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J Neurophysiol (March 1, 2003). 10.1152/jn.00834.2002
Submitted on Submitted 19 September 2002; accepted in final form 1 November 2002
1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190; and 2Oklahoma Foundation for Digestive Research, Basic Science Laboratories, V. A. Medical Center, Oklahoma City, Oklahoma 73104
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Qin, Chao, Beverley Greenwood-Van Meerveld, Dean A. Myers, and Robert D. Foreman. Corticosterone Acts Directly at the Amygdala to Alter Spinal Neuronal Activity in Response to Colorectal Distension. J. Neurophysiol. 89: 1343-1352, 2003. Administration of glucocorticoids to the amygdaloid nucleus facilitates visceromotor responses to colorectal distension in rats. The aim of this study was to determine if colorectal hypersensitivity develops through central modulation of spinal neuronal activity. Stereotaxic delivery of corticosterone (n = 10) or cholesterol (control, n = 10) onto the dorsal margin of the amygdala was performed on male Fischer-344 rats. Seven days later, extracellular potentials of single L6-S1 spinal neurons were examined for responses to colorectal distension (CRD, 20-80 mmHg, 20 s) in sodium pentobarbital anesthetized and paralyzed animals. The proportions of neurons that responded to noxious CRD in corticosterone-implanted (62/186, 33%) and cholesterol-implanted (55/163, 34%) animals were virtually identical. However, the mean excitatory response of spinal neurons to CRD in corticosterone-treated rats was significantly greater (26.7 ± 2.2 vs. 16.4 ± 1.8 imp/s, P < 0.01) and the duration was longer (37.0 ± 3.9 vs. 25.8 ± 1.5 s, P < 0.05) than in the control group. No significant differences were found in neural responses to nonnoxious and noxious mechanical stimulation of somatic fields between corticosterone-implanted and control groups. In conclusion, our data support the hypothesis that central stimulation of the amygdala by corticosterone sensitizes the lumbosacral spinal neurons that mediate visceromotor reflexes to CRD.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A growing body of
evidence reveals that changes in sensory processing of the CNS occurs
after peripheral sensitization by inflammatory irritants and in models
of neuropathic pain (Cervero 1995
; Gebhart
2000; Urban and Gebhart 1999). These
investigations have focused on peripheral hypersensitivity and the
central sensitization of spinal neurons secondary to peripheral
hyperalgesia. However, the possibility exists that supraspinal nuclei
may trigger and maintain primary central sensitization that results in
peripheral hypersensitivity of somatic structures and visceral organs.
The amygdala, in particular the central amygdaloid nucleus, may be a
candidate for inducing primary central sensitization because it serves
as a key limbic structure involved in autonomic or visceral responses
as well as the behavioral expression of chronic stress and anxiety
(Davis 1992, 1997; Rosen and Schulkin
1998). Stereotaxic delivery of corticosterone to the amygdala
up-regulates the expression of corticosterone-releasing factor (CRF) in
the central amygdaloid nucleus, increases indices of anxiety
(Shepard et al. 2000), and is associated with
hypersensitivity in visceromotor responses to colorectal distension
(CRD) (Greenwood-Van Meerveld et al. 2001). There is
also a direct link between excessive glucocorticoid production and
anxiety that is based on the interpretation of behavioral changes in
rats (Calvo et al. 1998; Corodimas et al. 1994; Lee et al. 1994; Makino et al.
1994a,b; Swanson and Simmons 1989; Watts
and Sanchez-Watts 1995). Several behavioral studies have shown
that manipulation of the amygdala through lesions or opioid stimulation
modulates noxious spinal reflexes induced by somatic stimuli
(Helmstetter et al. 1993; Helmstetter and
Bellgowan 1993; Manning and Mayer 1995a,b).
However, of significance to the current study, the mechanism of
descending influences from the amygdala on the spinal processing of
noxious peripheral inputs from the colon is currently unknown.
The purpose of the present study was to investigate the responses of
single lumbosacral spinal neurons to CRD in rats with corticosterone
micropellets implanted bilaterally on the dorsal margin of the
amygdala. These findings were compared with those observed in control
rats with bilateral implantation of cholesterol on the amygdala. Our
results support the concept that chemical activation of the amygdala
induces colonic hypersensitivity, at least in part, through modulation
of lumbosacral spinal neuronal activity. A preliminary report has been
published in abstract form (Qin et al. 2002).
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal preparation
Experiments were performed on 20 male Fischer-344 rats (Charles
River Inc.) weighing between 230 and 380 g that were fasted overnight with free access to water. Fischer-344 rats were chosen because this strain of rats is considered low-anxiety animals (Glowa and Hansen 1994; Gunter et al.
2000; Pare 1992). To reduce the stress
associated with the laboratory environment, rats were acclimated to the
animal facility for at least 1 week. Amygdala-implanted animals were
randomly divided into two groups: in treated rats (n = 10) micropellets containing corticosterone were stereotaxically implanted bilaterally at the dorsal margin of the amygdala using the
coordinates of Paxinos and Watson (1986), whereas
control rats (n = 10) had cholesterol micropellets
implanted at the same sites (Greenwood-Van Meerveld et al.
2001; Shepard et al. 2000). Briefly, animals
were anesthetized with a combination of ketamine (80 mg/kg ip) and
xylazine (10 mg/kg ip), and rats were mounted in a stereotaxic
headholder. A small hole was made in the skull at the coordinates 2.5 mm posterior to bregma and 4.2 mm right and left of midline. A 25-gauge
stainless steel cannula containing a micropellet of corticosterone (30 µg) or cholesterol (30 µg) was lowered 7.0 mm dorsally from the
dura mater to the dorsal margin of the central amygdaloid nucleus
(Greenwood-Van Meerveld et al. 2001; Shepard et
al. 2000). The micropellet was then expelled; the cannula was
removed, and gel foam was placed in the holes of skull. Analgesic
antibiotic cream was spread around the wound after the skin was closed.
Animals were returned to their cages. Of interest relative to our
experimental paradigm of a 7-day exposure of the amygdala to
glucocorticoids, elevation of peripheral glucocorticoids for only 3 days is insufficient to enhance anxiety. The longer treatments of
corticosterone are consistent with findings that changes in the CNS
following glucocorticoids depend on the duration of treatment
(Lee et al. 1994).
Spinal recordings
Seven days following implantation, animals were anesthetized with sodium pentobarbital (60 mg/kg ip initially, 15-20 mg/kg/h iv for maintenance). The right carotid artery and left jugular vein were cannulated to monitor blood pressure or inject drugs during the experiment, respectively. Paralysis was established with pancuronium bromide (0.2 mg/kg/h ip). A constant volume pump was used to provide artificial ventilation (50-55 strokes/min, 3.0-4.0 ml stroke volume). Body temperature was kept between 37 and 38°C using a thermostatically controlled heating blanket and overhead infrared lamps.
A laminectomy was performed to expose L6-S1 spinal segments for recording spinal neurons. Rats were mounted in a stereotaxic headholder and two spinal clamps attached to a metal frame were fixed at thoracic (T10-T12) and sacral vertebrae. The dura mater of exposed spinal segments was carefully removed. A small well was made with dental impression material and filled with agar (3-4% in saline) to improve recording stability and to protect the dorsal surface of the spinal cord from dehydration. Carbon-filament glass microelectrodes were used to record extracellular action potentials of single spinal neurons in a region from midline to 2 mm lateral and 0-1.2 mm deep from the dorsal surface of L6-S1 segments. We searched for spinal neurons with spontaneous extracellular potentials that were stable and large enough for analysis. Sometimes a burst of discharges that later disappeared could be recorded when the microelectrode was close to a neuron. This brief burst made it possible to find and study responses of neurons that did not have spontaneous activity. Signals were displayed on and stored in a computer using Spike-2 software, and the data were analyzed off-line.
Colorectal distension
To distend the colon, a 4- to 5-cm-long latex balloon connected
to a sphygmomanometer was inserted into the descending colon and
rectum. CRD was produced by inflating the balloon with air pressure (80 mmHg, 20 s) and was used as a noxious search stimulus (Ness
and Gebhart 1987, 1988; Qin et al. 1999).
Neurons responding to CRD at 80 mmHg were tested with this stimulus two
to three times to make sure the responses were consistent. Then graded distensions of 20, 40, 60, and 80 mmHg pressure for 20 s at
>1-min intervals were administered. A stimulus-response curve was
determined successfully in the majority of spinal neurons responsive to
graded CRD. Threshold pressure for the responses was calculated by
extrapolation of least-squares regression line derived from the
stimulus-response curve (Ness and Gebhart 1987, 1988).
Somatic fields
Neurons were characterized for cutaneous receptive fields on the lower body with innocuous stimulation, using a camel-hair brush or light pressure from a blunt probe, and by applying a noxious pinch of skin and muscles with blunt forceps. Neurons were classified as follows: wide dynamic range (WDR) cells responded to brushing the hair or light pressure of the skin and had a greater response to noxious pinching of the somatic field; high-threshold (HT) cells responded to noxious pinching of the somatic field only; low-threshold (LT) cells responded primarily to brushing stimuli. If a cutaneous receptive field was not found, moving the tail (MT) in a clockwise direction was tested.
Histology
To mark spinal recording sites of neurons that responded to CRD,
an electrolytic lesion (50 µA DC, anodal for 20 s, cathodal for
20 s) was made after a neuron was studied. At the end of the experiment, every animal was killed with an overdose of pentobarbital sodium. The lumbosacral spinal cord was removed and placed in 10%
buffered formalin solution. Frozen sections (55-60 µm) of the
lumbosacral cord were viewed to identify lesion sites using the
cytoarchitectonic scheme of Molander et al. (1984).
Data analysis
Original neuronal discharges were stored in a computer using the
CED 1401 capture system (Cambridge, UK) and evaluated using rate
histograms (bin width 1 s). Spontaneous activity of neurons was
determined by counting activity for 10 s and then by dividing by
10 to obtain impulses per second (imp/s). An excitatory response to CRD
(imp/s) was calculated by subtracting the mean of 10 s of
spontaneous activity from the mean of 10 s of the maximal activity during visceral stimulation, whereas an inhibitory response to CRD was
calculated by subtracting the mean of 10 s of minimal activity
during CRD from background activity. For each neuron, a given stimulus
was considered effective if the change in activity was 
20% of
control activity. Duration of responses was measured from the onset of
CRD-evoked responses to the time at which activity returned to control
level. Latency of responses was measured from the onset of CRD to the
point at which activity increased or decreased 20% of control
activity. Statistical comparisons were made using Student's paired or
unpaired t-test and 
2 analysis.
Slopes of stimulus-response curves obtained from cells responding to
graded CRD were compared between corticosterone- and
cholesterol-implanted animals. Comparisons of data were considered statistically different if P < 0.05. Descriptive data
are reported as means ± standard error (SE).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A total of 349 spinal neurons recorded from either the left (n = 321) or the right side (n = 28) of L6-S1 segments of the spinal cord were examined for responses to visceral and somatic stimulation. Noxious CRD (80 mmHg) changed the activity in 62/186 (33%) spinal neurons recorded in corticosterone-implanted rats and in 55/163 (34%) neurons recorded in control animals. Lesions made at the recording sites were identified histologically for 21 CRD-responsive neurons in corticosterone-implanted rats and for 17 neurons in control rats. The majority of neurons with colorectal inputs were located in laminae V, VI, VII, and X, and no significant difference was found in the distribution of neurons responding to CRD between corticosterone-implanted and control groups (Fig. 1).
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Response patterns
Four patterns of neuronal responses to CRD were classified as excitation (E), inhibition (I), excitation-inhibition (E-I), and inhibition-excitation (I-E). Examples of these responses are shown in Fig. 2A-F. No significant differences were found between the proportions of CRD-response patterns in corticosterone- and cholesterol-implanted animals (Fig. 2, G and H). Spinal neurons excited by CRD were divided into the following two groups based on their background activity: silent neurons with low spontaneous activity (<0.5 imp/s) and active neurons with high spontaneous activity (>0.5 imp/s). The ratio of silent and active neurons in corticosterone-implanted rats was similar to those in control animals (14/23 vs. 13/19). A comparison of the characteristics of spontaneous activity and CRD responses of spinal neurons from corticosterone- and cholesterol-implanted animals are presented in Table 1. In general, spontaneous activity of neurons recorded in corticosterone-implanted rats did not differ from those in the control group, except for E-I neurons (Table 1). However, the mean change in activity and duration of response to CRD was significantly greater and longer in E spinal neurons recorded from corticosterone-implanted rats than those recorded from control rats (Table 1). Distribution of the recording sites of the four patterns of responsive neurons to CRD in corticosterone-implanted animals was not different from the control group (Fig. 1).
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Short- and long-lasting responses
Based on the recovery time of neuronal activity to the control
level after termination of noxious CRD (80 mmHg), neurons excited or
inhibited by CRD were further subdivided into the following two
subgroups: neurons with recovery time 
5 s were classified as
short-lasting excitatory (SL-E, Fig. 2A) or inhibitory
(SL-I, Fig. 2C), and neurons with recovery time >5 s were
classified as long-lasting excitatory (LL-E, Fig. 2B) or
inhibitory (LL-I, Fig. 2D). The LL-E neurons were
encountered more frequently in corticosterone-implanted rats compared
with control animals (31/37 vs. 14/32, P < 0.01).
Quantitative analyses of spontaneous activity, excitatory responses to
CRD, duration, and latency of responses in SL-E and LL-E neurons are
shown in Table 2. LL-E neurons
characterized in corticosterone-implanted rats had significantly
greater responses and longer durations of responses than those of LL-E
neurons in control rats. Excitatory responses of SL-E neurons to CRD in
corticosterone-implanted rats also were greater than those in control
rats; however, no significant difference in response duration was found
between corticosterone- and cholesterol-implanted groups (Table 2).
Responses of different groups of spinal neurons to graded CRD (20, 40, 60, 80 mmHg, 20 s for each distension) were then examined in most neurons and indicated that these neurons encode intensity of CRD in a
linear manner. Examples are shown in Fig.
3, A-J. Slopes of
stimulus-response curves of SL-E and LL-E neurons in
corticosterone-implanted rats were significantly higher than those in
control rats with cholesterol implants (Fig.
4, A and B).
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Low- and high-threshold responses
Based on the CRD pressure that produced a response, neurons
excited by CRD were divided into the following two subgroups: LT
neurons responded to intracolorectal pressure 20 mmHg; HT neurons
responded to 40 mmHg pressure of CRD (Andrew and Blackshaw 2001). Examples of these neurons are shown in Fig. 3,
A-J. Neurons in corticosterone-implanted rats were more
likely to have LT responses to CRD than control rats (32/35 vs. 17/30,
P < 0.01, Fig. 3K). There is also a
significant decrease in the percentage of HT neurons responsive to CRD
in corticosterone-implanted rats compared with controls (Fig.
3K). The relationship between neuronal responses and graded
CRD in corticosterone- and cholesterol-implanted groups is shown in
Fig. 4, C and D. The slopes of stimulus-response
curves of LT-E or HT-E neurons in corticosterone-implanted rats were significantly higher than those in control rats (Fig. 4, C
and D). Extrapolated threshold pressures (4.2 ± 1.0 mmHg, n = 30) for excitatory responses to CRD in
control rats were lowered by corticosterone activation of the amygdala
to 1.8 ± 0.5 mmHg (n = 34, P < 0.05).
Responses to somatic inputs
Of 117 neurons responsive to CRD that were tested for somatic inputs, 55/62 (83%) neurons in the corticosterone-implanted group and 50/55 (91%) neurons in the control group received convergent inputs from cutaneous receptive fields and tail rotation. Cutaneous receptive fields were generally on the ipsilateral scrotum, perianal region, lower back, and areas around the zone of the tail. Figure 5, A-C, shows three examples of neurons that received inputs from somatic fields (LT, WDR, and HT). No statistically significant differences in the proportions of somatic field properties of CRD-responsive neurons between corticosterone- and cholesterol-implanted groups were observed (Fig. 5D). Of neurons that did not respond to CRD, 98/124 (79%) neurons in corticosterone-implanted animals and 84/108 (78%) neurons in control animals received somatic inputs. Classes of somatic field properties of these neurons are shown in Fig. 5E; no significant differences were found between corticosterone-implanted and control groups.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous studies have shown that glucocorticoids modulate
amygdaloid function to enhance anxiety-like behavior and visceral hyperalgesia (Greenwood-Van Meerveld et al. 2001;
Shepard et al. 2000). The present study extends these
observations by demonstrating that stereotaxic placement of
corticosterone micropellets at the dorsal margin of the amygdala
exaggerates the responses of lumbosacral spinal neurons to noxious CRD.
The spinal neuronal sensitization produced by chemical activation of
the amygdala induced an increase in excitatory response magnitude and
duration to noxious CRD in lumbosacral spinal neurons and was
associated with a decrease in threshold pressure for excitatory
responses. In general, these results are consistent with changes in
spinal sensory processing secondary to peripheral sensitization
produced by various inflammatory agents and neuropathic manipulations
(Cervero 1995; Gebhart 2000; Urban
and Gebhart 1999). However, in the current study, the colon was
neither inflamed nor infused with agents that would cause primary
peripheral hypersensitivity; the only challenge was stereotaxic implantation of corticosterone on the amygdala.
Spontaneous activity
Central sensitization secondary to peripheral hyperalgesia is
usually accompanied by an increase of spontaneous activity in spinal
neurons responsive to visceral and somatic stimuli (Al-Chaer et
al. 1997; Cervero 1995; Ness and Gebhart
2001; Olivar et al. 2000). For example, acute
inflammation of the colon with mustard oil or turpentine induces an
increase in spontaneous activity of postsynaptic dorsal column or
spinal neurons responsive to colorectal distension
(Al-Chaer et al. 1997; Ness and Gebhart 2001). However, in the present study, no significant difference in spontaneous activity of spinal neurons with excitatory responses to
CRD between corticosterone-implanted and control groups was observed,
although spontaneous activity of excitatory-inhibitory neurons in
corticosterone-implanted rats was lower than in control animals. This
observation suggests that primary central sensitization triggered and
maintained by amygdaloid corticosterone has a different effect on
spinal neuronal responsiveness compared with secondary central
sensitization produced by peripheral inflammatory agents.
SL-E and LL-E responses to CRD
At least six populations of spinal neurons encoding for colorectal
afferent signals were distributed in similar proportions in
corticosterone- and cholesterol-implanted animals. These categories agree with the results published in our previous study (Qin et al. 1999). This discussion will focus on the populations of
spinal neurons with excitatory responses and not the inhibitory
responses, because only the excitatory responses were modified in
corticosterone-implanted animals. Spinal neurons that respond to CRD in
a graded fashion throughout the noxious range are categorized as
short-lasting and long-lasting excitatory responses (Qin et al.
1999) or abrupt and sustained neurons (Ness and Gebhart
1987, 1988). The role of these different subpopulations in the
evocation of CRD-related sensations and reflexes is not yet determined
completely. Some of these neurons have long ascending axonal
projections to the brain, are inhibited by analgesics, and are affected
by spinal inputs from distant segments (Ness and Gebhart 1987,
1988; Ness 2000; Qin et al.
1999). It is reasonable to speculate that the abrupt neurons
are more likely to be involved in the localization of painful events,
whereas neurons with sustained activity are related to the clinical
phenomenon of poor localization of visceral pain (Ness and
Gebhart 2001).
In the present study, an increased responsiveness to CRD was observed
in both the SL-E and the LL-E subgroups of neurons in corticosterone-implanted rats when compared with control rats with
cholesterol implants in the amygdala. Also, spinal neurons with
long-lasting excitatory responses were encountered more frequently, while those with short-lasting responses were found less frequently in
the corticosterone-implanted group compared with the neurons in the
control group. Furthermore, the spontaneous activity of these two
populations of neurons with excitatory responses to CRD was not
different when the two groups of animals were compared. Our
observations differ from those in which spinal neuronal sensitization is secondary to local inflammation of the colon and rectum (Ness and Gebhart 2001). In this earlier study, sustained neurons
show increased spontaneous activity and greater CRD-evoked responses following colorectal inflammation, whereas abrupt neurons have decreased spontaneous activity and CRD-evoked responses. Additionally, the proportions of the two subgroups of excitatory neurons in animals
with inflamed or with normal colons are similar. It should also be
noted that Al-Chaer et al. (1997) show that postsynaptic dorsal column cells have increased spontaneous activity and greater CRD-evoked responses in animals with inflamed colons.
Several reasons can explain these differences observed in spinal
neurons with excitatory responses to CRD, including site and method of
treatment, time after onset of treatment, and the strain of rats.
Previous studies have used the colonic inflammatory model to examine
changes in cell processing in response to CRD, whereas the present
study observed changes in neuronal activity that resulted from
corticosterone stimulation of the amygdala in animals in the absence of
a peripheral sensitizing event, such as colonic inflammation. Central
sensitization of spinal neurons secondary to peripheral hyperalgesia
(Al-Chaer et al. 1997; Ness and Gebhart
2001; Olivar et al. 2000) can be attributed to
sensitization of receptors of peripheral afferent fibers and activation
of silent nociceptors. Ness and Gebhart (2001) suggest
that the neurophysiologic basis for inflammation-induced increases in
reflex responses to CRD is due to an alteration in the balance between
activity of abrupt and sustained neurons. We believe it is most likely
that changes in the visceral afferents did not occur in the present study because the colons in our animal model were not inflamed experimentally. However, we found that activation of descending pathways from the amygdala produced changes in CRD-evoked responses of
SL-E and LL-E neurons.
LT and HT responses to CRD
Low- and high-threshold responses of lumbosacral spinal neurons to
CRD in rats were first identified by Andrew and Blackshaw (2001) and are similar to classification of the responses of
peripheral mechanosensitive afferent fibers or receptors located at the
rat colon (Sengupta and Gebhart 1994). Low-threshold
neurons respond within the nonnoxious range and also to distending
pressure in the noxious range (>20-30 mmHg). High-threshold neurons
do not begin to respond until the distending pressure is at or exceeds pressure that is likely noxious. The present study showed that threshold pressure for excitatory responses of neurons to CRD significantly decreased in corticosterone amygdaloid implanted animals
compared with neurons of control animals. Furthermore, the proportion
of low-threshold neurons responsive to CRD in corticosterone-implanted animals was much higher than those in control animals. The results are
consistent with generalized phenomena, i.e., nociceptive sensitivity for responses to CRD can be increased by colorectal pathological stimuli in both animals and patients with functional gastrointestinal disorders, such as irritable bowel syndrome (Cervero
1995; Gebhart 2000; Mertz et al.
1995; Naliboff et al. 1997). However, we believe that the changes in spinal neuronal threshold for responses to CRD most
likely occurred in the current study because the spinal neurons were
modulated by information transmitted via descending pathways rather
than by changes in activity of the viscerosensory fibers from the
gastrointestinal tract. Visceral afferent traffic very likely remained
the same between the corticosterone-implanted group and the control
group because no treatment was used to induce a colonic inflammation.
However, the decreased threshold for excitatory responses and the
higher proportion of low-threshold neurons responding to CRD after
corticosterone implantation in the amygdala correlate well with a
hypersensitive colon as demonstrated by an exaggerated visceromotor
response to an innocuous colorectal distention (Greenwood-Van Meerveld et al. 2001). We have no evidence to address the
possibility that descending influences from the amygdala might alter
the receptors or afferents transmitting viscerosensory inputs from the
colon. For example, descending pathways might alter efferent outflow to
change the interstitial chemical milieu of receptors of the colon and
thereby increase the afferent activity to spinal neurons.
Responses to somatic inputs
In the current study, there was no significant increase in
responsiveness of lumbosacral spinal neurons, either responsive or
nonresponsive to CRD, to somatic noxious stimulation in animals with
corticosterone amygdaloid implants. These findings suggested that
hyperexcitation of spinal neurons does not accompany sensitization of
somatic fields. Our results agree with previous studies in rats, in
which colonic inflammation increased the neuronal responses to CRD but
did not significantly change the neuronal responses to cutaneous
stimuli and the size of cutaneous receptive fields (Al-Chaer et
al. 1997; Olivar et al. 2000). Clinical studies
in patients with irritable bowel syndrome have shown that enhancement of sensitivity appears to be limited to the gut, since these patients were not hypersensitive to the hand immersion in ice-water test or
electrical stimulation of the hand (Accarino et al.
1995; Cook et al. 1987; Zighelboim et al.
1995). However, there are other clinical studies showing that
patients with irritable bowel syndrome present both visceral
hypersensitivity and cutaneous hyperalgesia in hand and foot
(Chang et al. 2000; Mertz et al. 1995;
Naliboff et al. 1997; Verne et al. 2001).
It is possible that sensory hypersensitivity of somatic structures
resulting from noxious visceral stimuli occurs in deep tissue and
muscles (Giamberardino et al. 1996). In the current
study we cannot answer this question, since we only examined properties
of cutaneous somatic field and did not test responses of deeper somatic
structures (for example, muscles and joints) to noxious peripheral stimuli.
Possible central mechanism
Although the descending effects of acute amygdaloid modulation
have not been studied on visceral nociceptive reflexes, effects of
acute stimulation or lesioning of the amygdala have been examined on
somatic nociceptive reflexes. Under experimental conditions, electrical
stimulation of the amygdala has antinociceptive activity (Oliveira and Prado 1998). Also, bilateral lesions of
the amygdala attenuate the effects of antinociception by suppressing
spinally mediated nociceptive reflexes (Helmstetter et al. 1993,
1998; Manning and Mayer 1995a,b). However, the
long-term effect of amygdaloid modulation with chronic glucocorticoid
administration appears to enhance visceromotor reflex responses to CRD
(Greenwood-Van Meerveld et al. 2001) and, in the present
study, facilitated responses of the spinal neurons. On the other hand,
high intensities of electrical stimulation or higher concentrations of
chemicals at some central sites (e.g., rostroventral medulla) commonly
suppress spinal neuronal responses to CRD and colorectal nociceptive
reflexes, whereas lower intensities of electrical stimulation or lesser concentrations of chemicals at the same site generally facilitate spinal visceral nociception and reflexes (Coutinho et al.
1998; Urban and Gebhart 1998 1999; Urban
et al. 1999; Zhuo et al. 2002; Zhuo and
Gebhart 2002). In the experimental paradigm of this study, modulation of amygdaloid function with corticosterone might produce similar effects as those seen with low concentrations of glutamate applied in the rostroventral medulla (Urban and Gebhart
1998; Zhuo and Gebhart 2002; Zhuo et al.
2002). To explain the sensitization of lumbosacral spinal
neurons observed in the current study, descending pathways from the
amygdala to the spinal cord could facilitate or disinhibit spinal
neurons. It has been suggested that the rostroventral medulla is part
of the descending pathway from the amygdala to the spinal cord that
might be involved in facilitation of nociceptive transmission for
colorectal information in the lumbosacral spinal segments (Urban
and Gebhart 1998; Zhuo and Gebhart 2002;
Zhuo et al. 2002). This possible route is proposed
because of the strong projections that exist from the amygdala to the
periaqueductal gray (Beitz 1982; Gray and
Magnuson 1992; Helmstetter et al. 1998; Rizvi et al. 1991) and from the periaqueductal gray to
the rostroventral medulla (Bodnar 2000; Fields
2000; McGaraughty and Heinricher 2002). An
argument might also be made that the hypersensitivity of spinal neurons
that was observed in the present study might be the result of
decreasing activity of the inhibitory pathways, leading to a
disinhibition. The potential for facilitation from decreased descending
inhibition is significant, since spinal visceral transmission is under
tonic descending inhibition from supraspinal nuclei (Akeyson et
al. 1990; Cervero 1983; Ness and Gebhart
1987, 1988; Qin et al. 2002).
In summary, stereotaxic delivery of corticosterone to the amygdala
enhanced responsiveness of lumbosacral spinal neurons to visceral
inputs from noninflamed colon and rectum. This suggested that
hyperexcitability of spinal sensory processing contributes to
production and development of primary central hypersensitivity originating from some brain sites. The neural mechanisms responsible for generation and maintenance of hyperexcitability states in spinal
neurons responsive to visceral inputs, as seen in the present study,
are unknown. We presumed that the release of descending inhibitory
and/or enhancement of facilitatory activity, as well as activation of
positive feedback loops of spinal and supraspinal structures, could
move the CNS to a new and more excitable state of central
sensitization, in which spinal neurons become more sensitive to
peripheral visceral afferents (Cervero 1995;
Jones 1992; Urban and Gebhart 1999).
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ACKNOWLEDGMENTS |
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The authors thank M. Gibson and M. Maline for animal preparation, and Dr. M. J. Chandler for helpful comments as well as D. Holston for technical assistance.
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants (DK-5728).
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FOOTNOTES |
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Address for reprint requests: C. Qin, Department of Physiology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190 (E-mail: chao-qin{at}ouhsc.edu).
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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  G. Ji and V. Neugebauer Pro- and Anti-Nociceptive Effects of Corticotropin-Releasing Factor (CRF) in Central Amygdala Neurons Are Mediated Through Different Receptors J Neurophysiol, March 1, 2008; 99(3): 1201 - 1212. [Abstract] [Full Text] [PDF]
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 B. Myers and B. Greenwood-Van Meerveld Corticosteroid receptor-mediated mechanisms in the amygdala regulate anxiety and colonic sensitivity Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1622 - G1629. [Abstract] [Full Text] [PDF]
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 V. Neugebauer, W. Li, G. C. Bird, and J. S. Han The Amygdala and Persistent Pain Neuroscientist, June 1, 2004; 10(3): 221 - 234. [Abstract] [PDF]
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C. Qin, B. Greenwood-Van Meerveld, and R. D. Foreman Spinal Neuronal Responses to Urinary Bladder Stimulation in Rats With Corticosterone or Aldosterone Onto the Amygdala J Neurophysiol, October 1, 2003; 90(4): 2180 - 2189. [Abstract] [Full Text] [PDF]
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C. Qin, B. G.-V. Meerveld, and R. D. Foreman Visceromotor and Spinal Neuronal Responses to Colorectal Distension in Rats With Aldosterone Onto the Amygdala J Neurophysiol, July 1, 2003; 90(1): 2 - 11. [Abstract] [Full Text] [PDF]
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, neurons excited
by CRD; 
, neurons inhibited by CRD;
, neurons excited/inhibited by CRD; 
,
neurons inhibited/excited by CRD. B: spinal laminae of gray
matter of L6 segment drawing from Molander et al.
(1984)
