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NEUROPHARMACOLOGY
Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina
Received December 9, 2002; accepted February 18, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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- and C-fibers was examined in
normal or carrageenin-inflamed rats before and after intravenous (i.v.) T62
administration. Intravenous T62, 3 mg/kg, had no significant effect in either
normal or inflamed conditions. These results support previous studies to
suggest that adenosine receptor modulators lack efficacy to acute nociceptive
stimuli in the normal condition, but reduce hypersensitivity during
inflammation through a central mechanism.
), including acute (Post,
1984; Sosnowski et al.,
1989; Fastbom et al.,
1990; Sollevi,
1997), neuropathic (Karlsten
and Gordh, 1995; Sollevi et
al., 1995; Sjolund et al.,
1998; von Heijne et al.,
1999), and inflammatory pain
(Malmberg and Yaksh, 1993;
Sawynok et al., 1998;
Poon and Sawynok, 1999) in
human and animals. However, unlike direct adenosine receptor agonists such as
R-phenylisopropyl-adenosine
(Sosnowski et al., 1989) or
5'-N-ethylcarboxamide adenosine
(Post, 1984), intrathecal
injection of adenosine itself does not produce antinociception to acute
stimuli in normal animals (Eisenach et al.,
2002). As an adenosine receptor modulator, T62
[2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene] has been
previously shown to reduce mechanical allodynia in rats with spinal nerve
ligation via a mechanism involving spinal A1 adenosine receptors
(Pan et al., 2001;
Li et al., 2002). However, the
effects of adenosine receptor modulators in inflammation-induced
hypersensitivity have not previously been reported.
The purpose of the current study was therefore to evaluate the efficacy of
the adenosine modulator, T62, in normal and inflamed rats and to test its site
of action using different methods of administration. Both thermal
(Hargreaves et al., 1988;
Dirig et al., 1997) and
mechanical withdrawal thresholds (Randall-Sellito) were determined. In
carrageenin-inflamed rats, thermal threshold was determined after i.t., i.v.,
and s.c administration of T62. Finally, in both normal and inflamed rats, the
effect of i.v. T62 on single-unit afferents was determined in normal and
inflamed conditions.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) under
halothane anesthesia by insertion of polyethylene tubing through a small hole
in the cisterna magnum and advancement caudad (8 cm) such that the tip of the
catheter lay in the intrathecal space at the lumbar enlargement. After
surgery, 90% animals showed normal neurologic behavior. Rats showing
neurologic deficits were immediately euthanized by an overdose of
pentobarbital; the other animals were allowed to recover for 4 to 5 days
before drug testing.
Thermal Testing in Normal Rats. To examine the effect of T62 in
normal rats to noxious heat, a plantar withdrawal method
(Dirig et al., 1997) was used,
with a lamp intensity set at 5.0 and 5.25 mA. Following habituation to the
environment of a clear plastic box on a raised floor of a clear heat-tempered
glass for 30 to 45 min, a projection bulb was illuminated and focused on the
plantar surface of one hind paw. Latency to withdrawal was determined and a
cutoff value of 30 s was not exceeded. Rats were intrathecally injected with
vehicle alone or one of four doses of T62 (0.5, 2, 10, or 40 µg),
n = 6/group. The experiments were executed by mixed and
double-blinded drug dosing. Each rat received a maximum of four drug
injections with experiments separated by at least 1 week (drug dose applied
randomly). After drug or vehicle treatment, the withdrawal latency (an average
of two tests at each time point, the same for the following inflamed rats) was
determined before and 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min
after injection. Withdrawal latency data were analyzed by two-way analysis of
variance followed by Fisher's protected least significant difference test
(Shapira et al., 1994).
P < 0.05 was considered significant.
Mechanical Testing in Normal Rats. One week after i.t. catheter
implantation, a group of 18 rats was used to test the effect of T62 against
noxious acute mechanical stimuli, using a Randall-Sellito device (Type 7200;
Ugo Basile, Comerio, Italy). Vehicle or one of three i.t. doses of T62 (1, 2,
or 20 µg) was injected, with n = 6/group. The experiments were
executed by mixed and double-blinded drug dosing. Each rat received a maximum
of four drug injections with experiments separated by at least 1 week (drug
dose applied randomly). After drug or vehicle injection, the withdrawal
threshold (an average of two tests at each time point) was determined before
and 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min after T62 injection.
Mechanical withdrawal threshold data were analyzed by two-way analysis of
variance followed by Fisher's protected least significant difference test
(Shapira et al., 1994).
P < 0.05 was considered significant.
Carrageenin Inflammation: Intrathecal T62. One week after i.t.
catheter implantation, 34 rats were used to test the efficacy of i.t. T62
following carrageenin inflammation
(Eisenach and Gebhart, 1995).
Briefly, the rat was habituated to the testing environment, and baseline hind
paw withdrawal latencies to radiant heat were obtained as described above
(Dirig et al., 1997).
Unilateral inflammation was induced by intraplantar injection of 2 mg of
freshly prepared carrageenin in 0.1 ml normal saline in the right hind paw.
Three hours after carrageenin injection, vehicle or T62 (0.2, 2, or 10 µg;
n = 7–11/group) was injected intrathecally in less than 20
µl of total volume with 5 to 10 µl of saline for flush. In all studies,
baseline withdrawal latencies were obtained immediately before carrageenin
injection, 3 h after carrageenin, then at 30-min intervals after drug
injection for another 3 h. Hind paw thickness at the midplantar level was
determined before and at the end of each experiment involving carrageenin
injection using a calibrated micrometer. Each rat was studied only once and
was killed at the end of the experiment by an overdose of pentobarbital.
Carrageenin Inflammation: Intravenous T62. Under halothane anesthesia, polyethylene tubing was inserted into the right jugular vein, and the catheter was externalized for drug administration. After surgery, all rats were allowed to rest for a week before study. On the study day, rats were injected with 2 mg of freshly prepared carrageenin. Three hours later, a single dose (3 mg/kg) of T62 was injected intravenously, and the withdrawal latency data were recorded for 300 min as described above (n = 6).
Carrageenin Inflammation: Local T62 Administration. On the study day, four rats were injected with 2 mg of freshly prepared carrageenin. Three hours later, a single dose (25 µg) of T62 was injected subcutaneously into the inflamed hind paw, and the withdrawal latency was recorded for 300 min as described above.
Single-Unit Afferent Recording. Under halothane anesthesia (1–1.5% halothane throughout the experiment), the left carotid artery was cannulated for monitoring blood pressure. The trachea was cannulated and the rat was mechanically ventilated. The right jugular vein was cannulated with polyethylene tubing for drug injection. At the end of preparative surgery, the rat was paralyzed with pancuronium bromide (1 mg/kg), with supplementary doses given at approximately 1-h intervals. Rectal temperature was maintained in the range of 37 to 38°C with circulating water heating pad and heat lamps throughout the experiment. The left sciatic nerve at the middle and distal part was exposed through a restricted skin incision over the posterior hindlimb, and the overlying fascia and sheath were carefully removed. The nerve was then draped on a platform and covered with warm mineral oil. Small nerve filaments were transected in the middle of the sciatic nerve, teased gently from the nerve segment under an operating microscope (model M900; D.F. Vasconcellos S.A., São Paulo, Brazil), and connected to the recording electrode of a bipolar stainless electrode. Reference electrodes were placed on the surrounding tissues. The nerve filaments were then dissected gradually until single-unit activity of afferents was detected. The action potential of the afferent was amplified 10,000 to 30,000x by an a.c. differential amplifier (DAM80; World Precision Instruments, New Haven, CT) and output to an audio amplifier (AM8; Grass Instruments, Quincy, MA) and displayed on an oscilloscope (450; Gould Instrument Systems Inc., Cleveland, OH). The neurogram was recorded on a thermal-sensitive recorder (K2G; Astro-Med, West Warwick, RI). A single unit was identified initially by examining the wave form and the spike amplitude on the oscilloscope at a rapid sweep speed, as well as by checking the recorded sound frequency related to each spike activity. Furthermore, the signals were digitized at a sampling rate of 20 kHz and fed into a PC-compatible computer through an analog-to-digital interface card for subsequent off-line analysis. An amplitude threshold was set for recording firing frequency. When nerve activity was detected, the associated wave form (6 ms) would be extracted and displayed continuously in a separate software oscilloscope window (DataWave Technology, Inc., Longmont, CO). Single-unit recording was ensured by checking the constancy of the shape and polarity of the displayed spike wave form. Discharge frequency was quantified by using data acquisition and analysis software (DataWave Technology, Inc.), and a histogram was created for each filament. Accurate counting of the afferent discharge frequency (an average of 4 s) was verified for each afferent by comparing the constructed histogram with the hard copy, which was recorded simultaneously.
Isolation, Identification, and Classification of Fibers. To search
for units, we used two approaches: 1) electrical stimulation of sciatic nerve
fibers at a site between the recording site and the fiber's receptive field
(RF); and 2) mechanical stimulation of their hind paw receptive fields.
Electrical stimulation was performed with transcutaneous needle electrodes
that were placed in the heel area to permit multiunit stimulation of plantar
and sural nerve fibers. Stimulus duration was 0.2 ms for A
- and
A-fibers and 0.5 to 0.75 ms for C-fibers. The amplitude of stimuli was
usually set at 1.5 times the fiber response threshold, whereas the frequency
of stimuli was usually 1 Hz. Responses to natural stimulation of their
receptive fields and conduction velocity (CV) of fibers were the main criteria
used for physiological characterization and classification. Two types of
mechanical stimulation of receptive fields were used: 1) noncalibrated search
stimuli such as tapping, stroking, or moderately firm pressure applied with a
cotton-tipped swab to plantar surfaces; and 2) stimuli using calibrated von
Frey hairs (Stoelting Co., Wood Dale, IL) for more precise physiological
characterization of units. Conduction velocities were calculated by dividing
the distance between the stimulating and recording electrodes by the latency
of the electrically evoked spike. Units with CVs >15 m/s were identified as
A-fibers; units with CVs of 2.5–15 m/s were identified as
A-fibers; and units with CVs <2.5 m/s were identified as
C-fibers.
Afferent Activity in Normal Animals. After obtaining a stable single-unit afferent recording, the baseline discharge and response to a set of stimuli from calibrated von Frey filaments (10-s application with 1-min interval) were recorded in duplicate over 15 to 30 min. These measurements were repeated at 30 and 60 min after i.v. T62 injection, 3 mg/kg. After the last stimulus, the conduction velocity of the recorded afferents was measured using electrical stimulation. Finally, the rats were sacrificed by an overdose of pentobarbital.
Afferent Activity Following Inflammation. After obtaining a single-unit afferent recording, the baseline discharge and response to a set of stimuli from von Frey filaments were recorded as described above. Two milligrams of freshly prepared carrageenin solution, 0.1 ml, was injected into the RF. Three hours after the carrageenin injection, the baseline discharge and response to von Frey filament stimulation in the RF were recorded again, followed by i.v. T62 injection, 3 mg/kg. Then, the baseline discharge and response to von Frey filament stimulation in the RF were recorded 30 and 60 min after injection.
Electrophysiological data are presented as mean ± S.E.M. Discharge activity of afferents was averaged before and after each T62 treatment. The T62 effect on afferent activity was determined by analysis of variance followed by the Dunnett's post hoc test. P < 0.05 was considered to be statistically significant.
Materials. T62 was provided by King Pharmaceuticals (Cary, NC).
Pancuronium bromide was purchased from Abbott Diagnostics (Abbott Park, IL).
Carrageenin, dimethyl sulfoxide (DMSO), and remaining chemicals were purchased
from Sigma-Aldrich (St. Louis, MO). Hydroxypropyl--cyclodextrin was
dissolved as a 45% solution in saline as drug vehicle. T62 was gradually
dissolved into cyclodextrin solution to a final concentration of 0.2
µg/µl as a stock solution for i.t. injection and 1 µg/µl for i.v.
injection, or dissolved in DMSO/cyclodextrin (1:100) mixture at 1 µg/µl
as a stock solution for a 10-µg i.t. injection.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Baseline withdrawal threshold to paw pressure using the Randall-Sellito apparatus in normal rats was 126 g. Intrathecal injection of vehicle did not significantly affect withdrawal threshold to this mechanical stimulus. Similarly, no dose of i.t. T62 affected withdrawal threshold (Fig. 2).
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T62 in Carrageenin Inflammation. After receiving 2 mg of freshly prepared intraplantar carrageenin, the withdrawal latency to thermal testing was reduced from 10 to 3.5 s (Fig. 3). Intrathecal T62 reversed this hypersensitivity to precarrageenin levels in a time- and dose-dependent manner over the 300-min observation period. Although thermal hypersensitivity slowly diminished (withdrawal latency increased) over this 300-min period in vehicle controls, the effect of T62 was nonetheless obvious and significant. In contrast, i.t. T62 did not affect paw edema induced by carrageenin injection (Fig. 4).
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Intravenous T62, 3 mg/kg, produced a modest increase in withdrawal latency to the thermal stimulation in carrageenin-inflamed rats (Fig. 5). In contrast, subcutaneous injection of T62, 25 µg into the inflamed hind paw failed to affect withdrawal latency during carrageenin inflammation (Fig. 6).
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Effect of Intravenous T62 on Single-Unit Afferent Activity in Normal and
Inflamed Rats. Data were obtained from four A-(average CV at 4.4
m/s) and six C- (average CV at 0.84 m/s) fibers in normal rats
(Fig. 7), and five A-
(average CV at 6.6 m/s) and five C- (average CV at 1.6 m/s) fibers
(Fig. 8) in
carrageenin-inflamed rats. Mechanical stimulation with calibrated von Frey
filaments increased the unit firing frequency of both A- and C-fibers
in a stimulus-dependent manner. Neither A- nor C-fiber responses to
mechanical stimulation were inhibited by i.v. T62 in normal rats. Similarly,
T62 had no effect on response to mechanical stimulation in A-nor
C-fibers after carrageenin inflammation
(Fig. 8).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). Previous studies using synthetic adenosine analogs,
either nonselective or preferring the A1 receptor, demonstrate both
antinociception in the normal animal to mechanical stimuli
(Keil and DeLander, 1992), as
well as reversal of the hypersensitivity in animals with inflammation
(Malmberg and Yaksh, 1993).
However, studies in humans suggest that i.t. adenosine itself does not cause
antinociception to acute thermal stimuli
(Eisenach et al., 2002). The
results from the current study are therefore in agreement with previous
results with the endogenous ligand adenosine.
Single nerve fiber recording is a classical and useful method for studies
of peripheral action, since by their nature, they preclude any effect in
central nervous system (Pogatzki et al.,
2002). The lack of effect of i.v. T62 to reduce afferent activity
in either the normal or inflamed condition is consistent with a central, but
not peripheral, site of action of this drug. In contrast, 0.2 µg of i.t.
T62 almost totally reversed the hypersensitivity from carrageenin
inflammation, consistent with a spinal site of action. In agreement with this
hypothesis, we previously demonstrated that the antihypersensitivity effect on
mechanical stimulation of oral T62 following peripheral nerve injury was
reversed by i.t. injection of A1 adenosine receptor antagonist
(Li et al., 2002).
Furthermore, injection of T62 directly in the inflamed paw in the current
study failed to affect thermal hypersensitivity or paw edema, suggesting that
an action for T62 at nerve terminals is unlikely. According to previous
results (Segerdahl and Sollevi,
1998), central sites of actions most likely explain analgesic
actions of adenosine through A1 receptor. In addition to changes in receptive
field area and sensitivity, carrageenin inflammation causes sensitization of
spinal cord neurons (Neumann et al.,
1996). However, the above results do not necessarily support an
absence of A1 receptors at peripheral sites. Although A1 receptors have not
been reported by immunohistochemistry in peripheral afferent terminals, they
are present on dorsal root ganglion cell bodies
(Macdonald et al., 1986) and
central terminals of primary afferent neurons
(Santicioli et al., 1993). In
addition, peripheral A1 receptor activation by synthetic adenosine analogs
(Karlsten et al., 1992) or
metabolism inhibitors (Sawynok et al.,
1998) reduces hypersensitivity in rats with peripheral
inflammation. The lack of efficacy of peripherally applied exogenous adenosine
or T62 in reducing hypersensitivity caused by inflammation is curious in this
regard and may reflect rapid absorption in the case of adenosine or minimal
endogenous adenosine release at the site of inflammation in the case of
T62.
In addition, carrageenin paw injection is a commonly used model of
inflammatory pain, resulting in hypersensitivity to both thermal and
mechanical stimuli following intraplantar injection. The inflammation caused
by carrageenin results in an increase in receptive field size and spontaneous
nerve fiber activity (Woolf and King,
1990; Neumann et al.,
1996). In addition, adenosine A2 receptor activation produces
antiinflammatory effect in rats after carrageenin
(Cronstein et al., 1995). In
the current study, T62 did not alter inflammatory edema, consistent with the
notion that T62 does not act on A2 receptors.
In summary, intrathecal and intravenous, but not local, injection of the positive allosteric modulator of A1 adenosine receptors, T62, reverse hypersensitivity from carrageenininduced inflammation. These results coupled with the lack of effect of T62 in normal animals and its lack of effect on afferent activity, suggest that central, likely spinal, changes in the sensitization uncover the analgesic potential of adenosine and adenosine modulators.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: T62, 2-amino-3-(4-chlorobenzoyl)-5,6,7,8-tetrahydrobenzothiophene; RF, receptive field; CV, conduction velocity; DMSO, dimethyl sulfoxide.
1 Current address: Department of Anesthesiology, The Pennsylvania State
University College of Medicine, Hershey, PA 17033-0850. 
Address correspondence to: Dr. Xinhui Li, Assistant Professor of Anesthesiology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157-1009. E-mail: xli{at}wfubmc.edu
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