral mentor is Dr. Baozhong Shen.
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induced vasodilation without influencing MT. Furthermore, effects of SCS at 500 Hz aremediated via activation of TRPV1-containing fibers and a release of CGRP.
Fig. 1 – SCS at three different frequencies produced similarMT. The graph shows MT from SCS 50, 200, and 500 Hz fromleft (n=11) and right sides (n=11) of the spinal cord. Eachdata point represents mean±SEM. There is no statisticaldifference among three groups.
1. Introduction
Cook et al. (1976) reported that spinal cord stimulation (SCS)produced a marked improvement in blood flow to lower limbsin patients with peripheral vascular disease (PVD). Since then,SCS has been consistently reported to show beneficial effectsin the treatment of PVD (Cameron, 2004; Claeys, 1997; Horschand Claeys, 1994). The clinical benefits from SCS include painrelief and increased walking distance resulting from anincreased peripheral circulation and reduced ischemia (Wuet al., 2006). In the past, the clinical use of SCS in the treatmentof PVD spread rapidly worldwide, especially in Europe. Thelargest number of implantations for this indication wasperformed during the eighties and early nineties after whichimplantation frequencies decreased. The obvious reason wasunsatisfactory long-term outcomes due in a large part to aninability to select the proper cases for SCS therapy at that time.However, it is estimated thatmore than 16,000 new cases havebeen treated with SCS each year—but only a minor part ofthem have been for ischemic problems (Linderoth andForeman, 2006; Wu et al., 2008b). After completion of severalprospective, randomized studies (Jivegard et al., 1995; Klompet al., 1999; Ubbink et al., 1999; Ubbink and Vermeulen, 2003)and Cochrane reviews (Ubbink and Vermeulen, 2003) thatexamined the efficacy of SCS treatments for leg ischemia, theuse of SCS for PVD is again increasing, with strict criteria forpatient selection (Linderoth and Meyerson, 2000; Ubbink et al.,2003).
Two putative physiological mechanisms have been pro-posed to explain the SCS benefits. One mechanism is that SCSattenuates sympathetic outflow, reduces vascular resistance,and thus increases peripheral blood flow (Linderoth et al.,1991a,b; Linderoth et al., 1994). The second mechanism is thatSCS activates the ERK and AKT intracellular signaling path-ways and releases GABA in the spinal gray matter (Wu et al.,2008a) that, in turn, antidromically activates dorsal rootafferent fibers. These fibers increase peripheral vasodilationby releasing calcitonin gene-related peptide (CGRP) ontoreceptors on the blood vessel walls. In addition, CGRPactivates nitric oxide-induced endothelium-dependent vaso-dilation (Croom et al., 1997a,b; Tanaka et al., 2001, 2003b, 2004;Wu et al., 2007a). Recent studies also revealed that thecapsaicin-sensitive sensory nerves [transient receptor poten-tial vanilloid receptor (TRPV1) containing fibers] includingunmyelinated C fibers and thin myelinated Aδ fibers areimportant in producing the SCS-induced vasodilation (Tanakaet al., 2003b; Wu et al., 2006, 2007a).
The frequencies of SCS most often used in the clinic havevaried between 40 and 125 Hz, but frequencies around 50 Hzare most commonly used. In previous animal studies, SCSparameters have often been 50 Hz; 0.2 ms via monophasicrectangular pulses at intensities of 60%–90% of motor thresh-old (MT); mimicking clinical SCS therapy, although SCS at300% and 10 times of MT have also been reported (Tanaka etal., 2001, 2003a,b, 2004;Wu et al., 2006, 2007a,b, 2008a,b, 2007c).
However, no basic studies have been performed to determinewhether SCS at higher frequencies would produce morebenefits from SCS.
The purpose of the present study was to investigatewhether SCS at higher frequencies produced more improve-ments in peripheral circulation than the lower frequenciescurrently in use. Three questions were addressed to comparethe effects of SCS at 50 Hzwith higher frequencies: (1) does SCSat higher frequencies (including 200 and 500 Hz) change theMT? (2) does SCS at higher frequencies produce enhancedvasodilation? (3) does SCS at 500 Hz activate TRPV1 sensoryfibers and release CGRP to produce vasodilation? The resultssupported the notion that SCS at higher frequencies showedenhanced effects on peripheral blood flow via antidromicmechanisms, as will be described in detail below.
2. Results
SCS at three frequencies including 50, 200, and 500 Hzproduced similar MT (50 Hz =493±28 μA, 200 Hz=455±34 μA,500 Hz=460±36 μA, n=22) as shown in Fig. 1. Also, MTmeasured from the left (ipsilateral) and right (contralateral)sides of spinal cord did not differ (left side: 50 Hz=498±24 μA,200 Hz=447±29 μA, 500 Hz=455±32 μA, n=11; right side:50 Hz=517±24 μA, 200 Hz=501±35 μA, 500 Hz=479±32 μA,n=11). However, SCS at 500 Hz triggered a higher increase incutaneous blood flow and a greater decrease of vascularresistance compared to the flow and resistance observed at 50and 200 Hz (P<0.05, n=8; Fig. 2). There was no statisticaldifference between blood flow changes at 50 and 200 Hz.
Furthermore, we investigated the potential mechanisms ofhowSCS at 500Hz induces vasodilation. In a group of 6 rats, weexamined the effects of resiniferatoxin (RTX) i.v. on SCS-induced vasodilation as described above. Typical recordings of
Fig. 2 – SCS-induced vasodilation at three different frequencies. (A) Typical recordings of cutaneous blood flows and arterialblood pressure in response to 2 minutes of SCS at 50, 200, and 500 Hz. (B) Percent changes in blood flow to the ipsilateral andcontralateral hindpaws in response to 2 minutes of SCS at 50, 200, and 500 Hz. (C) Percent changes in vascular resistance in theipsilateral and contralateral hindpaws in response to 2minutes of SCS at the frequencies of 50, 200, and 500 Hz. Each data pointrepresents the mean±SEM (n=8). *P<0.05.
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cutaneous blood flow in the ipsilateral and contralateralhindpaw and in arterial blood pressure in response to2 minutes of SCS at 500 Hz before RTX administration areshown in Fig. 3A. The administration of RTX (2 μg/kg, i.v.)
initially increased arterial blood pressure and cutaneous bloodflow. The changes of blood pressure and blood flow returnedto baseline within 3 minutes as described in our previousstudy (Wu et al., 2006). The mean blood pressures before and
Fig. 3 – RTX attenuation of vasodilation induced by SCS at 500 Hz. (A) Typical recordings of cutaneous blood flow in thehindpaws and in arterial blood pressure with 2 minutes of SCS before and after RTX intravenous injection. (B) Percent changesin blood flow to the ipsilateral and contralateral hindpaws in response to 2 minutes of SCS at 500 Hz before and after RTXintravenous injection. (C) Percent changes in vascular resistance in the ipsilateral and contralateral hindpaws in response to2 minutes of SCS at 500 Hz before and after RTX intravenous injection. Each data point represents the mean±SEM (n=6).*P<0.05.
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after RTX were 101±6.06 vs. 100±11.7 mm Hg (mean±SEM).However, 20 minutes after the RTX injection, SCS-inducedipsilateral vasodilationwas attenuated bymore than 80% at all
tested intensities including 30%, 60%, and 90% of MT (Fig. 3A).Effects of SCS at 500 Hz on peripheral blood flow and vascularresistance before and after RTX are illustrated Figs. 3B and C to
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demonstrate that SCS failed to trigger peripheral vasodilationafter RTX administration, indicating an important role ofTRPV1 in SCS-induced vasodilation. In another group of 6 rats,we examined whether CGRP8–37 affected the SCS-induced
Fig. 4 – CGRP8–37 attenuation of vasodilation induced by SCS at 5hindpaws and in arterial blood pressure with 2 minutes of SCSchanges in blood flow to the ipsilateral and contralateral hindpawCGRP8–37 intravenous injection. (C) Percent changes in vascular rresponse to 2 minutes of SCS at 500 Hz before and after CGRP8–37
mean±SEM (n=6). *P<0.05.
vasodilation. Typical recordings of cutaneous blood flow in theipsilateral and contralateral hindpaw and arterial bloodpressure in response to 2 minutes of SCS at 500 Hz beforeCGRP8–37 administration are presented in Fig. 4A. CGRP8–37
00 Hz. (A) Typical recordings of cutaneous blood flow in thebefore and after CGRP8–37 intravenous injection. (B) Percents in response to 2 minutes of SCS at 500 Hz before and after
esistance in the ipsilateral and contralateral hindpaws inintravenous injection. Each data point represents the
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(2.37mg/kg) was slowly injected intravenously and produced atransient decrease in blood pressure. Twenty minutes later,SCS at the three intensities was repeated again. The meanblood pressures before and after CGRP8–37 were 101±9.2 vs. 97± 10.4 mm Hg (mean±SEM). Vasodilation produced by SCS at500 Hz was attenuated more than 80% after CGRP8–37 at alltested intensities (Fig. 4A). Figs. 4B and C summarize theeffects of SCS at 500 Hz on peripheral blood flow and vascularresistance changes before and after CGRP8–37. The datashowed that administration of CGRP8–37 blocked vasodilation(increased peripheral blood flow and decreased vascularresistance) induced by SCS. These data are consistent to ourprevious reports that the release of CGRP is critical in SCS'seffects on peripheral circulation. We have reported in severalprevious papers that the vehicle for RTX and CGRP8–37 per sedid not alter SCS-induced vasodilation (Wu et al., 2006, 2007a;Yang et al., 2008).
3. Discussion
In the past 20 years, the clinical use of SCS has spreadworldwide. Accumulating reports have shown that SCSproduced very positive effects on vascular ischemia andpain-related diseases (Linderoth and Foreman, 2006; Wu etal., 2008b). In parallel, relevant basic studies have beenperformed to elucidate the potential mechanisms for relievingpain and increasing peripheral circulation. Previous experi-mental data have focused on SCS using clinical parameters(e.g., 50 Hz, 0.2ms,monophasic rectangular pulses). Twomainmechanisms have been proposed to explain how SCS mayproduce peripheral vasodilation, an essential feature forrelieving ischemic pain. One mechanism is that SCS increasescutaneous blood flow froma reduction of efferent sympatheticactivity (Linderoth et al., 1991a,b, 1994). In detail, these studieshave shown that SCS-induced cutaneous vasodilation in therat hindpaw at 66% of MT is abolished by both completesurgical sympathectomy and administration of nicotinicganglionic blockers, such as hexamethonium and chlorison-damine. There are some conflicting data because somepatients demonstrated vasodilation with SCS even afterchemical or surgical sympathectomy (Broseta et al., 1986;Jacobs et al., 1988; Meglio et al., 1986), but even in animalexperiments, it was extremely difficult to obtain a completelumbar sympathectomy; and furthermore, partially sympa-thectomized rats still produced a partial SCS response inaccordance with a sympathetic pretest (Linderoth et al.,1991a,b). Another proposed mechanism is that SCS mayantidromically activate small sensory neurons and triggerthe release of vasoactive substances that results in increasedperipheral blood flow. Recent work from our laboratorysuggested that SCS activated TRPV1-containing sensoryneurons to release vasodilators in nerve endings near pe-ripheral vessels (Wu et al., 2006, 2007a,c, 2008a,b). SCS alsoindirectly induces the release of nitric oxide from endothelialcells during SCS-induced vasodilation (Wu et al., 2007a).Importantly, it should be emphasized that sympathetic andantidromic mechanisms are not in conflict but work togetherto result in vasodilation. The antidromic mechanism seemsmore important in the early phase and sympathetic inhibition
appears to sustain the vasodilatation (Linderoth and Foreman,2006; Wu et al., 2008b). The balance between the twomechanisms is due to different conditions in individualpatients (clinic) or different animal experimental setups andstrains (basic research) (Linderoth and Foreman, 2006).
Recently, small clinical trials have indicated that SCSapplied at higher frequencies could improve its clinicalefficacy (personal communication: Dr. Bengt Linderoth).However, there are no controlled studies to support the ideathat frequencies beyond 120–150 Hz would be more effectivefor induction of vasodilatation. On the contrary, use of neuralstimulation applied onto cell bodies at >130 Hz would likely beinhibitory; neural stimulation applied to axons (e.g., the dorsalcolumns) would also be mainly inhibitory but with thepossibility of inducing a low irregular firing of cells (Windelset al., 2003).
All the companies on the market producing SCS stimula-tion equipment supply pulse generators that produce fre-quencies up to 1200 Hz (Boston Scientific; Metronics; ST. JudeMedical, personal communication); this enables clinical trialswith the higher frequencies used in the present studies in therat.
In the current study, we showed that although the MTs forSCS at 50, 200, and 500 Hzwere similar, SCS at 500 Hz produceda significantly higher blood flow elevation and lower vascularresistance compared to the effects of SCS at 50 and 200 Hz.Thus, SCSs at higher frequencies are likely to enhance SCSbenefits in vasodilation without affecting MT. This observa-tion is controversial because a previous study has shown thatSCS at the high cervical cord with frequencies of 200 and2000 Hz did not increase cerebral blood flow in cats (Isono etal., 1995). This may be due to the different spinal segmentswhere SCS was applied and/or to the different animal models.
Extreme frequencies have rarely been used for SCS in thepast with the exception of Waltz in the late 1970s using 1000–1200 Hz applied cervically to reduce torticollis spasmodicus(Waltz, 1997).
In the current study, we also determined the potentialpathways of SCS at 500 Hz-induced vasodilation, particularlyantidromic mechanisms since it was a predominant cause ofvasodilation in our previous studies of SCS at 50 Hz (Wu et al.,2006, 2007a,c, 2008a,b; Yang et al., 2008). We observed ablocking effect of RTX and CGRP8–37 on the vasodilationtriggered by SCS at 500 Hz, indicating that the effects of SCSat 500 Hz aremainly due to the activation of TRPV1-containingsensory fibers and the release of CGRP. This observation is inaccordance with what we found in the studies of SCS at 50 Hz.However, we were not able to fully elucidate the mechanismsby which a higher stimulation of SCS improves peripheralblood flow. The possibilities includemore recruited fibers and/or release of more vasodilators including CGRP and nitricoxide. These factors will be investigated further in futurestudies.
Only a few of studies have been reported to evaluate thebenefits of higher frequencies of SCS and transcutaneouselectrical nerve stimulation (TENS) on pain relief. The resultsare still controversial. SCS at 4 and 60 Hz wasmore effective inreducing hyperalgesia than higher frequencies of SCS (100 Hzand 250 Hz) in the study of Maeda et al. (2008). Other studiesreported that TENS (Sluka et al., 1998; Somers and Clemente,
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2006; Vance et al., 2007) at 100 Hz showed more benefits forreducing hyperalgesia compared to TENS at lower frequenciesin models of inflammation and nerve injury. Using C-fosstaining, a recent study also indicated that low frequencies (4and 60 Hz) of SCS at lumbar segments activated supraspinaland spinal mechanisms, while a higher frequency (100 Hz) ofSCS activated spinal mechanisms (Maeda et al., 2009). Inanother study, spinal cord stimulation at 300 Hz restoredlocomotion in animal models of Parkinson's disease (Fuenteset al., 2009).
Future studies are necessary to address whether the SCSmechanisms discovered in normal animals (Barron et al., 1999;Croom et al., 1996, 1997a,b; Tanaka et al., 2001, 2003a,b, 2004;Wu et al., 2006, 2007a,c, 2008a) including that in the currentstudy are similar to those in animals with peripheral arterialdiseases (PAD). With advanced surgical techniques, moreanimal models related to PAD (Brown et al., 2005) andvasospasm are emerging (Gherardini et al., 1999; Linderothet al., 1995), which could be used to determine the SCSmechanisms in pathological conditions. Also, to confirm thefindings in this and in our previous studies regardingantidromical mechanisms in SCS-induced vasodilation, it isof importance to determine alteration (synthesis and distri-bution) of CGRP and TRPV1 in dorsal root ganglion (L3–L5),sensory fibers, and their nerve endings before and after SCStreatment.
In conclusion, to the best of our knowledge, this is the firststudy of SCS's effects at higher frequencies on peripheralblood flow. The information from this study provides a basis toconsider using SCS at higher frequencies in clinical trials forpatients suffering from ischemic symptoms of differentetiologies.
4. Experimental procedures
The protocol of this study was approved by the University ofOklahoma Health Sciences Center Institutional Animal Careand Use Committee.
4.1. Experimental setup
Experimental details for the setup in this study have beendescribed previously (Barron et al., 1999; Croom et al., 1996,1997a,b; Tanaka et al., 2001, 2003a,b, 2004; Wu et al., 2006,2007a,c, 2008a,b). Briefly, male Sprague-Dawley rats (350–480 g; Charles Rivers, MA) were anesthetized with sodiumpentobarbital (60 mg/kg, i.p.). A cannula (PE-50) was insertedinto the left common jugular vein to administer a constantinfusion of supplemental pentobarbital (15–25 mg/kg/h) andpancuronium (0.2 mg/kg/h) for muscle paralysis. A secondcannula (PE-50) was inserted into the left common carotidartery to monitor arterial blood pressure. The rats weretracheotomized and artificially ventilated with room air(CWE ventilator model SAR-830). Body temperature wasmaintained between 36 and 38 °C with an automatic heatingpad. A laminectomy was performed to expose the dorsalsurface of lumbar spinal segments 2–3. A spring-loadedunipolar ball electrode was usually placed on the left or rightside of the subdural surface at L2–L3. SCS at L2–L3 achieves the
optimal effect on vasodilation in rat hindlimb and foot (Croomet al., 1997b). SCS at L2–L3 triggers the neurons in L3–L5 andactivates signals to TRPV1 peripheral endings via dorsal rootganglia in L3–L5 (Tanaka et al., 2003b; Wu et al., 2007a).Cutaneous blood flow in the hindlimb footpads of the ratswas measured with laser Doppler flow perfusion monitors(wavelength, 780 nm; probe 407, PeriFlux 5001; Perimed AB,Inc., Stockholm, Sweden). Responses to SCS were determinedas percent change from the baseline blood flow. Controlresponse levels of cutaneous blood flow and arterial bloodpressure (ABP) were obtained for 2 minutes of SCS at differentintensities.
The MT stimulus intensity was determined in each animalat 50, 200, or 500 Hz (0.2 ms pulse duration), respectively, byslowly increasing the SCS current from zero until a clearretraction of the left hindlimbwas observed. Experimental SCSwas performed for 2 minutes at 30%, 60%, or 90% of MT inrandom orders of stimulus intensities with at least 5-minuteintervals in between.
In one group of animals, resiniferatoxin (RTX) (1 ml salinecontaining 2 μg RTX, 1 μl of 95% ethanol, and 1 μl of Tween 80;2 μg/kg) was injected intravenously to determine the effects ofRTX, an ultrapotent analog of capsaicin and the TRPV1receptor agonist, on the SCS responses. In previous studies,we have shown that RTX deactivates TRPV1 receptors inapproximately 20 minutes (Wu et al., 2006, 2007b). In anothergroup, CGRP8–37, a CGRP-1 receptor blocker (2.37 mg/kg), wasinjected intravenously to investigate the roles of CGRP on SCSresponses. The effects of SCS on blood flow before and afteradministrations of RTX or CGRP8–37 were measured and com-pared. The dose chosen for the RTX and CGRP8–37 experimentswas chosen based on our previous studies for SCS at 50 Hz(Croom et al., 1997a; Tanaka et al., 2001;Wu et al., 2006, 2007a).
CGRP8–37 was provided by the Molecular Biology ResourceFacility (University of Oklahoma Health Sciences Center,Oklahoma City, OK, USA) and RTX and other complementarychemical agents were purchased from Sigma Chemical Co. (St.Louis, MO, USA).
4.2. Statistical analysis
The analysis has been described in our previous studies (Wu etal., 2006, 2007a,c, 2008a,b). In brief, the unit of blood flowmeasurement is presented as volts (V). The changes inperipheral blood flow were described as the percentage ofchanges of the peak amplitude from baseline and reported asmean±SEM.Mean blood pressure was calculated as follows: 2/3×diastolic blood pressure (BP)+1/3×systolic BP. Vascularresistance was calculated as follows: peak mean bloodpressure/peak blood flow. Differences in blood flow andvascular resistance before and after RTX, or CGRP8–37 admin-istration were examined with a one-way ANOVA followed byTukey's test. The significant level was set at P<0.05.
Acknowledgments
We thank D. Holston (University of Oklahoma HealthSciences Center) for her expert technical assistance. Thisresearch was supported by NIH grant HL075524 and NS35471
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(R.D.F.), 2005 University of Oklahoma Health Sciences CenterGraduate Student Association Research Grant (M.W.) andAmerican Heart Association (AHA) Predoctoral Fellowship0615642Z (M.W.).
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