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Research Reports |
DL Somers, PT, PhD, is Associate Professor, Department of Physical Therapy, Duquesne University, 113 Health Sciences Bldg, Pittsburgh, PA 15282-0011 (USA)
FR Clemente, PT, PhD, is Associate Professor and Chair, Department of Physical Therapy, Duquesne University
(somers{at}duq.edu). Address all correspondence to Dr Somers
Submitted June 9, 2005;
Accepted December 5, 2005
 | Abstract |
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Key Words: Causalgia • Electroacupuncture • Transcutaneous electrical nerve stimulation
| Introduction |
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 TopAbstract Introduction MethodResultsDiscussionConclusionReferences |
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The pain of CPSII is managed by pharmacological or nonpharmacological interventions. Pharmacotherapy includes the use of antidepressants, antiepileptics, and opioids. Although these treatments are somewhat effective, they are associated with side effects. Administration of antidepressants to people with neuropathic pain improved their symptoms 50% of the time.3 However, when people with chronic pain of multiple origins were treated with antidepressant medication, dizziness, sedation, gastrointestinal dysfunction, or dry mouth occurred in about one third of those subjects.3 Administration of the antiepileptic drug, gabapentin, to people with postherpetic neuralgia—a painful condition similar to CPSII—reduced their perception of pain by 33%.4 Although the magnitude of side effects was relatively low, 27% of the subjects who took gabapentin experienced somnolence, 24% had dizziness, and 7% had ataxia. Opioid therapy can likewise reduce the pain of CPSII by as much as 33%,5 but this form of pharmacotherapy is associated with constipation, sedation, and physical dependence.6–8
Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that is used to reduce the pain of CPSII. The modality is delivered to peripheral sensory nerves through surface electrodes and is believed to produce analgesia by both peripheral and central nervous system mechanisms.9–11 Like pharmacological interventions, TENS is somewhat effective at reducing the pain of CPSII. Application of TENS to humans with neuropathic pain substantially reduced the pain in 53% to 81% of those treated.12–14 When TENS is used to manage the pain of CPSII in animal models of the syndrome, it also is somewhat effective. Trancutaneous electrical nerve stimulation delivered to rats with CPSII reduced thermal allodynia,15,16 mechanical allodynia,17 and mechanical and heat hyperalgesia.18 In a fashion reminiscent of humans with CPSII, TENS did not in all cases reduce the symptoms of neuropathy in these rats. Accordingly, some rats with CPSII treated daily with TENS experienced substantial relief of thermal allodynia, whereas other TENS-treated rats did not experience such relief.15,19
Although TENS and pharmacological intervention are both variably effective when used to manage the pain of CPSII, TENS produces none of the side effects associated with drug therapy. There is a risk of skin irritation or an allergic reaction from application of electrodes to the skin, but these problems are relatively rare and are easily managed by shifting the electrode position.12 Therefore, TENS represents a viable, nonpharmacological intervention for the management of CPSII.
There is no consensus on how TENS should be applied to best relieve neuropathic pain. Transcutaneous electrical nerve stimulation may be applied at high frequency (80–110 Hz) or low frequency (2–10 Hz),20,21 but it is unknown which of these frequencies will best prevent or alleviate the pain of CPSII. Electrodes to deliver TENS may be positioned on skin located ipsilateral or contralateral to a nerve injury,22 but it also is unknown which of these locations would best prevent or reduce neuropathic pain. Although the effects of frequency and electrode positioning on CPSII-like pain has not been examined, there are reasons to suspect that these parameters may influence treatment effectiveness.
High-frequency (80–110 Hz) and low-frequency (2–10 Hz) TENS20,21 differ in their ability to relieve pain and in the central nervous system alterations they produce. Thirty minutes of high-frequency TENS applied to the upper extremity in humans who were healthy produced an increase in the mechanical pain threshold when assessed in the ipsilateral hand.23 Low-frequency TENS applied to the same location, however, failed to increase mechanical pain threshold in the hand.20 Differences in effectiveness between high- and low-frequency TENS also are present when these 2 options for stimulation are compared in animal models of pain. Inflammation produced by injection of 3% carrageenan into the rat hind paw induces thermal and mechanical allodynia in the injected paw. When high-frequency TENS is applied directly to the inflamed hind paw, thermal and mechanical allodynia are reduced, but neither symptom is relieved when low-frequency TENS is applied to the identical sites.24
The central nervous system alterations believed to underlie high- and low-frequency TENS-induced pain relief are also distinct. Although both frequencies of stimulation are effective at reducing secondary allodynia (an allodynia that develops in a region or body segment other than the area of original injury) in the hind paws of rats following experimentally induced knee inflammation, the neurotransmitters involved in producing this reduction are somewhat different for the 2 frequencies. High-frequency TENS relieves secondary allodynia via muscarinic25 and µ opioid26 receptor-dependent mechanisms, and low-frequency TENS relieves secondary allodynia via serotonin,27 muscarinic,25 and 
opioid26 receptor-dependent mechanisms. In addition, recent evidence indicates that high- and low-frequency TENS may produce distinct cortical activation patterns when producing analgesia.28
Because high- and low-frequency TENS differ in their mechanism of action and in their ability to relieve pain, it is conceivable that perhaps one frequency of TENS will relieve the painful symptoms of CPSII better than the other frequency of stimulation. It is also conceivable, that high- and low-frequency TENS may differentially alter individual painful symptoms associated with the syndrome. Therefore, one purpose for the present study was to directly compare the ability of high- and low-frequency TENS to prevent the development of the painful symptoms of CPSII.
The effectiveness of TENS when delivered ipsilateral or contralateral to a CPSII-inducing nerve injury has not been directly compared. However, in TENS-treated rats with CPSII, we recently discovered a relationship between spinal cord neurotransmitter content and mechanical allodynia,29 suggesting that the location of stimulation is an important treatment parameter. In that study, high-frequency TENS was applied to the right side of rats with a right-sided chronic constriction injury (CCI) to the sciatic nerve, and the content of pain-related neurotransmitters30,31 was evaluated bilaterally in the dorsal horns of the spinal cord. Following daily TENS treatment, mechanical allodynia in the right hind paw was reduced in some rats but not in others, and a strong relationship developed between the magnitude of allodynia present and the neurotransmitter content in the spinal cord. As the dorsal horn content of glutamate and glycine increased within the right side of the spinal cord and decreased within the left side, mechanical allodynia decreased. A similar relationship was not present in untreated CPSII rats. These results indicate that both sides of the spinal cord are important to TENS-induced pain relief, even when CPSII is present unilaterally. Moreover, because the TENS-induced relationship between mechanical allodynia and spinal cord neurotransmitter content is strikingly different between the 2 sides of the spinal cord, we suspect that contralateral and ipsilateral TENS treatment could differ substantially from each other in the pain relief they produce. Therefore, a second purpose for the present study was to directly compare the ability of TENS to prevent or reduce the painful symptoms of CPSII when it is delivered ipsilateral or contralateral to a nerve injury.
| Method |
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TopAbstractIntroductionMethodResultsDiscussionConclusionReferences |
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One hundred fifty-seven male Sprague-Dawley rats (170–200 g) were used for the experiments. The rats were housed in a controlled environment on a 12-hour light-dark cycle with unlimited access to food and water. All experiments were carefully conducted according to the ethical guidelines for the use of experimental pain in conscious animals put forth by the International Association for the Study of Pain.32
Procedure
To produce CPSII, the rats were deeply anesthetized with sodium pentobarbital (50 mg/kg) via intraperitoneal injection. Four chromic gut sutures were applied to the right sciatic nerve according to the CCI procedure of Bennett and Xie.33 The CCI model of CPSII was chosen because this procedure is well documented and produces symptoms that are quite similar to those seen in people with CPSII.33,34 At the conclusion of an experiment, the sciatic nerve was re-exposed and the integrity of the sutures was confirmed.
Mechanical pain threshold was assessed with calibrated Semmes-Weinstein monofilaments.35,36 The filaments (0.41, 1.2, 3.63, 8.51, and 15.13 g) were used to give graded pressure to the plantar surface of the hind paws. Care was taken to keep the stimulations in the mid-region of the foot between the toes and the heel because this area is innervated exclusively by the sciatic nerve.37 Rats were placed on a metal grid and covered with a plexiglass cover. The lowest-caliber filament (0.41 g) was pushed onto the plantar surface of the right hind paw until the filament bent. This procedure was repeated 5 times with 2 to 3 seconds between pushes. Five minutes later, the left paw of the same rat was similarly assessed. Not less than 5 minutes after the left paw was assessed, the entire procedure was repeated. In this way, the right and left paws were pushed by the 0.41-g filament 10 times, and the number of withdraws was recorded. In ascending order, each filament was so tested until the rat withdrew from all 10 pushes of a single-size filament or the largest-caliber filament was tested.
To estimate the force from which the rat withdrew 50% of the time, force (in grams) was regressed on withdraw frequency for all 5 filaments using linear regression. The force at which the rat withdrew a paw on 5 of 10 pushes (50% withdraw threshold [WT]) was predicted using the regression equation. If the 50% WT so calculated was greater than 15.13 g, the highest-caliber hair used (15.13 g) was recorded as the gram force. If the rat failed to respond to any of the filaments, 15.13 g was recorded as the 50% WT. We have found that the intratester reliability of data obtained with this method is quite good (intraclass correlation coefficient [ICC]=.98).15 The same investigator always performed this test.
Thermal pain threshold was assessed by withdraw latency (WL) from a radiant heat source as originally described by Hargreaves et al.38 Radiant heat was applied to the right and left paws 5 times each with 5 minutes separating irradiations. The latency to withdraw (in hundredths of a second) was recorded for each irradiation. Twenty seconds was the maximum irradiation time. The 5 latency measurements obtained for each paw were averaged to obtain a mean latency for the right and left paws. We have found that the intratester reliability of data obtained with this method is quite good (ICC=.83).15 The same investigator always performs this test.
The TENS was applied to rats through self-adhesive surface electrodes (Empi SoftTouch 9000*) using an Empi Epix XL transcutaneous electrical nerve stimulator.* This device uses a symmetrical, biphasic waveform. Pulse duration (0–400 µs) and amplitude (0–40 mA) are interlocked and set by a single intensity control. The frequency of stimulation was either 100 Hz or 2 Hz. For 100-Hz stimulation, surface electrode placement was on the denuded, presumably uninvolved, skin overlying either the right (ipsilateral to nerve injury in CCI rats) or left (contralateral to nerve injury in CCI rats) paraspinal musculature. Electrodes were cut to 45 mm (length) by 5 mm (width) and positioned as shown in Figure 1. The stimulated skin is innervated by the dorsal rami of lumbar spinal cord segments L1 through L6.39 This placement spans the dermatomes of spinal cord segments that also innervate the painful right paw in CCI rats.37,39 Stimulation was delivered to nonpainful skin because this strategy is frequently used clinically to manage neuropathic pain,13,14 represents an electrode position that can be used by those who cannot tolerate TENS directly over the painful skin,40 and was previously successful when used to manage lower-extremity neuropathic pain in humans and rats.13,15,40 The intensity of stimulation was 80% of that needed to produce a visible muscle contraction.
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The TENS was delivered daily and commenced on the day of surgery while the rats were still under the influence of sodium pentobarbital for both 100-Hz and 2-Hz stimulation. On subsequent days, TENS was administered to rats while they were lightly anesthetized with halothane (4%, maintained at 0.2%–0.5%).
Design
Five groups of rats received a CCI to the right sciatic nerve. The first group of CCI rats (n=23) received high-frequency TENS through stimulating electrodes positioned on skin overlying the right paraspinal musculature (ipsilateral to nerve injury). The second group of CCI rats (n=15) received high-frequency TENS through stimulating electrodes positioned over the left paraspinal musculature (contralateral to nerve injury). The third group of CCI rats (n=23) received low-frequency TENS through stimulating electrodes positioned over acupuncture points in the right hind limb, and the fourth group of CCI rats (n=12) received low-frequency TENS through the same acupuncture points in the left hind limb. The TENS was delivered to these 4 groups for 90 minutes commencing immediately after the CCI surgery and then daily for 60 minutes for the next 11 days. The fifth group of CCI rats (n=28) was treated exactly like the rats that received TENS, including halothane administration, except that no TENS was administered.
Three groups of rats did not receive a CCI and were used as controls. To determine whether mechanical or thermal pain threshold changed over time, a group of rats (naive; n=20) was included that was treated exactly like rats that received high-frequency TENS, including paraspinal skin preparation and halothane administration, except that no TENS was delivered. Paraspinal skin preparation, rather than acupuncture point skin preparation, was the control condition because this group was completed first. We also examined several additional control rats that had received only halothane anesthesia and skin preparation to acupuncture points and could see no perceptible difference between paraspinal and acupuncture point skin preparation. We aborted the acupuncture point control condition in order to minimize the use of rats.
To determine whether TENS administration altered mechanical or thermal pain threshold, a second group of control rats (n=24) received high-frequency TENS to the right paraspinal musculature using a schedule analogous to that used with rats that received a CCI. To minimize the use of rats, data from this second group were used for 2 purposes. Mechanical and thermal pain thresholds assessed in the right hind paw were used to determine the effects of high-frequency TENS when delivered ipsilateral to the assessed extremity. Mechanical and thermal pain thresholds assessed in the left hind paw were used to determine the effects of high-frequency TENS when delivered contralateral to the assessed extremity. A similar strategy was used with the third group of control rats (n=12) to determine whether low-frequency TENS administration altered mechanical or thermal pain threshold.
All rats were assessed once for mechanical and thermal pain thresholds 3 days after their arrival. A second baseline measurement was taken 1 day after the first, and the 2 measurements were averaged to give a single baseline pain threshold for each assessment. All rats were subsequently assessed 12 days after surgery or on the analogous day if no CCI surgery occurred. We have previously found that thermal and mechanical allodynia reach a maximum intensity by 12 days after a CCI.15 The postsurgery assessment was performed at least 12 hours after the final TENS treatment or halothane anesthesia. The final TENS treatment occurred 11 days after the surgery. Following the last assessment on day 12, the sciatic nerve of all CCI rats was re-examined to determine the integrity of the lesion. If 1 or more of the 4 ligatures was untied, the rat was eliminated from consideration. Three rats were dropped from the study for this reason, and are not included in the numbers above.
Data Analysis
Percentages of change from baseline for mechanical and thermal pain thresholds were calculated for the right hind paw of each rat using the following formulas:
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| Results |
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TopAbstractIntroductionMethodResultsDiscussionConclusionReferences |
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Daily high- or low-frequency TENS delivered to rats without a CCI did not alter mechanical pain threshold from that observed in naive control rats at 12 days (Fig. 3A). This finding was true regardless of whether measurements were taken ipsilateral or contralateral to the side of TENS treatment. Daily high-frequency TENS delivered to rats without a CCI likewise did not alter thermal pain threshold from that observed in naive control rats (Fig. 3B). However, low-frequency TENS delivered to rats without a CCI significantly increased the thermal pain threshold from that observed in naive control rats (Fig. 3B).
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| Discussion |
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TopAbstractIntroductionMethodResultsDiscussionConclusionReferences |
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The mechanism of nerve injury, occurrence of symptoms, and mechanism of pain development are similar between CCI rats and humans with CPSII. The nerve injury that precipitates neuropathic pain in CCI rats is incomplete, affecting some but not all of the axons passing through the constriction.47 A recent meta-analysis of the literature revealed that a partial nerve injury also preceded the onset of CPSII in 92% of the subjects in the literature reviewed.48 The symptoms that develop following a partial nerve injury in both humans with CPSII and CCI rats also are quite similar. The presence of allodynia, hyperalgesia, and ongoing pain are experienced by the majority of people with CPSII and by CCI rats.48–50 In addition, skin temperature within the affected extremity often is altered in both humans with chronic regional pain syndrome (types I and II) and CCI rats, and in both cases whether the skin is warmer or colder than normal is variable.49,50 Not only are the symptoms and mechanism of nerve injury similar between CCI rats and humans with CPSII, the mechanism of pain development also appears to be similar. Rats with a CCI experience an increase in the dorsal horn content of the excitatory neurotransmitters glutamate and aspartate.19,51 This elevation is believed to play a role in pain development, and administration of broad glutamate/aspartate receptor antagonists block the development of painful symptoms in these rats.30 Likewise, administration of glutamate/aspartate receptor antagonists to people with CPSII reduces the painful symptoms of the syndrome.52
People with CPSII and CCI rats also are similar in how they respond to interventions intended to reduce pain. The same pharmacological agents that are used to reduce the pain of CPSII in humans are effective when used to treat CCI rats.53 Moreover, the response of people with CPSII and CCI rats to TENS intervention is similar. Both humans with CPSII and CCI rats have varied responses to TENS intervention, with the modality being effective in some cases, but not in others.12–15 In addition, for both people with CPSII and CCI rats, the timing of TENS intervention appears to be important. Intervention with high-frequency peripheral nerve stimulation in the first 2 months after a nerve injury in humans, rather than later, may augment the effectiveness of the treatment.54,55 In a similar fashion, TENS delivered to CCI rats reduced thermal allodynia when the treatment commenced immediately after the nerve injury, but not when started 3 days after the nerve injury.15
Because of these broad similarities between humans with CPSII and CCI rats, it is likely that the TENS-induced prevention of allodynia reported here also may occur in humans with CPSII. Even if this is so, CCI rats in the present study were treated immediately following the nerve injury. It cannot be expected that TENS intervention on the day of nerve injury is a reasonable option for people, because only a small percentage of people with a nerve injury will ultimately develop CPSII56 and prophylactic treatment of them all is untenable. It might be argued, then, that the results reported here are irrelevant to people who will develop CPSII. However, although CCI rats and humans with CPSII are strikingly similar, one difference between them is that humans develop symptoms after a nerve injury often more slowly than do CCI rats. The onset of measurable symptoms in CCI rats occurs between day 157 and day 7.15,49 Seventy percent to 90% of humans with CPSII experience the onset of pain within 1 to 4 weeks after the nerve injury.48 Consequently, there is a window with humans where symptom development can be monitored and early intervention can occur. For this reason, and because of the similarities between CCI rats and humans with CPSII, we believe the results presented here are indeed relevant to the care of humans following a nerve injury.
TENS Intervention Reduces Allodynia Only When Delivered Contralateral to a Nerve Injury
Regardless of the frequency used, daily TENS intervention reduced allodynia when applied contralateral, but not ipsilateral, to a nerve injury. This characteristic of TENS effectiveness appears to be specific to nerve-injured rats because unilateral low-frequency TENS increased thermal pain threshold bilaterally in rats that did not have a CCI. Why only contralateral delivery of TENS was effective at reducing allodynia in CCI rats is not known. However, peripheral nerves located contralateral to a nerve injury play a unique role in pain modulation within the dorsal horn on the side of nerve injury. On the nerve-injured side of CCI rats, wide dynamic range neurons in the dorsal horn are responsive to stimulation of the contralateral hind paw.58 When this stimulation is noxious, spontaneous activity of wide dynamic range neurons within the dorsal horn on the nerve-injured side is reduced.59 Because activity within wide dynamic range neurons is associated with the perception of pain,60,61 this reduction in activity is likely accompanied by a reduced perception of pain. It is not just painful stimulation to the contralateral hind paw that is capable of this modulatory effect on dorsal horn neurons of the nerve-injured side. A subcutaneous injection of lidocaine into the nonpainful hind paw of CCI rats suppressed spontaneous and pain-induced hyperactivity in wide dynamic range neurons of the nerve-injured side.62 This is true even though there is no evidence suggesting that contralateral peripheral nerves are hyperactive in animals or humans with unilateral CPSII.
Although the present research did not investigate activity of wide dynamic range neurons, it is possible that daily TENS delivered contralateral to a nerve injury is better able to reduce allodynia because this mode of delivery suppresses pain-mediating neurons on the side of nerve injury. Confirmation of this notion awaits further research, but the present data adds to an emerging body of evidence suggesting that contralateral treatment for unilateral neuropathic pain is a reasonable, effective treatment option.
There is a clinical perception that bilateral stimulation may be helpful in managing unilateral painful conditions.22 At least when bilateral stimulation is used to manage the pain of neuropathy, this perception appears to have merit. In one published report where this approach was used to treat a woman with unilateral painful, diabetic neuropathy, daily TENS was applied bilaterally in the lumbar paravertebral region.40 The treatment virtually eliminated the neuropathic pain experienced by the woman in the left lower extremity. The present results suggest that when bilateral TENS is used to manage neuropathic pain, at least in part, it is producing its beneficial effect through stimulation of peripheral nerves located contralateral to the nerve injury. Although TENS delivered on the side of nerve injury in CCI rats did not alter allodynia, it is unknown whether this side also contributes to pain relief when stimulation is delivered bilaterally. At a minimum, however, we believe the present results suggest that people with neuropathic pain should be treated with stimulation that in some way includes the side located contralateral to the nerve injury.
The Type of Allodynia Reduced by TENS Is Dependent on the Frequency of the Stimulation
When daily TENS was administered contralateral to a nerve injury, it reduced the development of thermal allodynia, but only when delivered at low frequency. The development of mechanical allodynia, however, was reduced only when daily TENS was delivered at high frequency. It appears, then, that the frequency of stimulation may determine which form of allodynia is most reduced. One caveat to this conclusion is that high-frequency TENS was delivered to skin overlying the paraspinal musculature, whereas low-frequency TENS was delivered to acupuncture points. Thus, it is possible that frequency was not the sole factor that determined whether mechanical or thermal allodynia was reduced. Nevertheless, there is evidence indicating that frequency of stimulation is a factor that may determine TENS effectiveness. For example, when high- and low-frequency TENS are delivered to the same acupuncture point in the lower extremity of humans who are healthy, only low-frequency TENS can produce analgesia in the ipsilateral hand.20,23 Moreover, the nervous system response to high- and low-frequency TENS delivered through the same electrode positions is somewhat unique. When humans who are healthy receive high- or low-frequency TENS through electrodes identically positioned on the hand or leg, high-frequency TENS increases the cerebrospinal fluid content of dynorphin and low-frequency TENS increases the cerebrospinal fluid content of enkephalin.63 Thus, although electrode position, in part, may explain why high- and low-frequency TENS differentially reduced the development of allodynia in the present study, it is likely that frequency, either alone or through an interaction with electrode position, is also a primary contributing factor.
Why high- and low-frequency TENS prevents mechanical and thermal allodynia, respectively, is not known. However, because the central nervous system mechanisms that undergird mechanical and thermal allodynia are somewhat distinct, this differential effect is not surprising. For example, glutamate neurotransmission is implicated in establishing and maintaining the pain of CPSII,64,65 but the glutamate receptors involved in maintaining mechanical and thermal allodynia are at least somewhat distinct. In humans with CPSII, pharmacological blockade of a binding site on the NMDA glutamate receptor reduces indicators of mechanical allodynia, but fails to reduce any measure of thermal allodynia.66 Similarly, pharmacological blockade of a non-NMDA glutamate receptor in neuropathic rats abolishes the presence of mechanical allodynia, but not thermal allodynia.67 It is possible that these different underlying mechanisms for the production of mechanical and thermal allodynia are best addressed by different frequencies of TENS treatment. Confirmation of this notion awaits further research.
Because high- and low-frequency TENS specifically prevent mechanical and thermal allodynia, respectively, it seems that a comprehensive clinical strategy would involve them both. Although a tested strategy for combining these 2 frequencies of treatment together has yet to be established, clearly exposing patients in the initial stages of CPSII development to both high- and low-frequency TENS is warranted. This notion has some precedent. In a recent report,68 people with radiculopathy were treated with stochastic or conventional (high-frequency) TENS. Stochastic TENS randomly alters the frequency of stimulus delivery, although the average frequency over time remains in the high-frequency range. Patients receiving this multiple-frequency form of TENS perceived significantly less pain than did their counterparts who received conventional TENS.68 Therefore, it appears that exposing the nervous system to different frequencies of TENS may promote pain relief. Our data would support this notion by indicating that people who are developing CPSII should be exposed to both high- and low-frequency stimulation in order to comprehensively reduce the development of allodynia.
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| Footnotes |
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Both authors provided concept/idea/research design, writing, data collection and analysis, and project management. Dr Somers provided fund procurement. Dr Clemente provided consultation (including review of manuscript before submission). The authors thank Jeremy W Snodgrass, Christopher M Bailey, Kelli D Marlow, Michelle L Gregg, and Mary Przybysz for data collection. They also acknowledge Leesa M DiBartola, RobRoy L Martin, Mary T Marchetti, and Christopher R Carcia for consultation (including review of manuscript before submission). The authors acknowledge the Empi Corporation for donating the transcutaneous electrical nerve stimulation units used in the study.
This study was approved by the Institutional Animal Care and Use Committee of Duquesne University.
This project was funded by the National Institutes of Health (1 R15 NS/OD 36315–01). It also was funded, in part, under a grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.
The data in this article were presented at the annual meeting of the Society for Neuroscience; November 14, 2005; Washington, DC.
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significant difference from naive control rats (single-factor analysis of variance, Tukey post hoc comparisons; P
.05).