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The Journal of Neuroscience, April 15, 1998, 18(8):3043-3049
Vagotomy-Induced Enhancement of Mechanical Hyperalgesia in the
Rat Is Sympathoadrenal-Mediated
Sachia G.
Khasar1,
Frederick J.-P.
Miao1,
Wilfrid
Jänig2, and
Jon D.
Levine1
1 Departments of Anatomy, Medicine, and Oral and
Maxillofacial Surgery, Division of Neuroscience and Biomedical Sciences
Program, University of California at San Francisco, San Francisco,
California 94143-0452, and 2 Physiologisches Institut,
Christian-Albrechts-Universität zu Kiel, 24098 Kiel, Germany
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ABSTRACT |
We have recently shown that subdiaphragmatic vagotomy enhances
bradykinin-induced hyperalgesic behavior and decreases baseline paw
withdrawal threshold to mechanical stimulation of the hindpaw skin in
rats by a peripheral mechanism. To elucidate the underlying mechanism,
we studied whether lesions of efferent neuroendocrine pathways could
prevent or reverse the potentiating effect of vagotomy. In groups of
sham-vagotomized or vagotomized rats, we surgically removed or
denervated the adrenal medulla. Bradykinin was injected intradermally
into the skin of the dorsal surface of the rat hindpaw. Threshold of
paw withdrawal to mechanical stimulation of the skin was measured.
Vagotomy induced a decrease in mechanical baseline paw withdrawal
threshold and enhancement of bradykinin-induced mechanical hyperalgesic
behavior, both of which were maintained over the 5 week testing period.
Adrenal enucleation or denervation of the adrenal gland by suprarenal
ganglionectomy prevented vagotomy-induced decrease in baseline paw
withdrawal threshold and enhancement of bradykinin-induced
hyperalgesia. In animals that had a demonstrated decrease in baseline
paw withdrawal threshold and enhancement of bradykinin-induced
hyperalgesia 2 weeks after vagotomy, additional denervation of the
adrenal medulla significantly reversed these effects over a 3 week
period.
These results imply that both the decrease in baseline paw withdrawal
threshold and enhancement of bradykinin-induced hyperalgesic behavior
after vagotomy are dependent on a hormonal signal released from the
adrenal medulla and suggest a novel mechanism of sensitization of
cutaneous nociceptors.
Key words:
bradykinin; hyperalgesia; nociception; pain; sympathoadrenal system; vagus
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INTRODUCTION |
In the rat, activity in vagal
afferents from abdominal organs modulates transmission of nociceptive
impulses in the spinal cord and probably elsewhere in the CNS and also
affects experimental pain behavior (Gebhart and Randich, 1992 ; Randich
and Gebhart, 1992; Watkins and Maier, 1995a,b). Recently, we have shown
that bradykinin (BK)-induced mechanical cutaneous hyperalgesia is
significantly enhanced after subdiaphragmatic vagotomy. A similar
effect was seen after cutting the celiac branches of the abdominal
vagus nerve but not after cutting only its gastric and hepatic
branches. Furthermore, baseline mechanical paw withdrawal threshold
decreased after vagotomy. The enhanced mechanical hyperalgesia produced by subdiaphragmatic vagotomy was specific for hyperalgesia induced by
BK. Hyperalgesia induced by the direct-acting hyperalgesic agent
prostaglandin E2 (PGE2) was not affected
by vagotomy (Khasar et al., 1997). These findings argue that
enhancement of BK-induced mechanical hyperalgesia and decrease in
baseline mechanical paw withdrawal threshold after abdominal vagotomy
are produced by a peripheral mechanism. However, as the experimental
results reported in this manuscript show, we do not exclude a central
component in enhancement of BK-induced hyperalgesia after vagotomy, as
predicted by the work of Gebhart and Randich (1992) and Randich and
Gebhart (1992).
In this study, we tested the hypothesis that vagotomy-induced
enhancement of BK-induced mechanical hyperalgesia and decrease in
baseline paw withdrawal threshold to mechanical stimulation are
mediated via a neuroendocrine mechanism. Our results suggest that the
sympathoadrenal system is an essential part of the circuit that
mediates these vagotomy-induced hyperalgesic behaviors.
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MATERIALS AND METHODS |
The experiments were performed on 46 lightly restrained male
Sprague Dawley rats (250-350 gm) purchased from Bantin and Kingman (Fremont, CA) and housed in the animal care facility of the University of California at San Francisco under a 12 hr light/dark cycle. Animal
care and use conformed to National Institutes of Health guidelines.
Experimental protocols were approved by the University of California at
San Francisco Committee on Animal Research. The nociceptive flexion
reflex was quantified using a Basile Algesimeter (Stoelting, Chicago,
IL) that applies a linearly increasing mechanical force to the dorsum
of the rat's hindpaw.
Before using the rats for experiments, they were trained in the paw
withdrawal reflex test at 5 min intervals for 1 hr each day for 5 d. This training procedure reduces variability and produces a stable
baseline paw withdrawal threshold measurement, thereby enhancing the
ability to detect the effect of interventions that modulate nociception
(Taiwo et al., 1989). On the day of the experiments, paw withdrawal
thresholds (in grams) were measured (i.e., rats were again exposed to
the test stimulus) at 5 min intervals for 1 hr. The mean of the last
six paw withdrawal thresholds was determined. This mean is defined as
the baseline paw withdrawal threshold before the injection of a test
agent. BK (0.1-1000 ng) was injected intradermally into the dorsum of
both hindpaws in a volume of 2.5 µl. Thresholds for paw withdrawal
were then redetermined at 10, 15, and 20 min after injection. The mean
of the paw withdrawal thresholds obtained at these three time points is
the mechanical nociceptive threshold at the dose of BK injected.
Increasing doses of BK (each greater than the previous dose) were
injected cumulatively at 25-min intervals. Because we have found that
injection of small volumes of BK locally in one paw does not affect the
threshold of the contralateral paw (our unpublished observation), each
paw was treated as an independent measure.
Surgical procedures. Surgery was performed on rats in groups
of six. Surgical procedures were performed on half of the group, whereas the other half underwent sham surgery as controls.
Subdiaphragmatic vagotomy. After lateral incision of the
abdominal wall in the left upper quadrant, the esophagus was fully exposed at the subdiaphragmatic level (Prechtl and Powley, 1985, 1986;
Miao et al., 1994). The vagus nerve was then dissected free from the
esophagus and cut bilaterally. A 2.0-2.5 cm section of the
subdiaphragmatic vagus nerve, together with its fine branches, was
removed during the surgery. Sham surgery was performed in the same way
but without cutting the abdominal vagus nerve. Changes of paw
withdrawal thresholds to mechanical stimulation after intradermal BK
injections were determined in these rats 7-35 d after vagotomy or sham
vagotomy.
Rats were between 250 and 270 gm in weight at the time of
subdiaphragmatic surgery. Most vagotomized rats did not display any
overt changes in general behavioral pattern. After losing some weight
in the first week after the surgery, most of the rats fully recovered.
If vagotomized rats did not begin to eat within 24 hr after surgery,
then they were unlikely to fully recover; this happened in ~10% of
vagotomized rats. Rats that failed to fully recover from the surgery
were excluded from the experiments.
Adrenal medullectomy. To remove adrenal medullas, the
adrenal glands were located in ether-anesthetized rats through an
incision in the lateral abdominal wall. The capsule of the gland was
cut open, and the adrenal medulla was removed (Wilkinson et al., 1981; Miao et al., 1992). Rats were given 0.5% saline to drink in place of
water for the first 7 d after surgery. Four weeks later, some of
the adrenal-medullectomized rats were vagotomized, as described above.
Adrenal medullectomy was performed at least 5 weeks before mechanical
nociceptive testing. The long postsurgical period was used to allow the
function of the hypothalamo-pituitary-adrenal (HPA) axis to recover;
however, in these rats, stress-induced changes in plasma corticosterone
levels were still somewhat lower than in normal rats (Wilkinson et al.,
1981).
Denervation of the adrenal glands. The greater splanchnic
nerve, the adrenal nerves innervating the adrenal gland, the suprarenal ganglion, and the connection to the celiac ganglion were exposed using
a retroperitoneal approach after making a lateral incision in the
abdominal wall (Celler and Schramm, 1981; Araki et al., 1984). All
connections of the suprarenal ganglion were cut, and the ganglion was
removed. The wounds were closed. In one group of rats, denervation of
the adrenal medullas preceded vagotomy by 7 d. In another group of
rats, the two surgeries were done in the same session. In some rats the
adrenal glands were denervated 2 weeks after subdiaphragmatic vagotomy.
Recovery of the rats was uneventful. Mechanical nociceptive testing in
all groups of rats was started 7 d after surgery.
Groups of rats tested. The groups of rats tested for the
different experimental interventions were independent. For each group of rats undergoing vagotomy, removal of the adrenal medulla, or denervation of the adrenal glands, a sham control group was also studied. Rats in which the time course of decrease of paw withdrawal threshold and of enhanced BK-induced mechanical hyperalgesia after vagotomy and their reversal after denervation of the adrenal glands were studied consisted of three subgroups: (1) rats that were only
vagotomized and that were repeatedly tested over 5 weeks; (2) rats that
were first vagotomized in which the adrenal glands were then denervated
2 weeks later and that were repeatedly tested for 5 weeks after
vagotomy; and (3) rats in which the surgical interventions were the
same as in group 2 but that were only tested before vagotomy and after
denervation of the adrenal glands. An experimental control group of
animals that underwent sham vagotomy was tested repeatedly up to day 35 after surgery to show that baseline paw withdrawal threshold and
BK-induced mechanical hyperalgesia did not change significantly during
repeated testing (see Figs. 4-6).
Statistical analysis. Data are presented as mean ± SEM
and were analyzed statistically using one-factor or repeated-measures ANOVA. The one-factor ANOVA was used to analyze paw withdrawal threshold in the different groups of rats. Data for the vagotomy and
sham vagotomy groups at day 7 were the common reference for the
different experimental groups. Fisher's protected least significant difference post hoc test was used to determine pairs of
groups in which differences occurred. The repeated-measures ANOVA was used to analyze stimulus-response relationships. The accepted level of
significance was p < 0.05.
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RESULTS |
Effect of vagotomy on baseline paw withdrawal threshold and
BK-induced hyperalgesia
Baseline paw withdrawal threshold of sham-vagotomized rats was 108 gm and was significantly decreased to 90 gm 7 d after
subdiaphragmatic vagotomy (SDV) (p < 0.01; Fig.
1). Seven days after SDV, intradermal injection of BK produced significantly greater mechanical hyperalgesia compared with its effect in sham-vagotomized rats (Fig. 1, compare open triangles, closed circles).
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Figure 1.
Baseline and decrease of paw withdrawal threshold
to mechanical stimulation of the dorsum of the rat hindpaw induced by
bradykinin (BK-induced behavioral mechanical hyperalgesia) in
sham-vagotomized rats (closed circles;
n = 18), in vagotomized rats (open
triangles; n = 16), in rats in which
adrenal medullas were removed (adrenal medullectomy) (open
squares; n = 12), and in rats with removed
adrenal medullas and that were also vagotomized (closed
squares; n = 12). Experiments were
conducted 5 weeks after removal of the adrenal medullas and 7 d
after additional vagotomy. Paw withdrawal thresholds of rats that were
only vagotomized and the other three groups of rats were significantly
different (p < 0.05). Paw withdrawal
thresholds of adrenal medullectomized rats and rats that were adrenal
medullectomized and also vagotomized were significantly different
(p < 0.05). Threshold
(ordinate scale, in grams) is defined as the force at
which the rat withdraws its paw. The abscissa scale is
the log dose of BK in nanograms, injected in a volume of 2.5 µl, into
the skin of the dorsal aspect of the hindpaw. In this and subsequent
figures: SDV, subdiaphragmatic vagotomy;
AM, adrenal medullas. Sham-vagotomized and vagotomized
data are the same as those of Khasar et al. (1997), their Figure
1.
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Effect of adrenal medullectomy on baseline paw withdrawal threshold
and BK-induced mechanical hyperalgesia in the presence and absence
vagotomy
In adrenal medullectomized rats, vagotomy produced a small but
significant reduction in the baseline paw withdrawal threshold and a
significant increase in BK-induced hyperalgesia when compared with
adrenal medullectomy alone (p < 0.05; Fig. 1,
compare closed squares, open squares). Adrenal
medullectomized rats that were also vagotomized did not differ
significantly from sham-vagotomized rats in their baseline paw
withdrawal threshold or in response to BK (p > 0.05; Fig. 1, compare closed squares, closed
circles). However, the decrease in paw withdrawal threshold after
vagotomy was significantly larger in animals with intact adrenal
medullas than in animals with removed adrenal medullas
(p < 0.05; Fig. 1, compare closed
squares, open triangles). In rats in which adrenal medullas were surgically excised 5 weeks before experiments, baseline paw withdrawal threshold and BK-induced mechanical hyperalgesia were
not significantly different compared with sham-vagotomized control rats
(p > 0.05; Fig. 1, compare open
squares, closed circles; Table
1).
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Table 1.
Baseline paw withdrawal threshold and paw withdrawal
threshold in response to 1 ng of BK injected intradermally into the
hindpaw in different groups of rats
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Effect of denervation of the adrenal glands on baseline paw
withdrawal threshold and BK-induced mechanical hyperalgesia with or
without vagotomy
If the vagotomy-induced decrease in baseline paw withdrawal
threshold and increase in BK-induced hyperalgesia are mainly adrenal medulla-mediated phenomena, then denervation of the adrenal glands should mimic the effect produced by adrenal medullectomy; this was
indeed the case (compare Figs. 1, 2).
When adrenal-denervated rats were vagotomized, BK-induced hyperalgesia
was significantly greater when compared with BK-induced hyperalgesia in
rats that were only denervated (p < 0.05; Fig.
2, compare closed squares, open squares).
However, this increase in hyperalgesia was much smaller than BK-induced
hyperalgesia after vagotomy alone (Fig. 2, compare closed
squares, open triangles). In control experiments on
rats in which adrenal glands were denervated 7 d before
experiments, the baseline paw withdrawal threshold and BK-induced
mechanical hyperalgesia (Fig. 2, open squares) were not
significantly different from those in sham-vagotomized control rats
(p > 0.05; Fig. 2, compare open
squares, closed circles; Table 1).
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Figure 2.
Baseline and decrease of paw withdrawal threshold
to mechanical stimulation of the dorsum of the rat hindpaw induced by
BK in sham-vagotomized rats (closed circles),
vagotomized rats (open triangles), rats with denervated
adrenal medullas (open squares; n = 6), and vagotomized rats with denervated adrenal medullas
(closed squares; n = 10). In one
case, denervation of the adrenal medullas preceded vagotomy by 7 d. In another, vagotomy and denervation of the adrenal medullas were
performed in the same session. There was no significant difference in
response to BK in these two groups. Therefore, the results were pooled
together. Experiments were conducted 7 d after surgery. Change in
paw withdrawal thresholds between animals that were only vagotomized
and the other three groups of animals was significantly different
(p < 0.05). Change in paw withdrawal
thresholds between rats with denervated adrenal medullas and
vagotomized rats with denervated adrenal medullas was significantly
different (p < 0.05). Data in
sham-vagotomized and vagotomized rats are the same as in Figure
1.
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Effect of denervation of the adrenal glands 14 d
after vagotomy
Although onset of the decrease of baseline mechanical paw
withdrawal threshold and enhanced decrease of paw withdrawal threshold to mechanical stimulation generated by intradermal injection of BK was
observed as early as 24 hr after vagotomy, these changes progressed
slowly and reached peak effects 2-3 weeks after vagotomy. If the
decrease of baseline mechanical paw withdrawal threshold and enhanced
decrease of paw withdrawal threshold to mechanical stimulation
generated by intradermal injection of BK are related to a signal
released from the adrenal medullas that is dependent on activity in
sympathetic preganglionic axons, then one would expect both changes to
be reversed when the adrenal medullas are denervated.
Figure 3 shows that 21 d after
vagotomy (7 d after the denervation of adrenal medullas) there was a
significant reversal of vagotomy-induced enhancement of BK mechanical
hyperalgesia (p < 0.05; compare open
inverted triangles, closed squares). The response to BK
on days 28 (data not shown) and 35 after vagotomy (14 and 21 d
after adrenal medulla denervation) were not significantly different
from each other but still significantly different from sham-vagotomized
rats (p < 0.05; Fig. 3, compare
half-closed squares, closed circles).
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Figure 3.
Baseline and decrease of paw withdrawal threshold
to mechanical stimulation of the dorsum of the rat hindpaw induced by
BK in sham-vagotomized rats (closed circles),
vagotomized rats 14 d after surgery (open inverted
triangles; n = 6), and vagotomized rats in
which adrenal medullas were also denervated 14 d after vagotomy
(n = 6). Experiments were conducted 7 d
(closed squares) or 21 d (half-closed
squares) after denervation of the adrenal medulla in
vagotomized animals. The difference between vagotomized rats at 14 d and rats in which the adrenal medullas were additionally denervated
is statistically significant (p < 0.05) at
7 and 21 d after AM denervation.
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Baseline mechanical paw withdrawal thresholds of vagotomized rats and
vagotomized rats in which adrenal medullas were denervated 14 d
after vagotomy are shown in Figure 4. The
change in paw withdrawal threshold (i.e., the difference between paw
withdrawal threshold elicited by BK and baseline paw withdrawal
threshold; Fig. 5, open
triangles) and the absolute decrease of paw withdrawal threshold to mechanical stimulation (Fig. 6,
open triangles) in response to 1 ng of BK had a time course
similar to the time course of the decrease in baseline paw withdrawal
threshold (Fig. 4, open triangles) over a 5 week period.
Repeated testing of sham-vagotomized control rats over the same period
did not reveal a decrease in paw withdrawal threshold produced by 1 ng
of BK (Figs. 5, 6, closed circles). There was reversal of
both the decrease in baseline paw withdrawal threshold (Fig. 4) and paw
withdrawal threshold attributable to injection of 1 ng of BK (Figs. 5,
6) in vagotomized rats when the adrenal glands were denervated 14 d after vagotomy. The reversal of both parameters was independent of
whether the animals were repeatedly tested in the period between
vagotomy and denervation of the adrenal gland or not (Figs. 4-6,
half-filled squares, inverted closed triangles).
The paw withdrawal thresholds 14 and 21 d after denervation of the
adrenal gland were significantly higher than those measured in the
animals that were only vagotomized (p < 0.01;
Figs. 4-6, compare closed triangles, open
triangles, Table 1). Furthermore, the differences in paw
withdrawal thresholds in response to 1 ng of BK at 14 and 21 d
after denervation of the adrenal gland in vagotomized animals were not
significantly different from those in sham-vagotomized animals that had
repeatedly been tested for 5 weeks after surgery (Fig. 5, compare
closed triangles, half-closed squares with
closed circles).
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Figure 4.
Baseline paw withdrawal threshold in rats before
and 7-35 d after vagotomy (open triangles;
n = 6) and sham vagotomy (closed
circles; n = 8) and in rats that were first
vagotomized, followed by denervation of AM 14 d after vagotomy and
measurements taken up to 35 d after initial surgery. The latter
group of animals consists of two subgroups: rats that were tested after
vagotomy and after additional denervation of the AM (half-closed
squares; n = 6), and rats that were only
tested after additional denervation of the adrenal medullas
(closed inverted triangles; n = 4).
Ordinate scale is threshold in grams. Data of the sham
vagotomy and vagotomy group of rats were significantly different 7 d after vagotomy (p < 0.01). Data of
vagotomized rats with denervated AM and rats that were only vagotomized
were significantly different on days 28 and 35 (p < 0.01). Data between sham-vagotomized
rats and vagotomized rats in which the adrenal medullas were denervated
were not significantly different on days 28 and 35 (p > 0.05). Also see Figures 5 and 6.
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Figure 5.
Magnitude of the hyperalgesia (i.e., the decrease
in paw withdrawal threshold) induced by 1 ng of BK injected
intradermally minus the baseline paw withdrawal threshold for that day
(ordinate scale in grams) in rats before and 7-35 days
after vagotomy (open triangles), in rats before and
7-35 d after sham vagotomy (closed circles), and in
rats that were vagotomized first and in which the AMs were denervated
14 d after vagotomy and measurements taken up to 35 d after
initial surgery. The latter group of animals consisted of two
subgroups: rats that were tested after vagotomy and after additional
denervation of the AM (half-closed squares), and rats
that were only tested after additional denervation of the adrenal
medullas (closed inverted triangles). Data of
vagotomized rats with denervated AM and rats that were vagotomized only
were significantly different on days 21, 28, and 35 (p < 0.01). Data of sham-vagotomized rats
and vagotomized rats in which the adrenal medullas were denervated were
not significantly different on days 28 and 35 (p > 0.05).
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Figure 6.
Change of paw withdrawal threshold in response to
intradermal injection of 1 ng of bradykinin (1) before and 7-35 d
after vagotomy (open triangles), (2) before and 7-14 d
after vagotomy and 7-21 d after additional denervation of the adrenal
medullas (i.e., 21-35 d after vagotomy; half-closed
squares), (3) 21, 28, and 35 d after vagotomy (i.e., 7, 14, and 21 d after additional denervation of the adrenal medullas;
closed inverted triangles), and (4) during repeated
testing of a group of sham-vagotomized rats over 35 d
(closed circles). Data in Figures 4-6 were obtained
from the same groups of rats.
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DISCUSSION |
We have recently found that subdiaphragmatic vagotomy in rats is
followed by a decrease of baseline mechanical paw withdrawal threshold
and by enhancement of mechanical hyperalgesia induced by intradermal
injection of BK. This decrease of BK-induced mechanical hyperalgesia
involves afferents in the celiac branches of the abdominal vagus nerves
(Khasar et al., 1997). Because the hyperalgesic behavior induced by
intradermal injection of PGE2 was not affected by
subdiaphragmatic vagotomy, we suggest that the enhancement of
BK-induced mechanical hyperalgesia was generated by a peripheral mechanism. In the present study we report that decrease of baseline paw
withdrawal threshold and enhancement of BK-induced hyperalgesia by
subdiaphragmatic vagotomy are dependent on the adrenal medullas and
their preganglionic sympathetic innervation. The vagotomy-induced changes do not occur when the adrenal medullas are removed 4 weeks before vagotomy or denervated 7 d before vagotomy or at the same time as vagotomy is performed. The changes are largely reversed when
denervation of the adrenal gland is performed 14 d after vagotomy.
We suggest that vagotomy triggers the activation of sympathetic
preganglionic neurons innervating the adrenal medullas (Fig.
7) probably by removing central
inhibition acting at this sympathetic pathway, thus leading to the
release of a hormonal signal from the adrenal medullas. Interruption of
these sympathetic preganglionic axons (by denervation of the adrenal
glands) (Fig. 7) stops the release of this hormonal signal and
therefore prevents or reverses the decrease of baseline mechanical paw
withdrawal threshold and the enhancement of BK-induced hyperalgesia.
The hormonal signal released from the adrenal medullas has not yet been
identified. Candidates include epinephrine, an enkephalin, or an
enkephalin-containing neuropeptide that is released on impulse activity
in preganglionic sympathetic neurons innervating the adrenal medullas
(Jarry et al., 1985; Engeland et al., 1986).
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Figure 7.
Summary scheme of afferent, central, and efferent
pathways that may be involved in decrease of baseline and BK-induced
paw withdrawal threshold after subdiaphragmatic vagotomy. Activity in
vagal afferents that innervate small and large intestines and project
to the nucleus of the solitary tract (NTS) centrally
inhibit the pathway to preganglionic neurons innervating the adrenal
medullas and neurons of the nociceptive system, e.g., in the dorsal
horn. Interruption of these afferents leads to disinhibition of the
central pathway to the preganglionic neurons innervating the adrenal
medulla and of the central nociceptive system:
(1) subdiaphragmatic vagotomy and
(2) removal or (3)
denervation of the adrenal medullas.
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The decrease of paw withdrawal threshold (baseline as well as after
intradermal injection of BK) after vagotomy takes several days to reach
peak effect, and the recovery after additional denervation of the
adrenal medullas takes several days. The reason for the slow time
course of these changes is not clear at the moment; we are currently
studying the mechanism of this slow time course. The basis of the
decrease in paw withdrawal threshold to mechanical stimulation of skin
may be a decrease in threshold to mechanical stimulation of all or a
subpopulation of cutaneous nociceptors, the recruitment of normally
silent (very high threshold) cutaneous afferents (Kress et al., 1992;
Jänig and Koltzenburg, 1993; Michaelis et al., 1996), or both.
This type of change of sensitivity of a population of cutaneous
nociceptors generated by a hormonal signal in which the release is
regulated by the brain would be a novel mechanism of sensitization of
the population of cutaneous nociceptors.
We have recently shown that activity in vagal afferents that project
through the celiac branches of the abdominal vagus nerves and most
likely innervate small and large intestines can also change the gain of
a nociceptive-neuroendocrine feedback circuit in the control of
neurogenic inflammation in the knee joint synovium. Interruption of the
vagal afferents enhances the gain of the feedback circuit (Miao et al.,
1997a,b). This control circuit acts via the HPA axis to release
corticosterone from the adrenal cortex; the sympathoadrenal system does
not appear to be involved (Green et al., 1995, 1997). In the current
study, vagotomy-induced enhancement of BK mechanical hyperalgesia seems
to be under the control of the sympathoadrenal system, and the HPA axis
does not appear to be involved (our unpublished data). Thus, activity
in vagal abdominal afferents influences two different neural circuits
of the neuraxis in the neuroendocrine control of synovial neurogenic
inflammation and of cutaneous mechanical hyperalgesia, respectively;
one acts through the HPA axis and the central nociceptive system in the neuraxis, and the other acts through the sympathoadrenal axis. A third
mechanism by which vagotomy could affect peripheral transduction mechanisms is via the preganglionic input to the postganglionic sympathetic neuron in the lumbar sympathetic chain. However, we have
previously shown that interruption of the lumbar sympathetic preganglionic fibers (decentralization of the sympathetic chain) does
not affect vagotomy-induced enhancement of BK-induced mechanical hyperalgesia in the rat (Khasar et al., 1997).
Subdiaphragmatic vagotomy is a relatively large intervention that may
affect the animal and therefore also nociceptive behavior. That the
changes in paw withdrawal threshold and in BK-induced hyperalgesic
behavior are nonspecific consequences of vagotomy is unlikely, because
(1) the animals tested remained fairly healthy with no overt change in
their behavior; (2) cutting the celiac branches of the abdominal vagus
nerves also generated enhancement of BK-induced hyperalgesic behavior
without a change in baseline threshold; (3) vagotomized animals with
removed or denervated adrenal medullas did not exhibit the changes in
paw withdrawal threshold to mechanical stimulation; and (4) after
denervation of the adrenal medullas in vagotomized animals the changes
in paw withdrawal threshold to mechanical stimulation were
reversed.
Gebhart and Randich (1992) and Randich and Gebhart (1992) have shown
that electrical stimulation of high-threshold abdominal vagal afferents
leads to depression of nociceptive impulse transmission of dorsal horn
neurons in the lumbar spinal cord and to depression of the tail flick
reflex in rats. Similarly, Foreman (1989) has shown that electrical
stimulation of cardiopulmonary vagal afferents leads to depression of
impulse transmission in spinothalamic neurons that are involved in
cardiac nociception. In our behavioral experiments this central effect
of vagal activity is normally not seen after vagotomy, at least in part
because it is masked by the powerful effect of the endocrine signal
released from the adrenal medulla. However, in animals with
nonfunctioning adrenal medullas, the mechanical paw withdrawal
thresholds to intradermal injection of BK were significantly decreased
after vagotomy, although this decrease was smaller than in animals with
functioning adrenal medullas (Figs. 1, 2). This suggests that
subdiaphragmatic vagotomy has two effects leading to decrease of
baseline paw withdrawal threshold and paw withdrawal threshold in
response to intradermal injection of BK: one that is related to the
adrenal medulla and its preganglionic sympathetic innervation, and
another one that is related to removal of central inhibition of
nociceptive impulse transmission occurring probably in the dorsal horn
(Fig. 7), as would be predicted from the experiments reported by
Gebhart and Randich (1992) and Randich and Gebhart (1992). Thus, we
suggest that there are two different central pathways linked to the
abdominal vagal afferents: one mediating the influence on nociceptive
impulse transmission in the spinal cord, and one influencing activity in sympathetic preganglionic neurons innervating the adrenal medullas (Fig. 7).
As discussed in our previous papers on enhanced BK-induced mechanical
hyperalgesia (Khasar et al., 1997) and on neuroendocrine control of
BK-induced synovial plasma extravasation (Miao et al., 1997a,b), the
changes after vagotomy are generated by the interruption of vagal
afferents. This is now corroborated by the observations obtained on
animals in which the adrenal medullas were removed or denervated before
or after vagotomy. The vagal afferents involved most likely pass
through the celiac branches of the abdominal vagus nerves and innervate
the small and large intestine (Berthoud and Neuhuber, 1994; Berthoud et
al., 1994). Some of them are tonically active (Schwartz and Moran,
1994, 1996). It would be interesting to know whether excitation of
these afferents by physiological stimuli increases the mechanical
baseline paw withdrawal threshold as well as the mechanical paw
withdrawal threshold to intradermal BK.
In conclusion, we have shown that activity in subdiaphragmatic vagal
afferents modulates BK-induced mechanical hyperalgesia and baseline
mechanical paw withdrawal threshold in the rat. Subdiaphragmatic vagotomy decreases baseline paw withdrawal threshold and paw withdrawal threshold to intradermal injection of BK. Most of this decrease is
generated by an endocrine signal released by the adrenal medullas, because denervation or removal of the adrenal medullas prevented these
changes. The decrease is large, and paw withdrawal threshold to
mechanical stimulation after injection of 1 ng of bradykinin may drop
by 40-50 gm (from baseline of 100-110 gm). These results may imply
that (1) the brain is able to regulate sensitivity of nociceptors all
over the body by a neuroendocrine mechanism; (2) sensitivity of
nociceptors can be influenced by changes in parts of the body that are
remote from the location of the nociceptors; and (3) circulating
catecholamines can influence nociceptors in a way that is different
from those reported so far (Jänig and McLachlan, 1994;
Jänig, 1996; Jänig et al., 1996).
| |
FOOTNOTES |
Received Oct. 22, 1997; revised Jan. 8, 1998; accepted Jan. 28, 1998.
This work was supported by National Institutes of Health Grant NS
21445.
Correspondence should be address to Dr. Jon D. Levine, Department of
Medicine, Box 0452, S-1334, University of California at San Francisco,
San Francisco, CA 94143-0452.
| |
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Abstract
Introduction
