Responses and Afferent Pathways of Superficial and Deeper C1–C2
Spinal Cells to Intrapericardial Algogenic Chemicals in Rats
CHAO QIN,1 MARGARET J. CHANDLER,1 KENNETH E. MILLER,2 AND ROBERT D. FOREMAN1
Department of Physiology and 2Department of Cell Biology, University of Oklahoma Health Sciences Center,
Oklahoma City, Oklahoma 73190
1
Received 20 September 2000; accepted in final form 18 December 2000
Address for reprint requests: R. D. Foreman, Dept. of Physiology, University of Oklahoma Health Sciences Center, PO Box 26901, Oklahoma City, OK
73190 (E-mail: [email protected]).
1522
INTRODUCTION
Experimental studies suggest that the clinical expression of
neck and jaw pain resulting from ischemic episodes in the heart
(Sampson and Cheitlin 1971) appears to involve neuronal
processing in the upper cervical segments of the spinal cord.
Results from anatomical and electrophysiological studies have
shown that primary afferent fibers from the trigeminal nerve
converge with upper cervical spinal afferent fibers onto neurons of the C1–C3 segments (Bogduk 1997; Kerr 1961; Pfaller
and Arvidsson 1988). Recent studies have shown that stimulation of cardiac afferent fibers excites C1–C3 neurons that
receive convergent somatic inputs from the neck and jaw
region (Chandler et al. 1996; Zhang et al. 1997). Convergence
of visceral and somatic afferents onto these upper cervical
neurons provides a potential mechanism to describe the neck
and jaw pain that results from an ischemic heart. Previous
studies were designed to examine the convergence of somatic
receptive fields and visceral input from the heart onto C1–C2
spinothalamic tract cells in primates (Chandler et al. 2000). To
expand our understanding about viscerosomatic processing of
cardiac inputs in these segments, the responses of superficial
and deeper spinal neurons in the C1–C2 segments to algogenic
chemical stimulation of cardiac afferent fibers were studied in
rats.
Superficial laminae of the spinal dorsal horn have received
considerable attention as areas of relay and integration of
sensory inputs to the spinal cord since Christensen and Perl
(1970) reported that many superficial dorsal horn neurons were
excited specifically by somatic nociceptors. Many studies have
demonstrated that superficial neurons relay and transmit somatic nociceptive information to the thalamus and other supraspinal regions and are subjected to descending inhibitory
influences (Cervero et al. 1977; Light et al. 1986; Wall et al.
1979; Woolf and Fitzgerald 1983). A few investigators showed
that superficial neurons receive inputs from visceral organs
(e.g., cardiac sympathetic afferents, biliary system, splanchnic
nerve, and colorectal afferents), and some characteristics of
these neurons differed from those located in deep laminae
(Blair et al. 1981; Cervero and Tattersall 1987; Ness and
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Qin, Chao, Margaret J. Chandler, Kenneth E. Miller, and Robert
D. Foreman. Responses and afferent pathways of superficial and
deeper C1–C2 spinal cells to intrapericardial algogenic chemicals in
rats. J Neurophysiol 85: 1522–1532, 2001. Electrical stimulation of
vagal afferents or cardiopulmonary sympathetic afferent fibers excites
C1–C2 spinal neurons. The purposes of this study were to compare the
responses of superficial (depth ⬍0.35 mm) and deeper C1–C2 spinal
neurons to noxious chemical stimulation of cardiac afferents and
determine the relative contribution of vagal and sympathetic afferent
pathways for transmission of noxious cardiac afferent input to C1–C2
neurons. Extracellular potentials of single C1–C2 neurons were recorded in pentobarbital anesthetized and paralyzed male rats. A catheter was placed in the pericardial sac to administer a mixture of
algogenic chemicals (0.2 ml) that contained adenosine (10⫺3 M),
bradykinin, histamine, serotonin, and prostaglandin E2 (10⫺5 M
each). Intrapericardial chemicals changed the activity of 20/106 (19%)
C1–C2 spinal neurons in the superficial laminae, whereas 76/147
(52%) deeper neurons responded to cardiac noxious input (P ⬍ 0.01).
Of 96 neurons responsive to cardiac inputs, 48 (50%) were excited
(E), 41 (43%) were inhibited (I), and 7 were excited/inhibited (E-I) by
intrapericardial chemicals. E or I neurons responsive to intrapericardial chemicals were subdivided into two groups: short-lasting (SL)
and long-lasting (LL) response patterns. In superficial gray matter,
excitatory responses to cardiac inputs were more likely to be LL-E
than SL-E neurons. Mechanical stimulation of the somatic field from
the head, neck, and shoulder areas excited 85 of 95 (89%) C1–C2
spinal neurons that responded to intrapericardial chemicals; 31 neurons were classified as wide dynamic range, 49 were high threshold,
5 responded only to joint movement, and no neuron was classified as
low threshold. For superficial neurons, 53% had small somatic fields
and 21% had bilateral fields. In contrast, 31% of the deeper neurons
had small somatic fields and 46% had bilateral fields. Ipsilateral
cervical vagotomy interrupted cardiac noxious input to 8/30 (6 E, 2 I)
neurons; sequential transection of the contralateral cervical vagus
nerve (bilateral vagotomy) eliminated the responses to intrapericardial
chemicals in 4/22 (3 E, 1 I) neurons. Spinal transection at C6–C7
segments to interrupt effects of sympathetic afferent input abolished
responses to cardiac input in 10/10 (7 E, 3 I) neurons that still
responded after bilateral vagotomy. Results of this study support the
concept that C1–C2 superficial and deeper spinal neurons play a role
in integrating cardiac noxious inputs that travel in both the cervical
vagal and/or thoracic sympathetic afferent nerves.
CERVICAL SPINAL CELL RESPONSES TO CARDIAC NOXIOUS INPUT
METHODS
Experiments were performed in 66 male Sprague-Dawley (Charles
River, Boston, MA) rats weighing between 280 and 440 g. The
Institutional Animal Care and Use Committee of the University of
Oklahoma Health Sciences Center approved the experiments performed in this study. Experiments followed the ethical guidelines of
the International Association for the Study of Pain and the Guide for
the Care and Use of Laboratory Animals (Institute of Laboratory
Animal Resources Commission on Life Sciences and National Research Council 1996; Zimmermann 1983). After the animals were
anesthetized with pentobarbital sodium (60 mg/kg ip), catheters were
inserted into the right carotid artery to monitor blood pressure and into
the left jugular vein to inject saline and drugs. During each experiment, a continuous intravenous infusion of pentobarbital (10 –15 mg 䡠
kg⫺1 䡠 h⫺1 ) was injected to maintain the appropriate level of anesthesia. Animals were paralyzed with pancuronium bromide (0.4
mg/kg ip) and given supplemental doses (0.2 mg/kg ip) as needed to
maintain muscle relaxation during the experiment. After tracheotomy,
a tube was inserted into the trachea and the animal was ventilated with
a positive pressure pump (55– 60 strokes/min, 4.0 –5.0 ml stroke
volume). Arterial pressure and pupil diameter were monitored to
determine the anesthesia level. A thermostatically controlled heating
pad and overhead infrared lamps were used to maintain rectal temperature at 37 ⫾ 1°C.
Rats were mounted in a stereotaxic headholder and stabilized with
a clamp at the T1–T2 vertebrae. After laminectomies were performed
to expose the C1–C2 spinal segments for recording cells and C6–C8
segments for transection of the spinal cord, the dura mater was
carefully removed. Dental impression material was built up on the
tissue and bone surrounding the upper cervical spinal cord to make a
small well that was filled with warm paraffin oil to protect the cord
from dehydration. In some experiments, the upper cervical spinal cord
was covered with warm agar (3– 4% in saline) to improve stability.
Carbon-filament glass microelectrodes were used to record extracellular action potentials of single spinal neurons in the C1–C2 segments,
1–3 mm lateral from midline and 0.0 –1.4 mm deep. The microelectrode was mounted on a micro-manipulator at an angle of 60 –70°
from the vertical in the caudorostral axis. This angled approach made
penetration easier and reduced dimpling of the cord surface during
electrode insertion. We searched for spinal cells with spontaneous
discharges that were large enough for analysis. Sometime a burst of
discharges that later disappeared could be recorded when the microelectrode was close to a neuron. This phenomenon made it possible to
find and study responses of neurons that did not have spontaneous
activity. The search was restricted to depths of 0 – 0.35 and 0.36 –1.40
mm below the cord surface to isolate superficial and deeper neurons,
respectively. The depth selection for the two populations of neurons
was based on neuroanatomical work (Molander et al. 1989) and
electrophysiological studies (Ness and Gebhart 1989; Woolf and
Fitzgerald 1983), which demonstrated that selection of these depths
provided a comparison of superficial neurons in laminae I–III with the
deeper neurons of laminae IV–X in rats. Also, in the present study,
histologic reconstruction of electrolytic lesions in superficial and
deeper laminae of the spinal cord demonstrated that the depth of
electrode penetration accurately reflected the location within the spinal cord.
A catheter was placed in the pericardial sac using a modification of
the procedure described by Euchner-Wamser et al. (1994). The catheter was made of silicone tubing (0.020 ID, 0.037 OD, 14 –16 cm
length), and ⬃10 small holes were made in the distal 2 cm. A high
midline thoracotomy (left costal cartilages of ribs 1–3) was made to
expose the thymus gland and the heart. The thymus gland was opened
on the midline, and the catheter was carefully inserted into the
pericardial sac over the left ventricle. The catheter was fixed in place
by suturing together the two thymus lobes and the layers of the chest
wall. In testing the pericardial catheter, solutions were easily injected
and removed via a 1-ml syringe connected to the catheter.
Cardiac receptors were stimulated chemically with a modified
algogenic chemical mixture to excite both vagal and sympathetic
afferent endings (Handwerker and Reeh 1991). The mixture contained
bradykinin, serotonin, prostaglandin E2, histamine, and adenosine, all
of which may be released during myocardial ischemia (EuchnerWamser et al. 1994; Foreman 1999; Meller and Gebhart 1992). Drugs
were individually dissolved in normal saline to a concentration of
10⫺3 M and kept frozen. On the day of an experiment, stock solutions
were warmed and further diluted in normal saline to concentrations of
10⫺5 M (except adenosine, 10⫺3 M). The protocol for administering
the mixture of algesic chemicals was to inject warm saline (0.2 ml)
into the pericardial sac and withdraw after 60 s to determine volume
effects, to inject 0.2 ml of the chemical mixture and withdraw after
60 s, and to use two saline flushes (0.2 ml each) for rinsing the
chemicals within the pericardial sac. At least 20 min elapsed between
each injection of chemicals.
The vagi and spinal cord were prepared for interrupting visceral
afferent pathways. The left and right cervical vagus nerves were
FIG. 1. Lesion sites of neurons recorded in C1–C2 spinal cord. Drawings of
cervical spinal cord are from Molander et al. (1989). Black circles (●) represent
neurons excited by intrapericardial chemicals. Triangles (Œ) represent neurons
inhibited by intrapericardial chemicals. Squares (■) represent neurons excited/
inhibited by intrapericardial chemicals. I-X, laminae; CCN, central cervical
nucleus; IBN, internal basilar nucleus; LCN, lateral cervical nucleus; LSN,
lateral spinal nucleus; Pyr, pyramidal tract.
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
Gebhart 1989). Quantitative differences in the responses of
superficial and deeper spinal neurons to cardiac afferent inputs
have not been examined previously although early findings in
monkeys show that some superficial neurons of the thoracic
spinal cord are activated by cardiac sympathetic afferents
(Blair et al. 1981).
The purposes of this study were to compare the responses of
C1–C2 superficial and deeper spinal neurons to chemical noxious stimulation of cardiac/pericardial receptors and determine
the afferent pathways that transmit cardiac noxious information
to C1–C2 neurons. Results of this study showed that cardiac
noxious inputs from both vagal and sympathetic afferent pathways could either excite or inhibit C1–C2 spinal neurons. There
are some qualitative and quantitative differences in response
characteristics to chemical stimulation of cardiac afferents and
in somatic field properties between the superficial and deeper
neurons. Excitatory somatic receptive fields for these neurons
varied in size and location and usually included the head, neck,
and jaw regions. These data lend further support to the concept
that C1–C2 neurons play a role in integrating cardiac nociception. A preliminary report of portions of this work has been
published in abstract form (Chandler et al. 1998).
1523
1524
TABLE
C. QIN, M. J. CHANDLER, K. E. MILLER, AND R. D. FOREMAN
1. Responses of C1 and C2 spinal neurons responsive to
intrapericardial chemicals
Segment
Excitation
Inhibition
Excitation/
Inhibition
Total
C1
C2
Total
17
31
48
13
28
41
3
4
7
33/93 (36)
63/160 (39)
96/253 (38)
Values in parentheses are percentages of tested neurons that responded.
TABLE
RESULTS
Intrapericardial injection of the algogenic mixture changed
the activity of 89 of 232 neurons recorded in the left C1–C2
spinal cord and 7 of 21 neurons recorded in the right side.
Lesions made at recording sites were identified histologically
for 77 neurons that responded to intrapericardial chemicals
(Fig. 1). Three patterns of neuronal responses were observed:
excitation (E), inhibition (I), and excitation-inhibition (E-I).
The percentage of neurons that responded with each pattern
was not different for 93 neurons recorded in C1 segment
compared with 160 neurons recorded in C2 segment (Table 1).
Moreover, no differences between response characteristics to
intrapericardial chemicals were found for C1 neurons compared with C2 neurons (Table 2). Of 253 C1–C2 spinal neurons
examined, 106 were recorded from superficial dorsal horn
(depth, ⬍0.35 mm) and 147 were recorded from the deeper
spinal gray matter. Intrapericardial chemicals changed the activity of 20/106 (19%) neurons in the superficial laminae,
whereas 76/147 (52%) neurons in the deeper spinal gray matter
responded (Fig. 2, A and B). The proportion of responsive
neurons in the superficial laminae was significantly less than in
the deeper gray matter (P ⬍ 0.01).
Responses to intrapericardial chemicals
Intrapericardial injections of algogenic chemicals increased
the average activity of 48/96 (50%) C1–C2 spinal neurons from
8.1 ⫾ 1.3 to 21.6 ⫾ 2.6 imp/s. These neurons were subdivided
into two groups based on the time of recovery to control
activity after chemicals were removed: neurons responsive to
intrapericardial chemicals ⬍50 s were classified as short-lasting excitatory (SL-E, n ⫽ 22) and neurons with responses ⬎50
s were classified as long-lasting excitatory (LL-E, n ⫽ 26, Fig.
3, A and B). Table 3 compares the characteristics of SL-E and
LL-E neurons responsive to intrapericardial chemicals. Time to
reach the peaks of the responses in LL-E neurons was significantly longer than those in SL-E cells (P ⬍ 0.05), whereas the
latency to onset of the evoked responses was not different. The
duration of evoked responses after intrapericardial chemicals
were removed was significantly shorter in SL-E neurons
(17.3 ⫾ 3.5 imp/s, range 0 – 49 s) compared with the responses
of LL-E neurons (134.3 ⫾ 13.8 imp/s, range 56 –325 s, P ⬍
0.01). Maximal excitatory change in activity, however, was not
different for the two groups of neurons. No spontaneous ac-
2. Comparison of response characteristics of C1 and C2 spinal neurons excited or inhibited by intrapericardial chemicals
Classes
Segment
n
Spontaneous
Activity, imp/s
Latency, s
Time to
Peak, s
Time to
Recovery, s
Excitatory
Change, imp/s
Inhibitory
Change, imp/s
Excitation
C1
C2
C1
C2
17
31
13
28
5.5 ⫾ 1.5
9.5 ⫾ 1.8
18.6 ⫾ 5.3
13.3 ⫾ 2.5
12.8 ⫾ 2.3
12.6 ⫾ 1.2
12.9 ⫾ 2.4
9.9 ⫾ 0.7
25.8 ⫾ 6.8
29.8 ⫾ 4.2
30.6 ⫾ 6.9
29.2 ⫾ 4.7
75.5 ⫾ 14.8
83.5 ⫾ 15.5
65.2 ⫾ 22.3
84.0 ⫾ 12.8
13.6 ⫾ 2.4
13.5 ⫾ 2.5
/
/
/
/
8.8 ⫾ 2.3
7.8 ⫾ 1.4
Inhibition
Neuronal response characteristics are based upon the response to intrapericardial injection of algogenic chemicals (0.2 ml). Latency represents time from
stimulus onset to response of the neuron as measured from a histogram with 1-s bins; Time to Peak represents time from response of the neuron to maximal
evoked response. Time to Recovery represents time from removal of intrapericardial chemicals to return of cell activity to prestimulus base-line level. Values
are expressed as means ⫾ SE.
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
separated from the carotid artery and silk suture was looped around
each nerve trunk. To determine if cervical spinal cells were excited by
vagal afferents activated with chemical stimulation of the heart, the
algogenic mixture was injected before and after the vagi were
transected. The ipsilateral cervical vagus nerve was cut with a scissors
after gently pulling the tie around the nerve; if the cell still responded
to chemical stimulation of the heart, the contralateral cervical vagus
nerve was cut. If the C1–C2 neuron still responded to chemical
stimulation of the heart after bilateral vagotomy, the spinal cord was
transected at C6–C7 to determine if the cell was activated by cardiac
spinal (sympathetic afferent) input.
Cutaneous receptive fields of spinal neurons were tested for responses to innocuous brushing with a camel-hair brush, pressure with
a blunt stick, and noxious pinching of skin and muscles with a blunt
forceps. Neurons were categorized as follows: wide dynamic range
(WDR) cells were excited by brushing the hair and had a greater
response to noxious pinching of the somatic field; high-threshold (HT)
cells were excited only by noxious pinching of the somatic field;
low-threshold (LT) cells were excited primarily by hair movement. If
a cutaneous receptive field was not found, moving joints (MJ) of the
shoulder and forearm were tested. Outlines and descriptions of receptive fields were recorded manually for all neurons examined.
To mark spinal recording sites, an electrolytic lesion (50 ␮A DC,
anodal for 20 s, cathodal for 20 s) was made at most recording sites
after cells were studied. At the end of the experiment, the animals
were euthanized with an overdose of intravenous pentobarbital sodium or euthanasia-5 solution. The cervical spinal cord was removed
and placed in 10% buffered formalin solution. Frozen sections (55– 60
␮m) were cut to examine the locations of lesions. Laminae were
identified using the cytoarchitectonic scheme of Molander et al.
(l989). The segmental locations of C6–C7 transections also were
confirmed.
Data are presented as means ⫾ SE. Spontaneous activity of neurons
was determined by counting activity for 10 s and then dividing by 10
to obtain impulses per second (imp/s). Changes in neuronal activity
(imp/s) were calculated by subtracting the mean of 10 s of control
activity from the mean of 10 s of the greatest response to stimulation.
For each neuron, a given stimulus was considered effective if the
activity changed ⱖ20% of control activity (Hobbs et al. 1992). Latency to response, time to peak response, time to recovery of control
activity, and mean maximal response (imp/s) were measured after
pericardial drug administration. Statistical comparisons were made
using Student’s paired or unpaired t-test and ␹2 analysis. Differences
were considered statistically significant at P ⬍ 0.05.
CERVICAL SPINAL CELL RESPONSES TO CARDIAC NOXIOUS INPUT
1525
FIG. 2. Comparison of superficial and deeper C1–C2
neurons responsive to intrapericardial chemicals. A: superficial neurons. E, excitatory response; I, inhibitory response;
E-I, excitatory/inhibitory response; NR, neurons not responding to intrapericardial chemicals. B: deeper neurons.
C: number of neurons excited by cardiac afferents. SL-E,
short-lasting excitatory response neurons. LL-E, long-lasting excitatory response neurons. D: number of neurons
inhibited by cardiac afferents. SL-I, short-lasting inhibitory
response neurons. LL-I, long-lasting inhibitory response
neurons.
23) neurons (Fig. 3, C and D, and Table 3). Time to reach the
peaks of inhibitory responses of SL-I neurons was significantly
shorter than those in LL-I neurons (P ⬍ 0.01). Spontaneous
activity of LL-I neurons slowly returned to control levels with
an average time to recovery of 119.6 ⫾ 14.1 s (range 51–302
s), which was significantly longer than SL-I neurons (20.7 ⫾
3.8 s, range 1–50 s; P ⬍ 0.01). Control spontaneous activities
and maximal inhibitory responses were not different for SL-I
and LL-I neurons.
Of 96 neurons that responded to intrapericardial chemicals,
7 deeper neurons had an E-I response. Six E-I neurons exhibited excitation followed by inhibition after chemicals were
withdrawn (Fig. 3E), whereas another E-I neuron exhibited
early inhibition before intrapericardial chemicals were removed (Fig. 3F). Characteristics of E-I neurons are given in
Table 3.
A comparison of the response characteristics of superficial and
deeper spinal neurons responsive to intrapericardial injections of
the chemical mixture is presented in Table 4. In superficial gray
matter, excitatory responses to cardiac afferent input were more
likely to be LL-E than SL-E (Fig. 2C, P ⬍ 0.05), whereas no
significant difference between LL-E and SL-E neurons was found
in deeper laminae. Additionally, latencies to excitatory responses
of superficial LL-E neurons were significantly shorter compared
with LL-E neurons in deeper spinal cord (Table 4, P ⬍ 0.05). In
contrast, no significant differences between the occurrence of SL-I
and LL-I neurons were found in either superficial or deeper
laminae (Fig. 2D), and no differences were found for other characteristics of neurons inhibited by intrapericardial chemicals (Table 4).
Convergence of somatic receptive field and cardiac input
FIG.
3. Response patterns of C1–C2 spinal neurons to intrapericardial
chemicals (IC) and saline injections. A: SL-E response. B: LL-E response. C:
SL-I response. D: LL-I response. E and F: excitatory/inhibitory response.
Somatic receptive fields were found for 226/253 (89%)
C1–C2 neurons tested for their responses to intrapericardial
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
tivity was seen in 7/22 (32%) SL-E neurons and in 1/26 (5%)
LL-E neurons.
Chemical injections in the pericardial sac reduced spontaneous activity of 41/96 (43%) neurons from 14.8 ⫾ 2.3 to 6.5 ⫾
1.4 imp/s (44% of control). Spontaneous activity of these
neurons (14.8 ⫾ 2.3 imp/s, n ⫽ 41) was significantly higher
than spontaneous activity of neurons excited by intrapericardial
injection (8.1 ⫾ 1.3 imp/s, n ⫽ 48; P ⬍ 0.02). Similar to the
E neurons, I neurons responsive to intrapericardial chemicals
were subdivided into two groups: SL-I (n ⫽ 18) and LL-I (n ⫽
1526
TABLE
C. QIN, M. J. CHANDLER, K. E. MILLER, AND R. D. FOREMAN
3. Classes of C1–C2 spinal neurons responsive to intrapericardial chemicals
Classes
n
Spontaneous
Activity, imp/s
Latency, s
Time to
Peak, s
Time to
Recovery, s
Excitatory
Change, imp/s
Inhibitory
Change, imp/s
SL-E
LL-E
SL-I
LL-I
E-I
22
26
18
23
7
7.3 ⫾ 2.2
8.8 ⫾ 1.6
15.3 ⫾ 3.9
14.4 ⫾ 2.9
6.1 ⫾ 1.6
12.9 ⫾ 1.6
12.5 ⫾ 1.5
12.1 ⫾ 1.7
9.9 ⫾ 0.8
15.6 ⫾ 4.7
20.9 ⫾ 3.0
34.7 ⫾ 6.0*
18.3 ⫾ 2.8
37.8 ⫾ 5.8**
14.4 ⫾ 6.3
17.3 ⫾ 3.5
134.3 ⫾ 13.8**
20.7 ⫾ 3.8
119.6 ⫾ 14.1**
50.4 ⫾ 12.7
12.4 ⫾ 2.1
14.5 ⫾ 2.9
/
/
10.0 ⫾ 2.7
/
/
8.4 ⫾ 2.0
8.3 ⫾ 1.6
5.0 ⫾ 1.3
Values are means ⫾ SE. SL-E, short-lasting excitatory response; LL-E, long-lasting excitatory response; SL-I, short-lasting inhibitory response; LL-I,
short-lasting inhibitory response; E-I, excitatory-inhibitory response. * P ⬍ 0.05 and ** P ⬍ 0.01 compared to corresponding activity of SL-E and SL-I neurons.
TABLE
for somatic input. A comparison of the sizes of the somatic
fields revealed additional differences between neurons recorded in the superficial and deeper gray matter. The areas of
somatic fields were measured and were assigned to the following categories: small (ipsilateral, long axis ⱕ3 cm), medium
(ipsilateral, long axis ⬎3 cm), and bilateral fields. Representative samples are illustrated in Fig. 5, A–C. For the superficial
cardiosomatic neurons, 10/19 (53%) had small somatic fields
and 4/19 (21%) had bilateral fields (Fig. 5D). In contrast, 19/61
(31%) of the deeper neurons had small fields and 28/61 (46%)
had bilateral fields. These differences between somatic field
sizes of superficial and deeper neurons were significant (P ⬍
0.05). No differences were found for the medium-sized fields
of the superficial (26%) and deeper (23%) neurons.
Effects of cervical vagotomy
To determine if upper cervical spinal cells were excited by
chemical activation of cardiac vagal afferents, the chemical
mixture was injected before and after the ipsilateral and then
the contralateral cervical vagus nerves were cut. Transection of
the ipsilateral vagus nerve interrupted cardiac noxious input to
8/30 (27%, 6 E, 2 I) neurons (Fig. 6). Examples of an E and an
I neuron are shown in Fig. 7, A and B, respectively. No
significant differences were found in response characteristics
of E and I neurons (Tables 6 and 7, respectively) that still
responded to intrapericardial chemicals after transection of the
ipsilateral vagus nerve.
For 22 (15 E, 7 I) neurons that still responded to cardiac
noxious input after ipsilateral vagotomy, sequential transection
of the contralateral vagus nerve (bilateral vagotomy) eliminated responses to intrapericardial chemicals in 3 E and 1 I
neurons. Figure 7, C and D, shows responses of an E and an I
neuron that were abolished by bilateral cervical vagotomy.
Since four E and two I neurons were lost during contralateral
vagotomy, eight E and four I neurons still responded to intra-
4. Comparison of characteristics of superficial and deeper C1–C2 spinal neurons responsive to intrapericardial chemicals
Classes
Location
n
Spontaneous
Activity, imp/s
Latency, s
Time to
Peak, s
Time to
Recovery, s
Excitatory
Change, imp/s
Inhibitory
Change, imp/s
SL-E
Superficial
Deeper
Superficial
Deeper
Superficial
Deeper
Superficial
Deeper
2
20
9
17
3
15
6
17
7.5 ⫾ 3.7
7.2 ⫾ 2.2
5.1 ⫾ 2.8
10.7 ⫾ 1.9
21.3 ⫾ 12.3
14.1 ⫾ 4.1
11.3 ⫾ 9.9
15.6 ⫾ 3.8
13.0 ⫾ 4.0
12.9 ⫾ 1.6
7.1 ⫾ 2.1
15.3 ⫾ 1.7*
12.7 ⫾ 2.4
12.0 ⫾ 2.0
10.0 ⫾ 1.5
9.8 ⫾ 1.0
25.0 ⫾ 13.1
20.5 ⫾ 2.8
46.7 ⫾ 12.9
28.4 ⫾ 5.9
12.7 ⫾ 3.4
19.5 ⫾ 3.2
44.0 ⫾ 12.2
35.6 ⫾ 6.7
23.5 ⫾ 15.7
16.7 ⫾ 3.4
138.8 ⫾ 19.9
132.0 ⫾ 18.8
12.0 ⫾ 6.2
22.4 ⫾ 4.2
157.8 ⫾ 43.9
106.1 ⫾ 10.4
5.5 ⫾ 2.9
13.1 ⫾ 2.0
16.7 ⫾ 4.9
13.4 ⫾ 3.7
/
/
/
/
/
/
/
/
5.2 ⫾ 2.0
9.1 ⫾ 2.3
7.4 ⫾ 2.9
8.6 ⫾ 1.6
LL-E
SL-I
LL-I
Values are means ⫾ SE. * P ⬍ 0.05 compared to latency of superficial LL-E neurons.
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
chemicals; 98 neurons were superficial and 128 neurons were
in the deeper dorsal horn. Comparisons of receptive field
properties of neurons in superficial and deeper dorsal horn are
presented in Fig. 4. The majority of superficial (73/98; 74%)
and deeper (111/128; 87%) neurons received nociceptive inputs (HT and WDR) from somatic fields (Fig. 4, A and B).
Superficial neurons were significantly less likely to have HT
receptive fields compared with neurons in the deeper dorsal
horn neurons (P ⬍ 0.01), whereas superficial neurons were
significantly more likely to have WDR receptive fields compared with deeper neurons (P ⬍ 0.05). Furthermore superficial
neurons were significantly more likely to have LT receptive
fields (24/98; 24%) than the deeper dorsal horn neurons (7/128;
6%; P ⬍ 0.01). Additionally, 10 deeper neurons responded
only to joint movement (MJ), whereas one superficial cell was
an MJ neuron.
Superficial and deeper neurons were separated into somatic
or cardiosomatic groups based on the absence or presence of
cardiac responses (Fig. 4, C and D). Superficial neurons excited by noxious somatic stimulation (HT and WDR) were
more likely to receive only somatic input (54/73; 74%) than
neurons of the deeper dorsal horn (50/111; 45%; P ⬍ 0.01).
Furthermore HT and WDR superficial neurons with only somatic input were more likely to be classified as WDR (41/54;
76%) than neurons receiving convergent input from the heart
(9/19; 47%; P ⬍ 0.05). It should be noted that both superficial
and deeper cells with LT receptive fields responded only to
somatic stimulation and not to cardiac afferent stimulation
(Fig. 4, C and D). In addition, no differences in somatic field
types were found for cardiosomatic neurons that were classified according to their responses to intrapericardial chemicals
(Table 5).
Stimulation of the somatic fields from the head, neck, and
shoulder areas excited 85 of the 96 neurons that responded to
intrapericardial chemical injections. Ten of the neurons did not
have a detectable somatic field, and one I neuron was not tested
CERVICAL SPINAL CELL RESPONSES TO CARDIAC NOXIOUS INPUT
1527
FIG. 4. Comparison of characteristics of somatic field properties of somatic and cardiosomatic
neurons in superficial and deeper spinal cord. A: all
superficial neurons examined for cardiac input.
B: all deeper neurons examined for cardiac input.
C: properties of somatic and cardiosomatic neurons
in superficial spinal cord. D: properties of somatic
and cardio-somatic neurons in deeper spinal cord.
LT, low threshold; WDR, wide dynamic region;
HT, high threshold; MJ, moving joint.
section at C6–C7 abolished the evoked responses to intrapericardial chemicals in all E and I neurons tested. Thus responses
of 10/22 (45%) neurons to intrapericardial chemicals depended
on spinal (sympathetic afferent) pathways (Fig. 6).
Effects of transection at C6–C7 segments
For 12 neurons (8 E and 4 I) that still responded to intrapericardial chemicals after bilateral vagotomy, transections at
C6–C7 segments were performed to determine if these neurons
were activated by cardiac spinal (sympathetic) input. A comparison of response characteristics of these neurons after spinal
transection is shown in Tables 6 and 7; two neurons (1 E and
1 I) were lost during transection. Spontaneous activity of I
neurons after transection at C6–C7 (n ⫽ 3) was significantly
lower than control activity before or after ipsilateral vagotomy
(n ⫽ 9 and 7, respectively, P ⬍ 0.05), whereas no differences
in spontaneous activity of E neurons were found. Figure 7E
shows an example of an excitatory response that was abolished
by transection at C6–C7 segment of spinal cord. Spinal tranTABLE 5. Somatic input onto C1–C2 spinal neurons responsive to
intrapericardial chemicals
Classes
n
WDR
HT
MJ
Not Found
SL-E
LL-E
SL-I
LL-I
E-I
Total
22
26
18
22
7
95
9
8
7
7
0
31
12
13
8
12
4
49
0
2
0
2
1
5
1
3
3
1
2
10
WDR, wide dynamic range; HT, high threshold; MJ, moving joints.
FIG. 5. Comparison of somatic field size of superficial and deeper neurons
responsive to intrapericardial chemicals. A: examples of small somatic fields.
B: examples of medium fields. C: examples of bilateral fields. D: comparison
of somatic field size of superficial and deeper neurons responsive to intrapericardial chemicals.
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
pericardial chemicals (Fig. 6). Tables 6 and 7 show a comparison of spontaneous activity and evoked responses of C1–C2
spinal neurons to intrapericardial chemicals after bilateral vagotomy. Although evoked responses of E neurons that still
responded to cardiac afferent input after bilateral vagotomy
(n ⫽ 8) were significantly lower than evoked responses before
ipsilateral cervical vagotomy (n ⫽ 21, Table 6), no significant
differences between pre- and postvagotomy responses were
found in those 8 E neurons (8.9 ⫾ 1.6 vs. 7.6 ⫾ 2.2 imp/s,
n ⫽ 8).
1528
C. QIN, M. J. CHANDLER, K. E. MILLER, AND R. D. FOREMAN
6. Excitatory responses of C1–C2 neurons to
intrapericardial chemicals after cervical vagotomy and C6–C7
transection
TABLE
Pre-Transection
FIG. 6. Diagram showing effects of cervical vagotomy and transection at
C6–C7 segments on responses of C1–C2 neurons to intrapericardial injection of
chemicals. ICV, ipsilateral cervical vagotomy. CCV, contralateral cervical
vagotomy. A, abolished; R, responded; L, cell lost after intervention.
DISCUSSION
Activation of cardiac afferents
To examine effects of cardiac noxious input on C1–C2 spinal
neurons, intrapericardial administration of algogenic chemicals
was used as a tool to intensify cardiac nociceptor responses to
noxious stimuli. Previous studies have shown that a mixture of
algogenic chemicals excites nociceptors in a skin-nerve prep-
n
ICVN
CCVN
C6–C7
21
11
7
8.0 ⫾ 1.8
9.2 ⫾ 2.6
7.6 ⫾ 1.7
Excitatory
Change,
imp/s
n
14.3 ⫾ 3.6 15
7.4 ⫾ 4.3 8
6.9 ⫾ 2.6 7
Spontaneous
Activity,
imp/s
Excitatory
Change,
imp/s
8.1 ⫾ 1.5
6.0 ⫾ 1.4
7.0 ⫾ 1.9
11.3 ⫾ 4.4
7.6 ⫾ 2.4
/
Values are means ⫾ SE. ICVN, ipsilateral cervical vagus nerve; CCVN,
contralateral cervical vagus nerve.
aration more potently and with less tachyphylaxis than a single
substance (Handwerker and Reeh 1991) and excites cervical
spinothalamic tract (STT) neurons (Chandler et al. 2000) and
thoracic spinal neurons (Euchner-Wamser et al. 1994). Furthermore these algogenic chemicals excite both sympathetic
and vagal afferents (Meller and Gebhart 1992). It is reasonable
that stimulating cardiac/pericardial receptors with a mixture of
chemicals would be more effective than single algogenic substances, although we did not compare the effects of individual
compounds in this study.
Somatic receptive fields
In the present study, the majority of C1–C2 superficial and
deeper neurons (81%) received nociceptive (HT and WDR)
input from somatic fields. These results agree with studies in
cervical, thoracic, or lumbosacral spinal neurons of rat and cat
(Cervero and Tattersall 1987; Dado et al. 1994; Ness and
Gebhart 1987). The present study showed that superficial neurons were significantly less likely to have HT and more likely
to have LT receptive fields than the deeper dorsal horn neurons. However, the somatic field properties of superficial and
deeper neurons that received convergent input from cardiac
afferents were similar. Thus the differences observed in the
total population are primarily attributed to superficial neurons
FIG. 7. Examples of effects of cervical vagotomy and
spinal transection on spontaneous activity and evoked responses of C1–C2 neurons to IC. A and B: a C1 neuron
excited and a C2 neuron inhibited by intrapericardial chemicals. Their responses were abolished by ICV. C and D: a
C2 neuron excited and a C2 neuron inhibited by intrapericardial chemicals. Their responses were abolished by sequential CCV (bilateral vagotomy). E: a C2 neuron excited
by intrapericardial chemicals. Its response was abolished
by transection at lower cervical spinal cord.
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Results of this study showed that intrapericardial injections
of algogenic chemicals activated 38% of C1–C2 spinal neurons.
Of this population, a significantly larger portion of the neurons
in the deeper laminae responded to this chemical stimulus than
neurons in the superficial laminae (52 vs. 19%). These neurons
exhibited excitation (50%), inhibition (43%), and excitation/
inhibition, which could be either short- or long-lasting. Both
vagal and sympathetic afferent pathways were responsible for
transmitting nociceptive information from the heart to upper
cervical spinal neurons (Fig. 8). In addition, 84% of neurons
responsive to intrapericardial chemicals also received convergent noxious somatic input from head, ears, neck, and shoulder
areas. Superficial neurons tended to have smaller somatic receptive fields than neurons in the deeper laminae.
Transection
Spontaneous
Activity,
imp/s
Post-Transection
CERVICAL SPINAL CELL RESPONSES TO CARDIAC NOXIOUS INPUT
7. Inhibitory responses of C1–C2 neurons to
intrapericardial chemicals after cervical vagotomy and C6–C7
transection
TABLE
Pre-Transection
Transection
n
Spontaneous
Activity,
imp/s
ICVN
CCVN
C6–C7
9
5
3
15.9 ⫾ 3.3
14.3 ⫾ 3.3
10.6 ⫾ 2.9
Excitatory
Change,
imp/s
7.4 ⫾ 2.1
7.7 ⫾ 2.6
6.4 ⫾ 3.0
Post-Transection
n
Spontaneous
Activity,
imp/s
Excitatory
Change,
imp/s
7
4
3
12.5 ⫾ 2.7
12.6 ⫾ 4.6
5.9 ⫾ 1.2
7.8 ⫾ 2.4
7.6 ⫾ 4.3
/
Values are means ⫾ SE.
of algogenic chemicals. Results showed that these injections
changed activity of 38% of the C1–C2 spinal neurons: 19% of
the total number of neurons examined were excited, 16% were
inhibited, and 3% were excited/inhibited. In contrast, a study in
primates showed that algogenic chemical agents into the pericardial sac altered the activity of 68% of C1–C2 spinothalamic
tract neurons; 55% of the total number of neurons examined
were excited and 13% were inhibited (Chandler et al. 2000).
One explanation for the differences between the two studies is
that in monkeys recordings were exclusively from C1–C2 spinothalamic tract neurons (Chandler et al. 2000). Upper thoracic
STT cells in monkeys (Ammons et al. 1985) and spinoreticular
tract cells in cats (Bolser et al. 1989) also are primarily excited
by chemical stimulation of cardiac receptors. It is important to
note that unidentified thoracic spinal neurons in cats sometimes
were inhibited by chemical stimulation of the heart, whereas
identified spinoreticular neurons were either excited or unaffected by a chemical stimulus. The mixed responses of unidentified neurons in cats (Bolser et al. 1989) agree with the
variability of responses seen in the present study in rats. It is
not surprising that a functionally heterogeneous population of
neurons produced variable responses to a uniform stimulus,
since they might serve as excitatory or inhibitory interneurons
as well as neurons projecting to various brain nuclei or to more
caudal spinal segments (Clement et al. 2000; Malick et al.
2000; Qin et al. 1999; Zhang et al. 2000). It also should be
pointed out that species differences might account for some of
the disparities between the results from rats, cats, and primates.
Functional characteristics of response patterns
The long- and short-lasting response patterns of C1–C2 spinal neurons to intrapericardial administration of algogenic substances were similar to the responses reported for the small
population of thoracic spinal neurons in a previous study in rats
(Euchner-Wamser et al. 1994). We propose that the longlasting responses most likely play a role in visceral nociception. The long-lasting responses were most closely correlated
Responses to intrapericardial chemicals
Every spinal neuron recorded in the upper cervical segment
was tested for its responsiveness to intrapericardial injections
FIG. 8. Neural pathways by which cardiac noxious stimulation activates
C1–C2 spinal neurons.
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
that received only somatic input. These observations agree
generally with the study by Cervero and Tattersall (1987), who
reported that somatic neurons receive specific cutaneous inputs
from LT mechanoreceptors or from nociceptors.
Superficial neurons responsive to cardiac input tended to
have smaller somatic fields than deeper neurons. This organization is similar to that described for dorsal horn neurons
responding to stimulation of splanchnic nerves in lower
thoracic spinal cord in cats (Cervero and Tattersall 1987).
However these results differ from those of Ness and Gebhart
(1989), who showed that superficial dorsal horn neurons
excited by colorectal distension have larger cutaneous convergent receptive fields than neurons in deeper spinal laminae of thoracolumbar spinal cord in rats. This difference
may be due to differences in the definition of receptive field
size and the preparation (e.g., spinal segments, recording
electrodes, search stimulus for selection of neurons, anesthesia, etc.).
Cardiac pain during myocardial ischemia is referred to somatic areas on the chest and extends to the shoulder, arms,
upper back, and neck and even to the head and lower jaw
(Sampson and Cheitlin 1971). Ruch (1961) suggested that
visceral pain is referred to somatic structures because visceral
and somatic sensory inputs entering the same segments converge on the same neurons. Angina referred to the chest,
shoulder, and arms generally is attributed to activation of
sympathetic afferent fibers that enter upper thoracic spinal
segments (Kuo et al. 1984; Sampson and Cheitlin 1971; White
1957); primate STT neurons in these segments are strongly
excited by stimulation of cardiac sympathetic afferents (Blair
et al. 1981; Hobbs et al. 1992) and primarily inhibited by vagal
afferent input (Ammons et al. 1983). In contrast, afferent input
from both vagal and cardiopulmonary sympathetic afferent
fibers primarily excited C1–C3 STT cells in primates (Chandler
et al. 1996, 2000) and spinal neurons in rats (Fu et al. 1992;
Zhang et al. 1997). These neurons have excitatory somatic
receptive fields often located on neck and jaw regions. The
results of the present study are consistent with previous findings. In summary, the somatic response patterns of the upper
cervical neurons provide further evidence for a neural mechanism of referred pain that originates in the heart but is perceived in the neck and head.
1529
1530
C. QIN, M. J. CHANDLER, K. E. MILLER, AND R. D. FOREMAN
from the heart that travel in both the vagal and sympathetic
afferent pathways (Meller and Gebhart 1992; Nerdrum et al.
1986). Electrical stimulation of an individual nerve trunk simultaneously excites various types of nerve fibers, including
mechanical, thermal, and chemosensitive afferents, and also
generates a relatively synchronous volley to the spinal neurons.
The single route of transmission, the synchronous volley in the
afferent fibers, and the mixture of fiber types might account for
the predominately excitatory effects of electrical stimulation.
Another explanation for the differences might be the bilateral
activation of vagal and sympathetic afferents with chemical
stimulation. Electrical stimulation of the vagus nerve ipsilateral
to C1–C2 spinal neurons primarily produced excitation,
whereas inhibition occurred in ⬃50% of C1–C2 neurons that
responded to contralateral vagal input (Fu et al. 1992). Thus in
the present study, it is possible that bilateral activation of
afferent fibers with chemical stimulation could result in either
excitation or inhibition depending on the dominance of inputs
from ipsilateral or contralateral pathways.
Response patterns of superficial and deep neurons
Spinal organization
Characteristics of responses to intrapericardial injections of
algogenic chemicals were different for C1–C2 spinal neurons
located in superficial or deeper laminae. Latencies to the excitatory responses of superficial neurons were significantly
shorter than latencies to the responses of cells in deeper laminae. Additionally, in the superficial laminae, excitatory responses of neurons to cardiac afferent input were more likely
to be LL-E than SL-E, whereas no significant differences were
found in responses of neurons in the deeper laminae. Quantitative differences between superficial and deeper viscerosomatic neurons also have been reported in the thoracolumbar
spinal segments of rats when colorectal distension was used as
the noxious visceral stimulus (Ness and Gebhart 1989). We
suggested above that the SL-E responses of spinal neurons
might be due to the activation of mechanosensitive afferent
fibers. Since most neurons in the superficial laminae were
unresponsive to intrapericardiac chemicals, it is possible that
very few mechanosensitive afferent fibers terminate in the
superficial dorsal horn. This possibility is supported also by
evidence that the excitatory responses of SL-E neurons tended
to be less robust than the responses of SL-E neurons in the
deeper dorsal horn. This observation agrees with that of Ness
and Gebhart (1989), who found that maximum responses for
short-latency abrupt neurons in deep lamine were significantly
greater than for superficial neurons.
Intrapericardial chemicals activated 52% of the deeper
C1–C2 spinal neurons in the present study, which was significantly more than the 19% of superficial neurons activated by
the chemical stimulus. These findings differed from those of
Cervero and Tattersall (1987), who found that ⬃65% of both
the superficial and deeper neurons in the lower thoracic spinal
gray matter of cats responded to electrical stimulation of
splanchnic nerves. The differences may be due in part to the
use of electrical stimulation of splanchnic afferent fibers as
well as to the segmental location of the cells and the different
species. We have shown previously that electrical stimulation
of cardiopulmonary sympathetic afferent fibers excites all thoracic spinothalamic tract cells, but ⬍70% of the cells are
excited with chemical stimulation of the heart (Ammons et al.
1985). The lower percentage of neurons activated in C1–C2
segments compared with neurons in lower thoracic segments
might be due partially to the chemical stimulus used in the
present study.
The different response characteristics also might be explained by variations in organization of visceral afferent fibers
in upper cervical segments compared with thoracic segments.
Sympathetic cardiac afferent fibers enter primarily in the T2–T6
spinal segments and not the upper cervical segments (Hopkins
and Armour 1989; Kuo et al. 1984; White 1957). The specific
ascending pathway by which cardiac sympathetic afferent input reaches upper cervical segments has not been resolved. It is
possible that cardiac afferent information reaches C1–C2 neurons via ascending pathways from thoracic to upper cervical
spinal cord (Molenaar and Kuypers 1975, 1978). We have
shown in a previous study that cardiopulmonary sympathetic
input to C1–C3 segments travels bilaterally in the ventrolateral
quadrants of the rat spinal cord but does not involve dorsal
columns (Zhang et al. 1997). Furthermore stimulation of vagal
afferent inputs produces different effects in high cervical segments compared with thoracic segments. Stimulation of vagal
afferent fibers primarily excites C1–C2 STT cells in primates
and spinal neurons in rats but suppresses the activity of primate
C4–S1 STT neurons and rat lumbosacral cells (Ammons et al.
1983; Chandler et al. 1991, 1996; Fu et al. 1992; Hobbs et al.
Comparison to electrical stimulation of cardiopulmonary
afferent fibers
Electrical stimulation of cardiopulmonary sympathetic and
cervical vagal afferent fibers in rats produces excitatory responses in most ipsilateral C1–C3 cells (Fu et al. 1992; Zhang
et al. 1997). In contrast, stimulation of cardiac receptors with
intrapericardiac chemicals produced approximately equal numbers of excitatory and inhibitory responses in C1–C2 spinal
neurons. One possible explanation for these differences is the
types of afferent fibers activated by these different forms of
stimulation. Injections of the algogenic chemicals most likely
excited only chemosensitive and polymodal afferent fibers
Downloaded from http://jn.physiology.org/ by 10.220.33.6 on July 31, 2017
with the long-lasting responses observed for chemosensitive
vagal and sympathetic afferent fibers and dorsal root ganglion
cells that are predominately unmyelinated (Armour et al. 1994;
Baker et al. 1980; Kaufman et al. 1980; Nerdrum et al. 1986).
Because chemosensitive, and not mechanosensitive, afferent
neurons are sensitized with prostaglandins (Nerdrum et al.
1986), intrapericardial injections of the mixture of algogenic
chemicals containing PGE2 might have enhanced the responses
in LL-E or LL-I cells. In contrast to the nociceptive role of the
LL types of neurons, the SL-E or SL-I neurons might have
received inputs from afferent fibers that are more responsive to
mechanical stimulation and are more likely fibers in the Adelta range (Baker et al. 1980). Mechanosensitive sympathetic
afferents respond to chemical injections of bradykinin, but the
responses are shorter lasting and are not sensitized with PGE2
(Nerdrum et al. 1986). Mechanosensitive vagal afferents respond to bradykinin secondary to a change in hemodynamics,
but they do not respond to direct stimulation with bradykinin
(Kaufman et al. 1980).
CERVICAL SPINAL CELL RESPONSES TO CARDIAC NOXIOUS INPUT
1989; Ren et al. 1989). Different patterns of termination in
upper cervical segments for cardiac information might partially
account for different effects observed in C1–C2 neurons compared with responses to visceral inputs in thoracic neurons. No
anatomical studies have been done to elucidate the terminations of cardiac afferent information in the upper cervical
segments.
Relative contribution of vagal and sympathetic afferents
The authors thank Drs. J. P. Farber and R. W. Blair for helpful comments as
well as D. Holston and C. J. Jou for excellent technical assistance and
preparation of the figures.
This work was supported by National Institute of Neurological Disorders
and Stroke Grant NS-35471.
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Intrapericardial administration of algogenic chemicals most
likely excites both vagal and sympathetic afferent fibers
(Meller and Gebhart 1992); therefore both of these pathways
were candidates for transmission of nociceptive cardiac information to C1–C2 neurons. In this study, bilateral vagotomy
abolished the responses of 12/22 (55%) neurons that were not
lost during the procedure, and transection of C6–C7 segments
abolished the responses of the remainder of the neurons (45%).
These data are consistent with the concept that both vagal and
sympathetic inputs influence processing of nociceptive sensory
information in C1–C2 neurons of rats. These results differ,
however, from those reported by Chandler et al. (2000), which
showed that vagal fibers were the primary pathway for transmission of nociceptive information from the heart to C1–C2
STT cells of the primate. The differences may be due to
specific selection of STT cells as opposed to the heterogeneous
population examined in the present study. In addition, there
may be a species difference. The evidence that vagal afferent
fibers transmit nociceptive information from the heart to the
upper cervical segments agrees with the speculation from clinical observations that the vagus nerve may be involved with the
perception of cardiac pain referred to the neck and jaw (Foreman 1999; Lindgren and Olivecrona 1947; Meller and Gebhart
1992; White and Bland 1948).
In summary, this study revealed quantitative differences in
the responses of C1–C2 superficial and deeper spinal neurons to
noxious chemical stimulation of cardiac afferents. Furthermore
both cardiac vagal and spinal (sympathetic) afferents transmitted nociceptive information to upper cervical spinal neurons.
Spinal neurons in C1–C2 segments, particularly deeper neurons, participate in integrating cardiac nociception.
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