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Vol. 289, Issue 2, 840-846, May 1999
Physical Therapy Graduate Program (M.D., A.S., S.S., A.T.) and Neuroscience Graduate Program (K.A.S.), The University of Iowa, Iowa City, Iowa
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Transcutaneous electrical nerve stimulation (TENS) is commonly used for
relief of pain. The literature on the clinical application of TENS is
extensive. However, surprisingly few reports have addressed the
neurophysiological basis for the actions of TENS. The gate control
theory of pain is typically used to explain the actions of
high-frequency TENS, whereas, low-frequency TENS is typically explained
by release of endogenous opioids. The current study investigated the
role of µ, 
, and 
opioid receptors in antihyperalgesia produced
by low- and high-frequency TENS by using an animal model of
inflammation. Antagonists to µ (naloxone), (naltrinodole), or (nor-binaltorphimine) opioid receptors were delivered to the spinal
cord by microdialysis. Joint inflammation was induced by injection of
kaolin and carrageenan into the knee-joint cavity. Withdrawal latency
to heat was assessed before inflammation, during inflammation, after
drug (or artificial cerebral spinal fluid as a control) administration,
and after drug (or artificial cerebral spinal fluid) administration + TENS. Either high- (100 Hz) or low- frequency (4 Hz) TENS
produced approximately 100% inhibition of hyperalgesia. Low doses of
naloxone, selective for µ opioid receptors, blocked the
antihyperalgesia produced by low-frequency TENS. High doses of
naloxone, which also block and opioid receptors, prevented the
antihyperalgesia produced by high-frequency TENS. Spinal blockade of
opioid receptors dose-dependently prevented the antihyperalgesia
produced by high-frequency TENS. In contrast, blockade of opioid
receptors had no effect on the antihyperalgesia produced by either low-
or high-frequency TENS. Thus, low-frequency TENS produces
antihyperalgesia through µ opioid receptors and high-frequency TENS
produces antihyperalgesia through opioid receptors in the spinal cord.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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One
noninvasive treatment commonly used to manage arthritic pain is
transcutaneous electrical nerve stimulation (TENS). Studies have shown
that TENS reduces pain in people with rheumatoid and osteoarthritis
(Manheimer et al., 1978
; Manheimer and Carlsson, 1979; Kumar and
Redford, 1982). Although studies have demonstrated the effectiveness of
TENS for reducing pain in people with arthritis, the physiological
mechanism by which TENS produces analgesia is unknown. Two different
theories have been proposed. The most popular theory for the mechanism
of action of TENS is the gate control theory of pain (Melzack and Wall,
1965; Kumar and Redford, 1982; Garrison and Foreman, 1994; Hollman and
Morgan, 1997). This theory proposes that stimulation of
large-diameter afferent fibers inhibits second-order neurons in the
dorsal horn and prevents pain impulses carried by small-diameter fibers
from reaching higher brain centers.
The second explanation for the mechanism of action of TENS is that it
stimulates the release of endogenous opioids. Naloxone, an opioid
receptor antagonist, blocks the analgesia produced by low-frequency
electroacupuncture (<10 Hz), suggesting it works through the release
of endorphins (Mayer et al., 1977; Woolf et al., 1977; Cheng and
Pomeranz, 1979; Ha et al., 1981). Fox and Melzack (1976)
compared the use of TENS and acupuncture in the treatment of lower back
pain and concluded they have the same underlying mechanism of
action. Others have demonstrated an increased content of opioid
peptides in the cerebrospinal fluid in humans after administration of
TENS (Salar et al., 1981; Hughes et al., 1984; Almay et al., 1985; Han
et al., 1991).
Several studies indicate that high- (>10 Hz) and low- (<10 Hz)
frequency TENS work through different mechanisms. Abram et al. (1981)
investigated the role of opioids in analgesia produced by
high-frequency TENS. Specifically, no reversal of analgesia was seen
after administration of naloxone, suggesting to the authors that
high-frequency TENS does not work through the release of opioids.
High-frequency TENS is, therefore, believed to work through mechanisms
proposed by the gate control theory, producing only short-term
analgesia (Garrison and Foreman, 1994; Hollman and Morgan, 1997).
Conversely, low-frequency TENS is proposed to work through release of
endogenous opioids, which causes a more systemic and long-term response
(Sjound and Eriksson, 1979). Some studies, however, have demonstrated
that high-frequency TENS has a longer lasting effect than low-frequency
TENS (Manheimer and Carlsson, 1979; Walsh et al., 1995; Gopalkrishnan
and Sluka, 1998; Sluka et al., 1998). Furthermore, Woolf et al. (1977)
demonstrated that high doses of naloxone block the analgesia produced
by high-frequency TENS in rats. The different mechanisms by which high-
and low-frequency TENS works still remain unclear.
In response to the conflicting results of previous studies and the lack of research on the mechanisms through which TENS works, this study investigated the spinal mechanisms through which low- and high-frequency TENS exert their antihyperalgesic effects. We hypothesized that low-frequency TENS activates endogenous opioid receptors in the spinal cord.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Placement of the Microdialysis Fiber
All experiments were approved by the animal care and use
committee at our institution and are in accordance with National Institutes of Health guidelines. Male Sprague-Dawley rats (250-350 g;
n = 122) were implanted with a microdialysis fiber in
the dorsal horn (L4-L6
spinal level) for delivery of drugs to the spinal cord (Sluka and
Westlund, 1992). A microdialysis fiber (Hospal AN69 with a cutoff of 45 kDa) was prepared by marking a 2-mm gap and then applying an epoxy
coating to the remaining length of the fiber. This allowed diffusion of
the drug to occur only in the 2-mm gap to be positioned in the dorsal
horn of the spinal cord. Rats were initially anesthetized with sodium
pentobarbital (50 mg/kg i.p.) for placement of the microdialysis fiber.
A hole was drilled just under the lip of the pedicle on both sides of the T13 spinal segment with a manual drill. The
prepared microdialysis fiber was then threaded through the holes.
Polyethylene (PE 20) tubing was secured to both ends of the fiber with
super glue gel and epoxy. The fiber was positioned so that the 2-mm
section was in the dorsal horn of the spinal cord and then secured in
place with dental cement. The PE 20 tubing was then sutured to the
fascia to prevent any unnecessary movement. Staples were used to close the incision and the rat was then placed in its cage for recovery overnight. The next day, rats were divided into the following treatment
groups: 1) Artificial cerebrospinal fluid (ACSF) and no TENS treatment
(n = 6) control; 2) ACSF + low- (n = 8)
or high-frequency (n = 6) TENS; 3) Naloxone
hydrochloride (Sigma Chemical Co., St. Louis, MO; 1.0-10.0 mM) + low-
(1 mM, n = 3; 5 mM, n = 5; 10 mM, n = 7) or high-frequency (1 mM, n = 3;
5 mM, n = 6; 10 mM, n = 6) TENS; 4)
Naltrinodole hydrochloride (Sigma Chemical Co.; 0.01-1.0 mM) + low- (1 mM; n = 6) or high-frequency (0.01 mM,
n = 5; 0.1mM, n = 3; 1 mM,
n = 6) TENS; or 5) nor-binaltorphimine (nor-BNI; Research Biochemicals International, Natick, MA; 0.01 mM) + low- (n = 6) or high-frequency (n = 7) TENS.
All drugs were dissolved in ACSF and pH-corrected (7.2-7.4).
Behavioral Testing and Treatment Protocol
The day after implantation of the microdialysis fiber,
withdrawal latencies of both hindpaws were determined according to the
protocol described by Hargreaves et al. (1988). Rats were placed in
clear plastic cages on an elevated glass plate and allowed to acclimate
for 10 to 20 min. A radiant heat source was applied to the posterior
plantar surface of the hindpaw and the time for the rat to withdraw its
paw was measured. The light box had an on/off switch connected to a
timer, which measured the duration of the paw withdrawal latency (PWL).
If the PWL exceeded 20 s, the heat source was turned off to avoid
tissue damage. The average of five trials for each paw was determined.
The examiner was kept blinded to the treatment groups, both drug
treatment and TENS treatment. The knee-joint circumferences were
measured bilaterally with a flexible tape measure around the center of
the fully extended knee.
Injection of the Knee Joint.
After baseline behavioral
measurements, rats were anesthetized with 2 to 4% halothane via a face
mask for approximately 5 min and a solution of 3% kaolin and 3%
carrageenan (0.1 ml; pH 7.4) in sterile saline was injected into the
left knee joint to induce inflammation (Sluka and Westlund, 1993).
). The rats were then given either a drug or ACSF for 1 h through the microdialysis fiber. After the 1-h infusion, PWL and spontaneous pain-related behaviors were assessed.
TENS Treatment.
Rats were then lightly anesthetized with
halothane (1-2%, 20 min), their knee-joint circumferences were
measured, and TENS was applied to the knee joint. Rats received either
1) low-frequency TENS at sensory intensity to the inflamed knee joint
(4 Hz; 20 min.; EMPI Eclipse +; EMPI, Inc., Minneapolis, MN), 2)
high-frequency TENS at sensory intensity to the inflamed knee joint
(100 Hz; 20 min.; EMPI Eclipse +), or 3) halothane without TENS.
One-inch round pregelled electrodes were placed on the medial and
lateral aspects of the shaved knee joint. Sensory-intensity TENS was
determined by increasing the intensity until a palpable muscle
contraction was elicited and then reducing the intensity to just below
that point. The study minimized variability of stimuli by maintaining a
pulse duration constant at 100 µs and an intensity constant at
sensory-level intensity (see Sluka et al., 1998). Thus, only the
frequency of stimulation was varied. These parameters are based on
those used clinically (see Robinson and Snyder-Mackler, 1995) and those
previously published (Sluka et al., 1998).
Selectivity of Drugs.
To test selectivity of naloxone to
opioid receptors, 13 rats were implanted with microdialysis fibers. The µ opioid receptor agonist DAMGO
([D-Ala2,N-Me-Phe4,Glyy-ol5]-enkephalin)
(Research Biochemicals International; 1 mM; n = 4), the
opioid receptor agonist SNC8O
((+)-4-[(
R)--((2S,5R)-4-allyl-2,5dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide) (Tocris Cookson; 1 mM; n = 4), or the opioid receptor agonist U50,488
(trans-(+)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexy]benzenecetamide) (Tocris Cookson; 0.1 mM, n = 5) was infused into the
dorsal horn and PWL to radiant heat was tested. Naloxone (1, 5, or 10 mM) was tested for its ability to antagonize the analgesia produced by
the opioid receptor agonists. Similarly, the selectivity of the opioid receptor antagonist naltrinodole (n = 14) and
the opioid receptor antagonist nor-BNI (n = 13) was
tested against DAMGO (1 mM), SNC8O (1 mM), or U50,488 (0.1 mM). The
effects of 0.01, 0.1, and 1 mM naltrinodole and 0.1, 1, and 10 µM
nor-BNI were tested against the opioid agonists.
Statistical Analysis
To minimize variability between groups, data were assessed for
the percentage of inhibition by TENS for PWL with the following formula: (TENS or drug 
arthritis)/(base arthritis) × 100. Thus, 100% inhibition is a full reversal of hyperalgesia and 0% inhibition is no change from the hyperalgesia measured 4 h after induction of inflammation. The group effect of TENS and the group effect of drug on the percentage of inhibition of hyperalgesia were
assessed by an ANOVA (p < .05). Post hoc tests were
done with independent t tests for assessing differences
between groups.
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Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Control Arthritic Animals and Effect of TENS. Four hours after induction of arthritis, there was a significant decrease in PWL to radiant heat that was maintained throughout the testing period. There was also an increase in joint circumference and an increase in spontaneous pain-related behavior ratings 4 h after inflammation. Changes in joint circumference and spontaneous pain behavior ratings are given in Tables 1 and 2, respectively. There were no significant differences between groups for joint circumference or spontaneous pain-related behaviors at any time period (baseline, 4 h after inflammation, after administration of a drug or ACSF, or after TENS). ACSF had no effect on the decreased withdrawal latency normally observed after joint inflammation (Fig. 1). In the group of animals treated only with ACSF, the withdrawal latency decreased from 9.0 ± 0.22 s to 7.2 ± 0.24 s, 4 h after induction of arthritis. In contrast, treatment with either high- or low-frequency TENS produced approximately 100% reversal of the hyperalgesia (Figs. 1 and 2). In the group of animals treated with low-frequency TENS, the PWL increased from 6.7 ± 0.32 s, 4 h after induction of inflammation, to 8.3 ± 0.26 s after treatment with TENS (baseline = 9.0 ± 0.75 s). Similarly, in the group of animals treated with high-frequency TENS, the PWL increased from 7.2 ± 0.32 s, 4 h after induction of inflammation, to 10.1 ± 0.42 s after treatment with TENS (baseline = 9.8 ± 0.31 s). There was an overall significant effect across time (F1,66 = 131.95; p = .001) for changes in PWL in all of the groups of animals. A significant effect for group by time occurred for the percentage of inhibition of hyperalgesia after treatment with TENS (F14,66 = 4.05; P = .001) but not after infusion of drug (or ACSF) alone (F14.66 = 1.75; p = .08).
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Effects of Naloxone on TENS Analgesia. Spinal infusion of 1 mM naloxone had no effect on the inhibition of hyperalgesia produced by either high- or low-frequency TENS; the percentage of inhibition of hyperalgesia remained at approximately 100%. However, 5 and 10 mM naloxone prevented the inhibition of hyperalgesia by low- frequency TENS (Fig. 1). Thus, there was still a decrease in the PWL to radiant heat after TENS treatment similar to that observed 4 h after induction of inflammation. Only 10 mM naloxone blocked the inhibition of hyperalgesia produced by high-frequency TENS (Fig. 2).
To test selectivity of naloxone for different opioid receptors, naloxone was tested against agonists selective for µ (DAMGO), (SNC80), or (U50,488) opioid receptors. As Fig.
3A shows, all three agonists produced
analgesia as indicated by the significant increase in PWL
(p < .05). After administration of 1 mM naloxone, the
PWL remained significantly increased. After administration of 5 mM
naloxone, only the group receiving DAMGO (µ agonist) returned to the
baseline. Therefore, at a dose of 5 mM, naloxone selectively blocks µ receptors but not or opioid receptors. After increasing the
concentration of naloxone to 10 mM, all of the groups' PWL returned to
the baseline, indicating all opioid receptors (µ, , and ) were
blocked at this dose.
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Effects of Naltrinodole on TENS Analgesia.
Blockade of opioid receptors with 1 mM naltrinodole prevented the inhibition of
hyperalgesia produced by high-frequency but not low-frequency TENS
(Figs. 1 and 2). The effects of naltrinodole on preventing the
inhibition of hyperalgesia by high-frequency TENS were dose-dependent
(Fig. 2, inset).
(SNC80), and (U50,488) opioid receptors. Figure 3B
demonstrates that 1 mM naltrinodole selectively blocks opioid receptors. The analgesia produced by spinal infusion of DAMGO or
U50,488 was unaffected by naltrinodole.
Effects of nor-BNI on TENS Analgesia.
Blockade of opioid
receptors with nor-BNI had no effect on the analgesia produced by
either high- or low-frequency TENS (Figs. 1 and 2). The percentage of
inhibition of hyperalgesia was similar to that observed in animals
treated with ACSF and TENS and was not significantly different from
that group.
(SNC80), and (U50,488) opioid receptors. As Fig. 3C shows,
spinal infusion of 10 µM nor-BNI selectively blocks opioid
receptors. The analgesia produced by spinal infusion of DAMGO or SNC80
was unaffected by nor-BNI.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The current study supports the theory that TENS works through
release of endogenous opioids at the spinal cord level. Spinal administration of 5 mM naloxone, which selectively blocks µ opioid receptors, significantly reduced the antihyperalgesic effects of
low-frequency TENS. A greater, nonselective dose of naloxone (10 mM)
reduced the antihyperalgesia produced by high-frequency TENS,
suggesting the involvement of endogenous opioids acting at or opioid receptors, or both. The antihyperalgesic effect of
high-frequency TENS was reduced by blockade of opioid receptors but
not opioid receptors. Thus, the current study demonstrated that the
analgesia produced by high-frequency sensory TENS is mediated by opioid receptors spinally, and that produced by low-frequency sensory
TENS is mediated by µ opioid receptors spinally.
Previous studies support the conclusion that both high- and
low-frequency TENS result in the release of endogenous opioids. Increased 
-endorphin concentrations in the cerebral spinal fluid were observed after administration of either high- or low-frequency TENS (Salar et al., 1981; Hughes et al., 1984; Almay et al.,
1985). Han et al. (1991) analyzed the opioid peptides
Met-enkephalin-Arg-Phe (MEAP) and dynorphin A in the cerebral spinal
fluid of human subjects after application of either high- or
low-frequency TENS. They found that high-frequency stimulation produced
an increase in dynorphin A but not in MEAP, whereas low-frequency TENS
increased MEAP but not dynorphin A. Although similar frequencies of
stimulation were used by Han et al. (1991; 2 and 100 Hz), the intensity
of stimulation was greater, eliciting a motor contraction in the subjects. Previously, we demonstrated that increasing intensity of
stimulation resulted in an increase in inhibition of hyperalgesia in
carrageenan-inflamed rats (Gopalkrishnan and Sluka, 1998). Similarly, Garrison and Foreman (1996) showed an increased inhibition of responses to noxious stimuli with increased intensity of stimulation when recording from unsensitized dorsal horn neurons. Differences between the studies, thus, could be explained by differences in intensity of stimulation.
Several studies have demonstrated that acupuncture-induced analgesia is
reduced by naloxone in normal subjects and a variety of patient
populations (Mayer et al., 1977; Ha et al., 1981; Homma et al., 1985;
Eriksson et al., 1991). Similarly, low-frequency, high-intensity
electroacupuncture suppresses responses of dorsal horn neurons to
noxious stimuli and this suppression is reversed by naloxone (Pomeranz
and Cheng, 1979). Sjolund and Eriksson (1979) demonstrated that analgesia produced by low-frequency, high-intensity TENS but not high-frequency, low-intensity TENS is reversible by
administration of naloxone systemically. The dose used by Sjolund and
Eriksson (1979) was at a concentration expected to block µ opioid
receptors. In contrast, high-frequency TENS was unaffected by systemic
naloxone in patient populations (Abram et al., 1981; Freeman et al.,
1983). However, analgesia induced in rats by high-frequency TENS
was reversed by high doses of systemic naloxone expected to block µ,
, and opioid receptors (Woolf et al., 1977; Han et al., 1984).
The release of endogenous opioids in the spinal cord in response to
TENS stimulation could result from activation of local circuits within
the spinal cord or from activation of descending inhibitory pathways.
Opioid peptides, enkephalin, and dynorphin are contained in spinal
dorsal horn neurons (Hokfelt et al., 1977; Glazer and Basbaum,
1981). Likewise, µ and opioid receptors have been
localized to the dorsal horn, both presynaptically on primary afferent
fibers and postsynaptically on dorsal horn neurons (LaMotte et al.,
1976; Atweh and Kuhar, 1983; Cheng et al., 1997). By using
immunohistochemistry, Zhang et al. (1998) demonstrated that small
dorsal root ganglia neurons labeled for the opioid receptor also
contain Substance P and calcitonin gene-related peptide. Further spinal
localization of the receptor was reduced by dorsal rhizotomy,
suggesting presynaptic localization on primary afferents. Release of
the primary afferent peptides, Substance P and calcitonin gene-related
peptide, is blocked by opioid agonists (Yaksh et al., 1980; Collin et
al., 1991; Collin et al., 1993; Bourgoin et al., 1994), suggesting a
role for opioid receptors in presynaptic neurotransmitter release.
Specifically, activation of µ and opioid receptors inhibits the
release of Substance P and calcitonin gene-related peptide (Hirota et
al., 1985; Chang et al., 1989; Collin et al., 1991; Ray et al., 1991;
Yonehara et al., 1992). Furthermore, opioids applied directly to the
spinal cord block behavioral responses in animals to a noxious
stimulation and produce significant antinociception in humans
(Lazorthes et al., 1988; Hammond et al., 1998). For example,
intrathecal administration of agonists to either µ or receptors
reduces the behavioral response to formalin injection in rats (Hammond
et al., 1998). Wang et al. (1996) demonstrated that µ,
1, and 2 receptor
agonists inhibit activity of trigeminal dorsal horn neurons to A and C-fiber stimulation. Thus, the effects of TENS may be to
reduce the release of neurotransmitters from primary afferent terminals in the dorsal horn and/or to reduce activity of dorsal horn neurons through the release of endogenous opioids.
Opioid release in the dorsal horn can also occur through activation of
descending inhibitory pathways. The opioid peptides and their receptors
are distributed throughout the central nervous system in areas involved
in pain transmission including the spinal cord, medullary and pontine
nuclei, midbrain, amygdala, hypothalmus, thalamus, and cortex (Mansour
et al., 1988; Basbaum and Fields, 1984). Descending projections
originate in the reticular formation in the brainstem, the ventral
portion of the periaqueductal gray in the midbrain, and the rostral
ventral medulla (Besson and Chaouch, 1987; Basbaum and Fields, 1996).
All of these nuclei are involved in descending inhibition of the dorsal
horn neurons either by direct descending fibers or by intermediary
brainstem structures (Fields et al., 1988; Cross, 1994; Basbaum and
Fields, 1984). Descending raphe spinal axons exert their
antinociceptive effect through spinal opioid receptors because
intrathecal injection of naloxone blocks the analgesia produced by
stimulation of the raphe nucleus (Zorman et al., 1982). Support for a
role of descending systems in TENS comes from work on acupuncture
analgesia. Zhou et al. (1981) injected small amounts of naloxone into
different brain areas to assess its effect on acupuncture analgesia.
They concluded that the nuclei accumbens, amygdala, habenula, and
periaqueductal gray are sites where acupuncture exerts its analgesic
effect and that acupuncture involves the release of opioids at these sites.
Clinical Implications.
Knowledge of the mechanism of TENS will
better enable clinicians to determine which patients will benefit from
TENS treatment based on the type of medication the patient is currently
taking for pain control. Solomon et al. (1980) demonstrated that
patients who used opioids in amounts sufficient to produce tolerance
also experienced tolerance to the effects of TENS. This finding implies that the mechanism of action of TENS involves the same neural substrate
as opioid-induced analgesia. If the patient is taking opioids or has
taken opioids in the past, TENS may not be the modality of choice to
control pain. Solomon et al. (1980) also show that TENS could reduce
the need for postoperative opioids in a group of patients who had not
used opioid analgesics before the operation. This is significant
because, in addition to providing analgesia, opioid drugs produce
several unwanted side effects. These include respiratory depression,
nausea and vomiting, constipation, alteration of mood, mental clouding,
and increased tolerance to the drug with continued use. Thus,
the use of TENS in conjunction with opioids could lower the intake of
drugs and limit side effects.
found that naloxone blocks the
antinociceptive effects of the nonsteroidal anti-inflammatory drug (NSAID) flunixin in rats with an inflamed paw. They concluded that
naloxone acts as a noncompetitive antagonist to flunixin and that
spinal antinociception caused by the NSAID was mediated via release of
endogenous opioid peptides. This implies that TENS could be an
effective alternative to NSAIDs as an analgesic when used in conditions
of acute inflammation. Furthermore, if a patient is taking NSAIDs, TENS
may be less effective.
Conclusions.
Both high- and low-frequency TENS at sensory
intensity reverse the hyperalgesia produced by knee-joint inflammation.
The antihyperalgesic effects of low-frequency TENS are reversed by
spinal administration of low doses of naloxone that are selective for µ opioid receptors. However, the antihyperalgesia produced by
high-frequency TENS is prevented by blockade of opioid receptors in
the spinal cord. Thus, low-frequency TENS works through activation of µ opioid receptors and high-frequency TENS works through activation
of opioid receptors.
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Acknowledgments |
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We thank Dr. G. F. Gebhart for critically reading the manuscript and EMPI for providing the TENS units.
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Footnotes |
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Accepted for publication December 2, 1998.
Received for publication October 20, 1998.
1 This study was supported by grants from the Central Investment Fund for Research Enhancement from the University of Iowa and the Arthritis Foundation.
Send reprint requests to: Kathleen A. Sluka, P.T., Ph.D., Physical Therapy Graduate Program, The University of Iowa, 2600 Steindeler Bldg., Iowa City, IA 52242. E-mail: kathleen-sluka{at}uiowa.edu
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Abbreviations |
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TENS, transcutaneous electrical nerve stimulation; PWL, paw withdrawal latency; ACSF, artificial cerebral spinal fluid; MEAP, Met-enkephalin-Arg-Phe; NSAID, non-steroidal anti-inflammatory.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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opioid receptors in the superficial layers of the rat cervical spinal cord: Extrasynaptic localization and proximity to Leu5-enkephalin.
Brain Res
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) or treatment
with TENS + drug or ACSF (
) in the group of animals treated with
low-frequency TENS. A, inhibition of hyperalgesia after treatment with
ACSF (n = 6), low-frequency TENS (TENS,
n = 8), or naloxone at 1 (n = 3), 5 (n = 5), or 10 mM (n = 7). The percentage of analgesia was significantly increased after
treatment with TENS (p = .009) when compared with
animals treated with ACSF and no TENS. Treatment with 5 (p = .01) or 10mM (p = .02)
naloxone significantly prevented the analgesia produced by
low-frequency TENS. B, inhibition of hyperalgesia after treatment with
10 µM nor-BNI (n = 6) or 1mM naltrinodole
(n = 6). No significant difference was observed
between the group treated with ACSF + low-frequency TENS and those
treated with nor-BNI or naltrinodole. *, significantly different from
TENS group. Values are mean ± S.E.M.
