Download Effect of Tactile Inputs on Thalamic Responses to Noxious

J Neurophysiol
88: 1185–1196, 2002; 10.1152/jn.00977.2001.
Effect of Tactile Inputs on Thalamic Responses to Noxious
Colorectal Distension in Rat
HONG-QI ZHANG,1 ELIE D. AL-CHAER,2 AND WILLIAM D. WILLIS3
1
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong; and Departments of 2Internal
Medicine and 3Anatomy and Neurosciences, University of Texas Medical Branch, Galveston, Texas 77555
Received 29 November 2001; accepted in final form 22 May 2002
INTRODUCTION
As the highest cognitive center, the brain receives inputs
from different sources for integration. In terms of nociception,
the spinothalamic tract (STT) has traditionally been viewed as
the most important pathway for nociception, including visceral
pain, and previous studies of pain mechanisms have focused
mainly on this pathway and its related projection areas (for
reviews, see Millan 1999; Willis 1979, 1985a– c). There has
Address for reprint requests: H. Q. Zhang, School of Chinese Medicine,
Hong Kong Baptist University, Hong Kong (E-mail: [email protected]).
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been ample evidence to show that viscerosomatic convergence
is a common phenomenon in this pathway (Foreman 1977,
1984; Gokin et al. 1977; Hancock et al. 1970, 1973, 1975; Ness
and Gebhart 1991a,b; Selzer and Spencer 1969a,b; for review,
see Gebhart and Ness 1991). Recent studies, however, have
found that the dorsal column-medial lemniscus (DC-ML) system may also play an important role in nociceptive processing,
in particular for visceral pain (Al-Chaer 1996a– c; Berkley et
al. 1993; Rigamonti et al. 1978). A large number of neurons in
the dorsal column nuclei (DCN) respond to both visceral and
tactile stimulation (for review, see Al-Chaer et al. 1996a;
Berkley and Hubscher 1995; Willis et al. 1999). Recent studies
(e.g., Al-Chaer et al. 1996a– c, 1997a,b, 1998) have demonstrated that the role played by the DC system in mediating
colorectal sensory processing is more important than that of the
ventrolateral pathways to the thalamic ventrobasal complex.
Most DC-ML neurons that respond to visceral painful stimuli
are also sensitive to gentle skin manipulation, such as brushing
(Al-Chaer et al. 1996a,b, 1997a, 1998); therefore it is conceivable that light tactile inputs and nociceptive visceral inputs may
interact at any of several locations along the DC-ML pathway.
The DC-ML pathway, through which light touch information is
conveyed, thus appears to be an important system in which
interactions between visceral and somatic inputs may take
place. As it has been demonstrated that the pelvic visceral
inputs to gracile neurons are largely mediated by the postsynaptic DC pathway originating from neurons around lamina X at
the L6–S1 level, whereas cutaneous inputs are in part conveyed
directly to gracile nucleus by primary afferent fibers (Al-Chaer
et al. 1996a,b, 1998), it may be assumed that interactions
between the two inputs would most likely take place at or
above the level of the DCN.
The hypothesis to be tested in this study is that innocuous
tactile inputs may modulate the transmission of visceral pain
signals at the thalamic level. This interaction may be mutual
in that tactile inputs may inhibit the responses of central
neurons to visceral pain, or vice versa; it may also be
facilitatory instead of inhibitory. Preliminary results of this
study have been reported in abstract form (Zhang et al.
1999a,b).
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0022-3077/02 $5.00 Copyright © 2002 The American Physiological Society
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Zhang, Hong-Qi, Elie D. Al-Chaer, and William D. Willis. Effect
of tactile inputs on thalamic responses to noxious colorectal distension
in rat. J Neurophysiol 88: 1185–1196, 2002; 10.1152/jn.00977.2001.
Recent discoveries of visceral nociceptive inputs sharing the classical
tactile pathway in the dorsal-column medial lemniscus system have
opened a new venue for the investigation of somatovisceral interactions. The current study was designed to determine whether somatic
innocuous inputs modulate visceral nociceptive transmission at the
thalamic level. The investigation was carried out by means of extracellular single-unit recordings in the ventroposterior lateral nucleus of
the thalamus in rats anesthetized with pentobarbital. Noxious visceral
stimulation was achieved by reproducible colorectal distension (CRD,
20 – 80 mmHg) with a balloon catheter. Tactile stimulation was delivered by means of a feedback-controlled mechanical stimulator. The
response of the neurons to CRD was compared before and after the
conditioning procedure by giving tactile stimulation either immediately before CRD or overlapping it. Twenty-five ventroposterior lateral (VPL) thalamic neurons were found among numerous tactile-only
neurons to have convergent inputs from both tactile and visceral
sources. Their responses to CRD were excitatory (19), inhibitory (4),
or bimodal. When cutaneous tactile stimuli were delivered before
CRD, the responses were reduced in 18 cases. The reduction, however, was usually short-lasting, immediately following tactile stimulation and could not be enhanced by a prolonged conditioning procedure. It was unlikely to be attributable to neuronal habituation as the
inverted procedure, CRD stimulation before tactile, often produced
the opposite effect, that is, an enhanced response to skin stimulation.
Repeated CRD could bring about sensitization of the responses of
thalamic neurons as manifested by increased spontaneous discharge,
lowered response threshold, and increased response level. Under such
circumstances, the original effect of tactile stimulation on CRD responses could be weakened. In conclusion, tactile stimulation may in
most circumstances inhibit thalamic neuronal responses to visceral
nociceptive input produced by CRD. However, the effect appears to
be mild and short-lasting at the individual neuronal level in the VPL
thalamus.
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METHODS
Preparation and recording procedures
Stimulation and conditioning procedures
To excite neurons that were sensitive to gentle skin touch, such as
brushing and the application of von Frey hairs with weak bending
forces, mechanical pulses with a consistent displacement were delivered by means of a feedback controlled stimulator (Chubbock 1966).
A vibrotactile stimulus with a frequency of 10 –200 Hz (amplitudes:
50 –500 ␮m) superimposed on a steady skin indentation of 0.2–1 mm
and 20-s duration was delivered via a stimulator probe with a flat tip
(ⱖ2 mm in diameter) put on the most sensitive part of the cutaneous
receptive field as assessed with von Frey hairs (Fig. 1A). When tactile
stimulation was used for the purpose of conditioning, the maximum
neuronal discharge was generated with the smallest possible amplitude (typically 100 ␮m) to avoid spread of skin mechanical pulses to
an unnecessarily large area on the body.
Colorectal distension was achieved by means of a balloon catheter
inserted 1 cm into the rectum and the descending colon via the anus
(Fig. 1C). The balloon catheter was constructed from a latex glove
FIG. 1. Methods for somatovisceral interactions. A: neuronal response to 10-Hz skin pulses (500-␮m amplitude, superimposed
on a 20-s steady skin indentation) delivered to the skin receptive field on the tail mapped with a von Frey hair of 2.8 N in force.
The effect of conditioning skin stimulus on colorectal distension (CRD) response was tested as shown in B, and analysis of
responses and effect of conditioning was based on the formulae shown in C. C: visceral inputs generated by CRD (80 mmHg). The
peristimulus time histograms (PSTH) were constructed based on impulse counts for the spike traces shown above, though
sometimes there appears to be discrepancy due to closely spaced bursting activity of the neuron.
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Results were obtained from 13 male Sprague-Dawley rats (body
weight 240 –300 g) anesthetized with pentobarbital sodium (induction
by 50 – 60 mg/kg ip; maintained with an intravenous infusion of
pentobarbital at ⬃5 mg 䡠 kg⫺1 䡠 h⫺1). The trachea was intubated and
a jugular or femoral vein was cannulated to allow the infusion of
anesthetics. The femoral artery was cannulated in four experiments to
monitor blood pressure changes during the experiment. When the
femoral artery or vein was cannulated, the groin incision was on the
same side as the thalamic recordings to avoid disturbing the cutaneous
receptive fields of thalamic neurons from which recordings were to be
made. The body temperature was monitored and maintained near
37°C by a feedback-controlled blanket. A craniotomy was performed
(right side 12, left 1) above the thalamus.
Single-neuron recordings were carried out extracellularly with the
use of tungsten microelectrodes (125-␮m shank, 5–12 M⍀). The
electrode was advanced stereotaxically into the ventroposterior lateral
(VPL) nucleus of the thalamus according to a rat brain atlas (Paxinos
and Watson 1998). Thalamic neurons that were well isolated from
baseline noise were tested first for their tactile response properties to
somatic stimulation, including receptive field location and size, von
Frey hair sensitivity, the mechanical stimuli to which they responded
best, and the maximum discharge rate (Fig. 1), followed by testing
their responses to colorectal distension (CRD) with pressures ranging
from 20 to 80 mmHg (Fig. 1C). Only those neurons that responded to
both light cutaneous stimuli and CRD were investigated to determine
the interactions between the two modalities.
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finger tied to a 5- to 6-cm length of tygon tubing, inflated, and left
overnight to overcome the tension of the balloon wall (Al-Chaer et al.
1996b). The tubing was connected to a manual pump and, via a T
connector, to a pressure transducer. CRD was accomplished by inflation of the balloon by means of a sphygmomanometer to a pressure of
20 – 80 mmHg for 20 s or longer. Repetition of CRD was at a rate of
no more than once every 4 min to avoid over-stimulation and possible
sensitization of the colon and rectum (see Fig. 4 and DISCUSSION). CRD
stimuli with pressures ⱖ40 mmHg are considered noxious (Ness et al.
1990).
The standard conditioning procedure employed was designed so
that 20-s skin pulses were immediately followed by 20-s CRD at a
predetermined intensity (Fig. 1B). Alternatively, the sequence was
inverted to test the effect of CRD conditioning on tactile responses
(e.g., Fig. 5C) or the two stimuli were given simultaneously (e.g.,
Figs. 6 and 7).
Data-acquisition and analysis procedures
Histological verification of recording sites
A lesion was made at the site of recording or at the end of an
electrode track by passing 100- to 500-␮A DC current for 10 –30 s to
identify the locations of neurons recorded in the thalamus by histological examination. A marker electrode was sometimes left in place
at known coordinates for the same purpose. The fixed brain was
blocked and sectioned at a thickness of 50 ␮m. The locations of
recording sites within the thalamus were verified from nine specimens
by reconstruction of microelectrode tracks based on a rat brain atlas
(Paxinos and Watson 1998).
RESULTS
Among the numerous thalamic neurons that were isolated
using their responses to tactile stimulation, only 27 showed
responses to CRD. With exception of two neurons, all of these
(93%) had skin receptive fields that were detectable by tapping,
brushing, and von Frey hair testing. The 25 neurons with
cutaneous receptive fields were studied for their responses to
CRD as well as the interaction with tactile responses when
CRD was preceded by skin stimulation (Fig. 2). In terms of
their responses to CRD, 19 of the 25 thalamic neurons (76%)
increased their discharge rate above the background activity by
ⱖ20% and, thus, were considered to have an excitatory response to visceral input. Four neurons (16%) showed a ⬎20%
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FIG. 2. Population effect of skin conditioning on CRD responses. n, skin
receptive fields where the preceding tactile stimulation reduced the excitatory
CRD response; –, initial inhibitory CRD response that was further reduced
(enhanced inhibition) by tactile conditioning; ⫻ and 夹, an inconsistent effect;
E, no effect of skin pulses on CRD; I, bimodal neurons not testable for
conditioning effect.
reduction in their responses to CRD in comparison with the
background activity and were classified as having inhibitory
responses. The remaining two neurons showed variable responses to CRD that appeared to be influenced by fluctuations
in background activity, and they were classified as a bimodal
group.
Skin receptive fields
The cutaneous receptive fields of these thalamic neurons
were located in the caudal parts of the body, on the tail,
scrotum, hip region, or hind-limb or -paw (Fig. 2). The sizes
of most cutaneous receptive fields were small, and they were
sharply demarcated (as shown by the examples in Fig. 1A,
inset, and in Figs. 5–7), but three units had large receptive
fields, covering an area as extensive as a whole leg and hip.
Except for the receptive fields on the tail, most skin receptive fields were located contralateral to the thalamic recording site.
The neurons that responded to CRD were mixed among the
abundant neurons that were sensitive to tactile inputs only and
therefore in the locus to which the dorsal column-medial lemniscus projects (see Fig. 8). With only one exception, these
neurons could be activated by von Frey hairs with an average
force of 2.74 ⫾ 0.45 (range 1.65–3.8) Newton (N) and therefore were tactile sensitive neurons. The exceptional neuron was
only activated by a stronger, 4.2 N von Frey hair and probably
had input from deep tissues. The neurons were all most responsive to low-frequency mechanical pulses and therefore
appeared to derive inputs predominantly from hair follicle
receptors in the hairy skin or rapidly adapting receptors of the
glabrous skin (Leem et al. 1993a,b; Talbot et al. 1968). For the
purpose of somatic conditioning, the maximum response was
produced by 10-Hz sinusoidal mechanical pulses with an amplitude ⬍500 ␮m, although other frequencies and steady skin
indentation were often tested as well.
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The activities recorded from isolated neurons were captured by
means of Spike2 software with a CED 1401⫹ data-analysis instrument. The neuronal responses were analyzed on- and off-line mainly
by constructing peristimulus time histograms (PSTH). As there was
often moment-to-moment fluctuation in the thalamic neuronal excitability associated with a change in background activity (see Fig. 4;
also Al-Chaer et al. 1996b; Berkley et al. 1993) in contrast to tactile
neurons (Zhang 1994; Zhang et al. 2001), impulse counts in association with a stimulation procedure were compared with the background activity for the 20-s period immediately before the stimulation
took place (“net response”, see Fig. 1). If the impulse counts during
stimulation were 20% more or less than the background activity, the
neuron was then considered to have an excitatory (Fig. 1A) or inhibitory response (Fig. 1C), respectively.
After recording control responses when a skin stimulus or CRD was
given alone (Fig. 1, A and C), conditioning was carried out with one
stimulus preceding the other to test the interactions between the two
responses. The net impulse counts generated by the testing stimulus
after the conditioning stimulus were compared with the control, the
net impulses taken without conditioning (Fig. 1).
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Inhibitory effect of tactile stimulation on CRD responses
FIG. 3. Inhibition of nociceptive response to
CRD by tactile conditioning. The neuron could
be activated by noxious CRD (⬎40 mmHg),
and the response was a function of the CRD
stimulus intensity (Œ and ‚ in A). It had a tactile
receptive field on the lateral part of the heel and
could be activated by a 3.2 N von Frey hair. The
best response to skin stimulation was generated
by 10-Hz, 500-␮m mechanical pulses (C).
When the CRD was after the skin stimulation,
the response to CRD (● and E in A) was lower
in comparison with the control (Œ, ‚ in A, a
sample shown in C). ● and Œ in A plot the net
response to CRD for the whole 20-s period.
However, the conditioning effect was most obvious immediately following the skin pulses, as
shown by the E and ‚ that plot the first 10-s
CRD net response. The short inhibition was
unlikely attributable to the fatigue or habituation of the neuron, as the longer skin stimulation for 50 and 90 s, as shown in D, did not
bring about a systematic increase in the effect
(see DISCUSSION). The numbers in each histogram are impulse counts for the relevant 20-s
period, and the values with smaller fonts (being
subtracted in D) indicate the background activity level.
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Conditioning tactile stimulation had a predominantly inhibitory effect on later neuronal responses to noxious CRD, manifested as a reduction in impulse counts in response to CRD
with preceding tactile response in comparison with the control
responses. Of the 19 neurons that were excited by CRD, a
reduction in the visceral response was brought about by the
preceding skin stimulation in 16 units for which two examples
are shown in Figs. 3 and 5. The strongest reduction was often
immediately after skin stimulation and lasted for a short time,
⬍10 s (e.g., Figs. 3 and 5). The magnitude of the inhibitory
effect ranged from mild in the majority (e.g., Figs. 3 and 5) to
nearly 100% in a rare case. The remaining three neurons either
showed no effects (2) or inconsistent results in association with
the skin conditioning stimulation. For the four neurons that
initially had an inhibitory response to CRD, the preceding
excitatory tactile response enhanced the inhibition further (i.e.,
the impulse counts were further reduced, see Fig. 1) in two
units or had an inconsistent/complex effect (Figs. 6 and 7). An
example of an excitatory neuronal response to mechanical
stimulation of the skin and inhibitory response to CRD is
shown in Fig. 1. When a mechanical stimulus (10 Hz, 500 ␮m
for 20 s) was delivered to the receptive field on the tail, the
neuron clearly changed its discharge rate, as illustrated by the
well-isolated spikes and the PSTH. In comparison with a
background activity of 45 spikes for a 20-s period before the
stimulation (A1 segment), the neuron had 149 discharges during the 20-s mechanical stimulus (A2), and thus it was excited
by the tactile stimulus, with a net response (A2-A1) of 104/20
s. However, when the noxious CRD (⬎40 mmHg) was applied,
the same neuron responded with fewer impulses in comparison
with the spontaneous background activity. Thus it was considered to have an inhibitory response (Fig. 1C), with net responses of ⫺8, ⫺7, and ⫺19 to 20 s of 40, 60, and 80 mmHg
CRD, respectively. When the 80 mmHg CRD was preceded by
the skin stimulation to test for an interaction, as shown in Fig.
1B, the initial inhibitory response to CRD was further enhanced, as the net response now was ⫺33 in comparison with
⫺19 spikes/20 s generated before the conditioning procedure.
Because there was a 42% change associated with the preceding
tactile stimulation (B) in comparison with the control (C), it
appeared that the neuron’s response to nociceptive CRD was
strongly affected by the somatic conditioning.
Neurons that had excitatory responses to CRD under control
SOMATOVISCERAL INTERACTIONS IN THALAMUS
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FIG. 4. Sensitization of thalamic neurons in response to CRD. A: the
neuronal response to CRD (60 mmHg) at the beginning of the recording
session when the neuron had low spontaneous activity and high threshold for
response. The neuron’s response to CRD (C) as a function of the stimulus
intensity is plotted in the D, bottom curve, along with the averaged (⫾ SD, n ⫽
4) background/spontaneous activity when the CRD intensity was 0. After CRD
was repeated 15 times, the neuron’s spontaneous activity increased, from 50 to
110 imp/20 s as shown by the sample trace in B and the D, top curve. The
threshold for response to CRD was lowered from the 60 mmHg at the
beginning to 20 mmHg in the end, the end response level was higher than the
initial records. The inset in D shows the well-isolated neuronal spikes.
input was lower than that without the conditioning (sample in
E and the bottom curve in A).
Sensitization of thalamic neurons by repeated CRD
An example of the sensitization of the responses of thalamic neurons after repeated CRD is shown in Fig. 4. When
the CRD was delivered, the response threshold at the beginning was high and the neuron only showed a clear
response when the strength of CRD reached 60 – 80 mmHg,
as shown by the trace in A and by impulse counts as a
function of CRD intensity in D. After CRD was repeated for
15 times, the neuron’s responses appeared to have been
sensitized because its spontaneous activity increased dramatically, more than doubling (comparing the averaged
background activity, 50 ⫾ 6.04 vs. 110 ⫾ 14.2 imp/20 s,
when CRD intensity was 0 in Fig. 4D), the threshold for
response to CRD was lowered (from 60 to 20 mmHg), and
the response level was higher than that at the beginning. It
was noted in our experiments that an increased background
activity was often associated with an increased sensitivity to
noxious visceral input (see DISCUSSION). It was further noted
that the sensitized neuron often showed sustained high activity after CRD had ceased (afterdischarge; Fig. 4B).
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circumstances had their noxious visceral responses inhibited by
preceding tactile inputs in 16 of 19 (84%) cases. One example
is shown in Fig. 3 where the neuron’s net responses to CRD at
different pressures under control circumstances are plotted in A
(—) and shown by the example trace and PSTH in B. The
excitatory response of the neuron to the visceral nociceptive
input was a function of the stimulus intensity, increasing from
the near-zero background activity to ⬃80 imp/20 s in response
to 80 mmHg CRD. However, when the CRD response was
preceded by tactile input, 10-Hz mechanical pulses applied to
the skin receptive field on the contralateral heel, the response to
CRD was systematically reduced (Fig. 3A) in comparison with
the control.
It is worth pointing out that the reduction was the strongest
during the initial part of CRD following the somatic stimulation in the majority of the cases (with one exception), as
illustrated by the sample traces in Fig. 3. This effect is shown
in Fig. 3A where the net responses to CRD for the first 10 s are
plotted as ‚ and E. The reduction at 60 mmHg CRD, for
example, was 59% for the first 10 s in comparison with 21%
for the whole 20 s (for 80 mmHg, 43% vs.12% reduction). It is
unlikely, however, that such a short-lasting inhibition is attributable to habituation or fatigue of the neuron as, if it were, the
effect on the CRD response would be more or less a function
of the strength and/or duration of the preceding tactile stimulation. However, this was not the case, as illustrated in Fig. 3D.
When the tactile stimulation was prolonged from the standard
20 s to a longer period, 50 –90 s, the inhibitory effect was not
further enhanced systematically. Although there was a more
obvious reduction in impulse counts after 50 s of skin vibration, the same was not seen when the vibration was even
longer, for example 90 s. The reason for the smaller conditioning effect after the longer somatic stimulation is not altogether
clear, but it may be related to a change in the neuron’s sensitivity to the nociceptive inputs. It was noted that the background, spontaneous activity of the neuron increased gradually
after repeated CRD stimulation, and this change was often
found to be associated with an increase in sensitivity of the
neurons to nociceptive inputs (see Fig. 4). In this case, the
background activity of the neuron was low, 4 imp/20 s at the
start of the test, but it gradually increased with repeated CRD
stimulation and reached 17 imp/20 s when the 90 s trial of skin
vibration as the conditioning stimulus took place. The neuron’s
sensitivity may have been altered by this time and the weak
inhibitory effect may have been obscured or offset by the high
afterdischarge of the sensitized neuron (see the next 2 subsections and DISCUSSION).
For the four neurons that had an inhibitory response to CRD,
the preceding tactile stimulation further enhanced the inhibitory response in two cases; that is, the impulse rate in response
to CRD was further reduced following tactile stimulation (Fig.
1). The other two cells had inconsistent, or rather, more complicated effects from the somatic conditioning. The neuron
whose data are shown in Fig. 6 had a skin receptive field on the
medial side of the hind-paw (D) and could be excited by a von
Frey hair that bent at 2.8 N as well as by a controlled mechanical pulse train (C). The same neuron had an inhibitory response to CRD ⱖ40 mmHg, as shown by the sample trace in
B and the stimulus-response curve in A (top). When CRD was
preceded by a skin pulse train, the net response to the visceral
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Effect of CRD on skin responses
Responses to overlapping stimuli
In two experiments, when the standard conditioning procedures were completed, both somatic and visceral stimuli were
delivered simultaneously in an overlapped manner. One example is shown in Fig. 6F where, when the excitatory somatic
response overlapped with the inhibitory visceral one, the new
FIG. 5. Effects of tactile stimulation on the CRD response and vice versa. The neuron displayed an excitatory
response to the CRD (A). It also had a localized skin
receptive field on the heel of the contralateral foot, which
was sensitive to a von Frey hair of 3.2 N (⫽170 mg; inset
in A). B: when the excitatory skin response preceded the
CRD, it affected the latter in particular during the early part
of the CRD response. The net response to the 20-s CRD
was reduced from 67 to 53 imp, representing a 20% reduction comparing B with A. The reduction in the first 10 s was
most severe, with a net response of only 11 spikes (18
spikes in the first 10 s of CRD, minus 7 spikes in the last
10 s before skin stimulation). This suppression of the CRD
response was not attributable to habituation of the neuron,
as evidenced when the sequence of the stimuli were inverted, CRD before tactile stimulation where the CRD
response did not prevent the skin response at all. Instead,
the response to skin stimulation, in particular the early part,
was enhanced by the preceding CRD (C).
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If the short-lasting suppression of action potentials in response to visceral inputs were due to habituation, the same
could be expected to occur whenever a vigorous excitatory
response of a neuron occurred. However, when the conditioning procedure was inverted (skin vibration after CRD), a reduction in the response to skin vibration was never seen. In 19
cases tested in this arrangement, 8 neurons had their response
to skin stimulation increased, with the remainder showing
either inconsistent and small effect (4) or no change (7) in
association with the preceding CRD. In the example shown in
Fig. 5, the response to CRD was affected in particular during
the first 10 s by the conditioning somatic stimulation (comparing A with B of Fig. 5), but the inverted procedure (CRD before
skin stimulation) brought about an elevation rather than a
reduction in response to skin pulses (Fig. 5C). Furthermore, the
increased activity was most intense immediately following a
vigorous response to CRD. This observation provides further
support for the view that the suppressive effect of tactile
stimulation on the CRD response is a genuine inhibition rather
than habituation.
response level, 84 (⫽255–171) was lower than that of the
purely somatic net response (182 in C). However, the inhibitory effect associated with the skin conditioning stimulation
appeared to be weaker, although a trough is still visible in the
histogram in F, as the net response to CRD alone following the
overlapped stimulation was ⫺11 in contrast to ⫺74 imp/20 s
in E.
Figure 7 shows another example in which a conditioning
effect on an inhibitory CRD response was complex. The response of the neuron to CRD was inhibitory, although the
stimulus-response curve was nonlinear (A, top curve for control CRD response). In this case, the excitatory response to
tactile stimulation did not systematically alter the inhibitory
CRD response that followed as shown by comparing the bottom curve with the top one in A and the sample traces in B and
D (D, net response ⫺48 imp/20 s, in comparison with the
control, ⫺61 imp/20 s in B for CRD 60 mmHg). Instead the
inhibitory response to CRD appeared to be potent enough to
affect the neuron’s response to somatic stimuli when both
stimuli overlapped, as shown in E. The net excitatory response
to skin vibration was reduced practically to zero when the
tactile and visceral stimuli overlapped as shown in E in comparison with C and D. It thus appears that the inhibitory
response to CRD was a strong and dominant drive to this
particular neuron. However, the inhibitory effect on the CRD
response was somehow enhanced by the overlapping stimuli
because the net response to CRD alone was ⫺158 in E in
comparison with that in D, ⫺48 imp/20 s.
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Locations of the neurons in the thalamus
DISCUSSION
Of the nine brain specimens examined histologically, the 22
neurons that showed responses to and interactions between
somatic and CRD stimuli were found to be located in the lateral
part of the ventroposterior lateral (VPL) nucleus, consistent
with previous findings (Al-Chaer 1996b). An example is
shown in Fig. 8 in which two electrode tracks were identified.
Three thalamic cells were recorded in these two penetrations.
Neuron 1 in the lateral track had a skin receptive field on the
proximal part of the tail (sensitive to 2.8 N von Frey hair).
Neuron 2 in the more medial track in VPL had a large receptive
field on the hip and proximal leg. Both neurons 1 and 2 also
responded to convergent inputs from CRD. Neuron 3, also in
the more medial track, could be activated by a 3.6 N von Frey
hair applied on the foot but did not respond to CRD ⱕ60
mmHg. The depths of the cells shown in Fig. 8 are representative for neuronal locations in the thalamus in the current
study, that is, between 5.5 and 7.0 mm [6.5 ⫾ 0.48 (SD) mm]
from the cortical surface. As neurons with convergent somatic
and visceral inputs were mixed among the abundant cells that
responded to light tactile stimuli alone, they appear to be
located at the thalamic center to which the dorsal columnmedial lemniscus projects as verified in the brain specimens
examined and shown in previous studies as well (e.g., AlChaer et al. 1996b; Berkley et al. 1993). From our limited data,
there was no clear tendency for inhibitory neurons to cluster or
to be separate from those that had excitatory responses.
In the current study, we used controlled and reproducible
tactile and visceral nociceptive stimulation to investigate somatovisceral interactions in the thalamus to enhance our understanding of central pain mechanisms. In essence, the tactile
stimulation preceding CRD either caused a reduction in the
thalamic neuronal activity (in the majority of cases) or had no
convincing effect (in the remaining cases; Fig. 2). In no case
did the tactile stimulation increase or exacerbate the CRD
response. This was in contrast to the reversal of the conditioning procedure, CRD before skin stimulation, which resulted in
an exacerbation of the skin response in 8 of 19 neurons tested
(e.g., Fig. 5). Thus it appeared that vibrotactile stimulation
might have an inhibitory effect on nociceptive visceral responses in the majority of viscerosensitive thalamic neurons.
This effect was usually weak and short lasting (Figs. 1, 3, and
5–7) and could not be improved by prolonged somatic conditioning (Fig. 3). On the other hand, a preceding visceral nociceptive input might exacerbate responses to cutaneous stimulation that might help explain the clinical phenomenon of
referred pain (Zhang et al. 1999b). Furthermore, the ongoing
background activity appears to have an important influence on
neuronal sensitivity and responsiveness (Fig. 4), a phenomenon
that might be related to inflammation-related sensitization (AlChaer et al. 1996b; Herbert and Schmidt 1992; Neugebauer et
al. 1989; Schaible and Schmidt 1988; Schaible et al. 1987).
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FIG. 6. Effect of somatic conditioning on inhibitory
CRD responses. The neuron had a skin receptive field on
the hind-paw that could be excited by a light von Frey hair
of 2.8 N (D) and controlled mechanical pulse train (C; 10
Hz, 250 ␮m, superimposed on 0.5-mm step indentation).
The response to CRD ⱖ40 mmHg was inhibitory, as
shown by the sample traces in B, and plotted with Πin the
top curve in stimulus-response relation in A (counting the
net response levels for the 1st 10-s CRD response vs. 10-s
background activity immediately before the stimulation).
When the CRD was preceded by a skin pulse train in E, the
net response to the visceral inputs was lower than that
without the conditioning (A, bottom, E). When the excitatory somatic response overlapped the inhibitory visceral
one in F, the new response level, 84 imp/20 s (⫽ 255–171)
was lower than that of control excitatory skin response
(182 in C and 91 imp/20 s in E) but higher than the
inhibitory response to CRD alone in G (⫺77 imp/20 s).
Furthermore, the impulse count for the after-stimulation
period is 217/20 s in comparison with the background
activity of 171 (representing 27% change). This is in contrast to B and E where there was no such a change when the
background activity was low and when the tests were
conducted earlier.
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H. Q. ZHANG, E. D. AL-CHAER, AND W. D. WILLIS
Methodological concerns
Although many studies have demonstrated somatovisceral interactions in the CNS (e.g., Chung et al. 1984; Gerhart et al.
1981), our study used innocuous vibrotactile pulses for the somatic stimulation and thus differed from most previous ones
where inhibition was brought about by nocigenic stimuli. We
have demonstrated that gentle manipulation of the skin surface
may have a limited effect on thalamic neuronal responses to
visceral nociceptive inputs. For tactile conditioning, we specifically chose mechanical vibrotactile stimulation because it can be
quantitatively reproduced by feedback control, and no nociceptive
inputs are elicited at the amplitudes used in this study. Although
different frequencies were tested at the beginning of each trial, we
found that 10-Hz mechanical pulses were usually the best for the
generation of a maximal skin response. This is perhaps due to the
fact that most if not all thalamic neurons receive convergent inputs
J Neurophysiol • VOL
from many types of cutaneous receptors (Leem et al. 1993a,b;
Talbot et al. 1968; Zhang 1994; Zhang et al. 1996, 2001). Interestingly, several previous studies have also reported that the best
pain relieving effect was produced by low frequency vibration
(Lundeberg et al. 1984; Ottoson et al. 1981). Electroacupuncture
at 1– 4 Hz, with or without small trains of 100-Hz stimuli, often
produces the best pain relieving effect (Eriksson et al. 1979).
The current study used CRD to generate noxious visceral
inputs. In comparison with chemical methods, such as injecting
mustard oil into the colon, this method has the advantage of being
more natural (mimicking lower bowel obstruction that may elicit
pain), reversible and reproducible, which is crucial for an interaction study. As this method involves CRD, mechanical stretch of
the skin may be a concern. However, there was no visible abdominal wall movement with CRD up to the maximum strength
used (80 mmHg) unless the balloon was damaged. Furthermore,
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FIG. 7. Complex somatovisceral response
and interactions. The neuron showed an inhibitory response to CRD as shown by the top curve
in A under the control conditions and by the
sample trace in B. Its response to tactile stimulation on the skin receptive field of the lateral
part of the foot was excitatory as shown in C (10
Hz, 250 ␮m, superimposed on a 0.5-mm steady
indentation). Although the preceding skin pulses
did not significantly affect the CRD response as
shown by the bottom curve in A and the sample
trace in D, overlapping of the 2 stimuli in E
rendered a reduction of the response to skin
stimulation in comparison with the controls (C
and D), with a resultant virtually no net response
(200 –192). However, the inhibitory effect on the
CRD response was somehow enhanced by the
overlapping stimuli that preceded CRD as shown
in E, as the net response to CRD alone is ⫺158
now in comparison with that in D, ⫺48 imp/20 s.
The insets in B and C show superimposed spike
waveforms on an expanded time scale.
SOMATOVISCERAL INTERACTIONS IN THALAMUS
1193
as shown in Fig. 2, most cutaneous receptive fields observed were
located on the tail, scrotum, leg, and foot, regions that are not near
the abdominal area and therefore unlikely to be affected by any
abdominal movement.
The inhibitory effect of conditioning stimulation of the skin
on CRD responses observed in the current study is unlikely to
be attributable to a systemic effect, such as by autonomic
reflexes. First, in those four experiments where blood pressure
was continuously monitored, the change in blood pressure, if
any, in association with the CRD was small, ⬍10 mmHg.
Second, there was no blood pressure change in association with
somatic stimulation, and yet the interaction effect on CRD
response was most obvious immediately following tactile conditioning. As any blood pressure change due to reflex in
association with nociceptive CRD only occurs later than the
neuronal responses (see also Fig. 9 of Jänig 1993), the interaction effect is unlikely to be a reflex effect attributable to the
activation of baroreceptors.
Mechanisms of somatovisceral and tactile-nociceptive
interactions
Numerous studies have shown that viscerosomatic convergence appears to be the rule rather than an exception at both the
J Neurophysiol • VOL
spinal and supraspinal levels, as has been demonstrated by
many electrophysiological studies (for review, see Ness and
Gebhart 1990; Willis and Coggeshall 1991). In this study, the
majority of central neurons responsive to colorectal inputs did
have convergent inputs from the body surface, and almost all
thalamic neurons that responded to colorectal distension had
tactile receptive fields. This is consistent with previous reports
in which the majority of somatovisceral sensitive neurons had
low-threshold responses to skin inputs in monkeys (Al-Chaer
et al. 1998; Brüggemann et al. 1994; Chandler et al. 1992) or
in rats (56%) (Al-Chaer et al. 1996b; Berkley et al. 1993).
In this study, the effect of skin tactile conditioning stimulation on the CRD responses at the single thalamic neuron level
is predominantly inhibitory (Figs. 1, 3, and 5–7). This observation is in general agreement with some of the previous
electrophysiological studies in the dorsal horn of the rat (Ness
and Gebhart 1991a,b), the thalamus of the squirrel monkey
(Brüggemann et al. 1998), and psychophysical observations
that somatic stimulation reduced perception of gut distension in
humans (Coffin et al. 1994). There were also reports that
vibrotactile treatment may have a relieving effect for toothache
and other orofacial pains (Ottoson et al. 1981) as well as acute
and chronic musculoskeletal pain (Lundeberg et al. 1984).
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FIG. 8. Locations of recorded neurons in the thalamus. The section was cut in the coronal plain (corresponding to 2.8 mm caudal to the bregma) (see Paxinos
and Watson 1998) through the left brain. Two electrode
tracks (separation: 0.3 mm) are shown in which 3 cells
were recorded in the ventroposterior lateral (VPL) nucleus. Their locations were reconstructed based on the
recording depth from the cortical surface, taking into the
account the fixation shrinkage factor of 15%. See text for
the response features of these neurons. 3V, the third
ventricle; ml, corpus callosum. Nuclei: MD, mediodorsal;
CM, centromedial; CL, centrolateral; PC, paracentral;
VL, ventrolateral; VM, ventrmedial; LD, laterodorsal; Po,
post thalamic nuclear group; VPM, ventroposterior medial; ZI, zona incerta; Rt, reticular. The scale shows the
depth from the upper surface of the brain.
1194
H. Q. ZHANG, E. D. AL-CHAER, AND W. D. WILLIS
J Neurophysiol • VOL
longed by a long conditioning stimulus, is perhaps determined
by the neuronal circuitry. Of interest is that at the cortical (SII)
level, the inhibition by the preceding conditioning stimulation,
either somatic or visceral, on the following test response was
also reported to be short-lasting, ⬍100 ms (Chernigovskii et al.
1978). At the spinal level, when electrical stimuli were used for
interactions between visceral and cutaneous afferents to modify activity in the ventrolateral column, mutual inhibition was
also short-lasting (⬍300 ms) as assessed by means of cord
dorsum potentials and single-unit discharges (Selzer and Spencer 1969b).
Influence of background neuronal activity
Fluctuations in the background activity appear to reflect
changes in the responsiveness of the neuron as often an
increased ongoing activity is associated with a reduced
threshold and increased response magnitude (Fig. 4) as well
as the appearance of a prominent afterdischarge (Figs. 4 and
6). This finding is consistent with the reports in which
background activity increased along with decreased threshold and increased response level in neurons sensitized by
inflammation in the majority of units (e.g., Al-Chaer et al.
1996b; Schaible et al. 1987). In the case of colorectal
nociception, inflammation of the colon with mustard oil
could induce an increase in the background activity and
facilitate the responses to CRD in central neuron recordings,
including postsynaptic dorsal column and gracile neurons,
as well as neurons in the VPL nucleus of the thalamus
(Al-Chaer et al. 1996a– c, 1997b). To overcome the problem
of changing responsiveness of the neurons in association
with the background change, we always subtracted the background activity from the response impulse counts to derive
the “net response” to compare the effects of different trials,
not withstanding that the response change itself may not
necessarily be in proportion to the changes in the background activity.
Skin receptive fields of visceral nociceptive neurons
The current study has shown that the skin areas that may
interact with colorectal nociception at the thalamic level are
located in the caudal part of the body including the tail, leg and
foot, and perineal and hip regions. In terms of the spinal
segmental arrangement, they are within the lumbosacral dermatomes (Takahashi et al. 1994), the same segments that
innervate the hindgut (L2–S3). Despite having generally
smaller receptive fields on the extremities than those on the
abdominal wall, there was no clear correlation between the
type of interactions, whether excitatory or inhibitory, and the
skin receptive fields from our limited data. Whether the skin
spots, in particular the tender points, where the interactions
take place are related to acupoints and the meridians of traditional Chinese medicine remains to be investigated further,
preferably in primates.
The authors thank G. Gonzales and P. S. Chen for technical assistance.
This work was supported by Hong Kong CERG Grant HKBU2093/01M,
University of New South Wales Faculty of Medicine postdoctoral fellowship
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The suppression of visceral responses observed in this study
is unlikely to be attributable to habituation based on three
arguments. First, the suppression to the same extent of spontaneous neuronal activity was not seen when skin stimulation
was used alone (Figs. 1, 6, and 7) and only occurred when the
CRD response followed. Second, when the conditioning procedure was inverted, CRD before the skin stimulation, the
effect was often (8/19) opposite, that is, the response to the
somatic stimulus that followed was enhanced (Fig. 5). Third,
prolonged skin conditioning does not necessarily produce more
effect, as shown in Fig. 3. If the reduction in CRD response
was due to habituation, it ought to occur after any vigorous
neuronal discharge, but this was not the case. Thus the suppressing effect of the skin stimulation on the CRD response
appears to be a genuine inhibitory effect in which an inhibitory
neuronal circuit is involved.
Excitatory tactile inputs from the body surface may activate inhibitory interneurons along the pathway to the thalamus, and they in turn may suppress the responses of target
neurons to the visceral nociceptive inputs that followed. The
locations in which the inhibitory interneurons reside may
include the nucleus gracilis and/or the ventral posterolateral
nucleus of the thalamus itself. Because it is reported that the
rat VPL nucleus, unlike those of primates, lacks inhibitory
GABAergic interneurons in the ventrobasal complex (for
review, see Paxinos 1995), it is possible that the inhibition
observed in this study takes place mainly at the levels below
the thalamus, in particular the dorsal column nuclei (currently under investigation). Alternatively the skin manipulation may activate the endogenous pain control system by
activating opiate receptors (Yang et al. 1999; for review see
Han 1999); but because the inhibitory effect observed in this
study was usually immediate and short lasting, this mechanism is less likely the explanation.
The current study also demonstrated that the inhibitory
effect on the CRD response was generally weak and short
lasting (Figs. 1, 3, and 5–7) and cannot be improved by
prolonged tactile stimulation (Fig. 3). However, this is consistent with previous reports that the strongest inhibition
from skin only occurs when the stimulation reaches noxious
intensities (Chung et al. 1984; Gerhart et al. 1981). In
monkeys, although some inhibition can be evoked by stimulation of large myelinated axons of a peripheral nerve, the
inhibition is much more powerful if small myelinated or
unmyelinated afferents are stimulated as well (Chung et al.
1984). In Selzer and Spencer’s study (1969b) in which
electrical stimuli were used for interactions between visceral
and cutaneous afferents in the spinal ventrolateral column,
the inhibition of the visceral response did not appear until
the conditioning cutaneous stimulus reached 1.8 –2.0 times
threshold, when A␦ fibers were recruited, and only continuous pinching (not brushing) of the skin over the lateral
thigh strongly inhibited the visceral response. In transcutaneous electrical nerve stimulation (TENS), the stimulus
intensity also needs to be high to generate the best inhibitory
effect (e.g., Lee et al. 1985). Thus it appears that the
nociceptive suppression may still largely depend on a
counter-irritation mechanism rather than on the weak inhibitory effect generated by the light touch as shown in the
present study.
The short-lasting nature of the inhibition, which is not pro-
SOMATOVISCERAL INTERACTIONS IN THALAMUS
to H. Q. Zhang and National Institute of Neurological Disorders and Stroke
Grants NS-11255 and NS-09743.
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