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Annu. Rev. Physiol. 1999. 61:14367

Copyright c 1999 by Annual Reviews. All rights reserved

MECHANISMS OF CARDIAC PAIN

R. D. ForemanDepartment of Physiology, The University of Oklahoma Health Sciences Center,

Oklahoma City, Oklahoma 73190; e-mail: [email protected]

KEY WORDS: visceral pain, heart, cortex, sympathetic afferents, vagus, spinal cord

ABSTRACT

Angina pectoris often results from ischemic episodes that excite chemosensitive

and mechanoreceptive receptors in the heart. Ischemic episodes release a collage

of chemicals, including adenosine and bradykinin, that excites the receptors of

the sympathetic and vagal afferent pathways. Sympathetic afferent fibers from

the heart enter the upper thoracic spinal cord and synapse on cells of origin of

ascending pathways. This review focuses on the spinothalamic tract, but other

pathways are excited as well. Excitation of spinothalamic tract cells in the upper

thoracic and lower cervical segments, except C7 and C8 segments, contributes

to the anginal pain experienced in the chest and arm. Cardiac vagal afferentfibers synapse in the nucleus tractus solitarius of the medulla and then descend to

excite upper cervical spinothalamic tract cells. This innervation contributes to the

anginal pain experienced in the neck and jaw. The spinothalamic tract projects

to the medial and lateral thalamus and, based on positron emission tomography

studies, activates several cortical areas, including the anterior cingulate gyrus (BA

24 and 25), the lateral basal frontal cortex, and the mesiofrontal cortex.

INTRODUCTION

Patients with ischemic heart disease usually seek medical care when they ex-

perience the symptom of cardiac pain called angina pectoris. Heberden (1),

who experienced angina pectoris, described its most typical manifestation as

retrosternal with a crushing, burning, or squeezing characteristic. Pain may ra-

diate to the throat, neck, or ulnar aspect of the left arm, sometimes reaching to

the little finger. Less often, it radiates to the neck and jaw or either the right or

both arms. Intensity and pain location vary from person to person and from time

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144 FOREMAN

to time. Angina pectoris may also be associated with the subjective sensation

of anguish and fear of impending death.

Pain, however, is an inconsistent indicator of the presence or absence of tran-

sient myocardial ischemia because angina pectoris may consist of a continuum

of conditions. These conditions may span a spectrum of patients, from thoserevealing no signs of coronary artery disease with a hypersensitive cardiac neu-

ral network producing angina pectoris, to those manifesting severe coronary

artery disease with a hyposensitive cardiac neural network and no angina pec-

toris. One explanation for variation between painful and nonpainful effects of

myocardial ischemia may be that angina pectoris occurs late in the ischemic

cascade (2, 3). The typical sequence after onset of ischemia is left ventricular

dysfunction, electrocardiographic changes, and then onset of pain. Thus, some

ischemic episodes may end before the onset of angina pectoris. When pain is

present in patients, its character is similar for reversible episodes of myocardialischemia, acute myocardial infarction, and other causes (4). Nevertheless, pain

can serve as a protective reaction and warning signal that may become alarming

and sometimes disabling.

Coronary artery occlusion and chemical stimulation of receptors excite both

sympathetic and vagal afferent fibers that may be responsible for transmitting

the signals that give rise to pain from the heart during ischemia. The purpose

of this review is to explain how these two afferent pathways from the heart

contribute to the painful experience of angina pectoris. This review addresses

how sympathetic afferent fibers contribute primarily to the usual areas of painreferral, including the chest and arm. Neural mechanisms are also discussed,

to explain how vagal afferents contribute more to the pain sensed in the neck

and jaw. This chapter also reviews factors activating afferent endings and their

pathways, processing of information in the spinal cord, ascending pathways that

transmit nociceptive information to the thalamus and brainstem, and processing

of information in the limbic and cortical regions that contribute to the perception

of angina pectoris. Not enough space is available to discuss how spinal and

central processing could occur to contribute to silent myocardial ischemia;

however, other reviews have addressed this important issue (58).

AFFERENT PATHWAYS TRANSMITTINGNOXIOUS INFORMATION

Surgical interventions of sympathetic afferent pathways abolished or relieved

angina pectoris (911). These procedures include removal of the superior cer-

vical ganglia and stellate ganglia or the cervical thoracic trunk, and the sym-

pathetic chain; and dorsal rhizotomy from the level of the lower cervical to the

middle thoracic spinal cord. A summary of these studies shows that 5060% of

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CARDIAC PAIN 145

patients report complete relief from angina whereas 3040% report partial relief

and approximately 1020% report no relief at all (12). Surgical interventions

show that sympathetic afferents contribute to most of the pain experienced dur-

ing angina pectoris. This does not eliminate the possibility that other afferent

pathways are involved. Partial success in some of these patients could also beattributed to incomplete surgical sympathectomies. After surgical intervention

of sympathetic afferents was completed, pain was occasionally unmasked in the

neck and jaw or patients continued to experience pain in these regions during

ischemic episodes. It was proposed that the vagus nerve may be contributing to

that painful experience. Although patients experienced this pain, it was more

tolerable than the pain they experienced when sympathetic afferent pathways

were intact.

Characterization and Localization of Sensory Endings

The anatomical organization and functional characteristics of sensory nerve

endings that may contribute to angina pectoris have been studied. However,

much more research is required to understand how these endings contribute to

variable consequences of ischemia and other forms of heart disease that lead to

pain. Afferent fibers in the heart have diffuse or compact uncapsulated sensory

nerve endings that are branched and found primarily in the epicardium (13, 14).

The myocardium does not appear to contain sensory endings, but mixed myeli-

nated and unmyelinated nerves forming bundles are traced through connective

tissues of the septa between the muscles (13). Reflex activation of renal nervesshows that sympathetic afferent endings in the ventricle generally appear to be

close to the epicardial surface whereas vagal afferent endings are closer to the

endocardial surface (15, 16). It is also proposed, based on reflex responses, that

sympathetic afferent fibers may be distributed over the wall of the left ventricle

whereas vagal afferent fibers are distributed preferentially to the inferoposterior

wall (1720). Anatomical studies show that dorsal root afferent fibers innervate

predominantly the anterior portion of the left ventricle, and nodose ganglion

afferent fibers are concentrated in the inferoposterior wall (21, 22). Although

these findings agree with the reflex responses, this homogeneity could not beconfirmed when recordings were made directly from nodose ganglion afferent

fibers (23) and cardiac sensitive dorsal root ganglion cells of sympathetic af-

ferent fibers (24). Thus, reflexes may evoke responses that do not necessarily

define how pain is generated from nociceptors in the heart. Direct recordings of

afferent fibers agree with observations made in patients that patterns of anginal

pain do not vary with different ischemic sites in the heart (4, 25). The emerg-

ing field of the intrinsic nervous system of the heart adds to the complexity

about the processing of afferent information arising from the heart (26, 27).

Much more needs to be learned before we understand how this processing of

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146 FOREMAN

afferent information locally affects symptomatic and asymptomatic episodes of

myocardial ischemia.

Excitation of terminal sensory nerve endings may occur because of at least

two separate processes (28). One process may have a channel-linked receptor,

producing a spatially precise, immediate, and rapid response. The other processmay result from a nonchannellinked receptor causing synaptic modulation that

is slow and requires several hundred milliseconds to produce its effect. This

process most likely involves G-proteins and enzymatic reactions mediating

changes in the metabolism of the neuron and producing modulatory processes

that are spatially diffuse.

Visceral Sensory Encoding

Intensity and specificity theories have been proposed to describe stimulus trans-

duction in visceral afferent fibers (29). The specificity theory accounts for re-ceptor encoding mechanisms responding to specific stimulus intensities. This

theory is based on the idea that one population of receptors responds to low-

intensity innoxious stimuli and another population responds to noxious stimuli.

The intensity theory describes receptors that respond to a wide range of stimulus

intensities. These receptors discharge at low frequencies and, as the stimulus in-

tensity increases, increase their discharge rate until frequency reaches a thresh-

old, producing pain sensations. Both theories have supporters (29). Recently,

studies have shown that both specific nociceptors and intensity receptors exist in

the esophagus and urinary bladder (3032), but the existence of these two typeshas not been clearly delineated for the heart. Separation of sympathetic affer-

ents into intensity and specificity categories is attractive, but the concern is that

the curves of individual receptors show a continuum of responses when each

stimulus response curve is plotted. Also, the number of nociceptive-specific

fibers may be far fewer than those that participate in intensity coding.

Adequate Stimuli for Angina Pectoris

Debates about mechanical and chemical mechanisms to activate sensory re-

ceptors generating pain symptoms have continued for years. The mechanicalhypothesis centered on the idea that distension of the ventricular wall resulted

in pain (33). Clinical studies showing that painful and painless episodes of tran-

sient ischemia are produced by similar patterns of ventricular dilation do not

support this hypothesis (3). In addition, acute ventricular failure, valvuloplasty,

and myocardial biopsy all produce nonpainful ventricular dilation. Thus, the

general sense is that mechanical stimulation does not play a major role in the

pain associated with myocardial ischemia (3).

Both mechanosensitive and chemosensitive sympathetic afferent fibers ex-

ist in the heart. Mechanosensitive endings display a regular pattern of activity

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CARDIAC PAIN 147

with each cardiac cycle and respond vigorously and immediately to gentle

movement of a fine probe or bristle on the receptor field (34). Chemosen-

sitive endings discharge irregularly and infrequently without cardiac modula-

tion (35). A common feature of these two classes of cardiac afferent fibers

is that both respond to bradykinin; however, only chemosensitive endings aresensitized with prostaglandins, especially PGE1 (36, 37). After sensitization,

bradykinin increases the magnitude and duration of chemosensitive endings

but does not affect mechanosensitive endings. Because chemical stimuli acti-

vate mechanosensitive endings, they are classified as polymodal receptors (34).

These receptors discharge spontaneously when hemodynamic conditions are

normal and possess some degree of sensitivity (34). Their activity increases

during coronary artery occlusion or intracoronary injections of small amounts

of bradykinin. Malliani (34) argues that cardiac nociception occurs when a spa-

tially restricted population of polymodal nociceptors is strongly excited. Basedon recent evidence, however, it appears that chemical effects of these neurons

are far more dramatic than are mechanical effects for producing pain of angina

pectoris. Thus, chemosensitive endings are better candidates for carrying infor-

mation that leads to pain perception. Often the environment around receptors

is sensitized because the release of chemicals changes the responsivity of the

afferent endings.

Silent Nociceptors and Receptor Sensitization

Activation of silent nociceptors during myocardial ischemia also may con-tribute to angina pectoris. These receptors were first identified in joints (38),

but they have also been observed in the urinary bladder (32) and just recently

were recorded in the heart (39). The main characteristic of these receptors is

that they do not become activated until an organ or tissue is inflamed. Stud-

ies of the urinary bladder show that a population of unmyelinated and small

myelinated bladder afferent fibers respond weakly, if at all, to intense bladder

distension under normal conditions, but the rate of discharge increases dramat-

ically after acute inflammation. In a preliminary study (39), silent receptors

in the left ventricle responded to ischemia and bradykinin, but to date no onehas created inflammatory conditions in the heart to activate these receptors.

Possibly symptomatic and asymptomatic symptoms may occur because there

may be variability in the inflammation that may or may not activate silent noci-

ceptors. Thus, a population of fibers in the heart may be activated when the

heart undergoes inflammation resulting from myocardial ischemia. Indeed,

the heart does become inflamed during some of these ischemic episodes and

changes the characteristics of the fibers to respond to the stimulus. Sensitiza-

tion of nociceptors after injury or inflammation occurs when prostaglandins,

leukotrienes, substance P, and other chemical mediators are released from

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148 FOREMAN

local tissue damage. It is possible that intimal rupture or erosion of thrombosed

coronary atherosclerotic plaques releases sensitizing chemicals that inflame

the adventitia of coronary arteries, activate silent nociceptors, and sensitize

chemosensitive receptors (4042). The release of substances such as substance

P may sensitize nociceptors to intensify the pain experience felt in patients whoare infused with substance P and adenosine (43). Future studies will need to

find out if sympathetic afferent fibers are sensitized during inflammation of the

heart.

Chemical Stimulation of Sensory Endings

Unmyelinated sympathetic afferent fibers respond vigorously to chemical sub-

stances such as bradykinin, potassium, adenosine, acids, and veratridine when

applied to the epicardial surface and injected directly into coronary arteries

(36, 4450). Several chemicals have been examined for their role in activatingafferent fibers during myocardial ischemia; however, bradykinin has long been

used as a chemical of choice to produce nociceptive responses. Bradykinin is

an endogenous algesic chemical that results in pain in animals (51, 52) and in

humans, particularly in the cutaneous receptor fields (5360). Early reports sug-

gest that bradykinin is increased in the effluent of the coronary sinus following

coronary artery occlusion (61, 62). However, occlusion of the left anterior de-

scending coronary artery with percutaneous transluminal coronary angioplasty

occlusion elicits signs of myocardial ischemia, but no bradykinin was detected

in the coronary sinus (63). Human studies and animal experiments (64) showthat bradykinin, by itself, may not be sufficient to produce or mimic the pain of

angina pectoris. Intracoronary injection of bradykinin in patients does not lead

to angina-like pain (65, 66). These patients describe an unspecific discom-

fort or pain that is sensed over the whole body. Only a few patients experienced

chest pain. It is likely that a collage of substances, including bradykinin, adeno-

sine, lactate, and potassium, excite cardiac receptors that transmit nociceptive

information to the central nervous system. Pagani et al used this information,

coupled with the finding that conscious dogs do not respond in any specific way

to pain with bradykinin injections, to formulate or reformulate the intensity hy-pothesis (67). They suggested that a specific code be based on a specific spatial

temporal activation sequence where a discrete limited amount of myocardium

is activated. Sylven proposes an alternative hypothesis based on the nonlinear

sensitive dependence of angina pectoris on initial conditions (68). He proposes

that a model should be based on the deterministic, chaotic dynamics rather than

require classical mechanical and cause/effect relationships. The variability of

the pain sensation and its lack of direct relationship with myocardial ischemia

shows that a complex system may be operating in a way not yet discovered

because little is known about receptor characteristics of the heart and how theyare influenced by their environment.

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CARDIAC PAIN 149

Recent studies have shown that adenosine may be an important component

of the chemicals contributing to cardiac pain. Adenosine causes anginal-like

pain in healthy volunteers (69) and in patients suffering from ischemic heart

disease and those having angina pectoris (70) without any electrocardiographic

changes. A dose-dependent relationship exists between adenosine and painintensity (71). The adenosine receptor antagonist theophylline counteracted

the pain experience, and inhibition of the cellular uptake of adenosine with

dipyridamole increased pain. Intracoronary infusion of adenosine in patients

with chronic stable angina causes pain that mimics many aspects of the pain

experienced during daily life episodes of patients with transient myocardial

ischemia (72). This pain most likely originates from the heart because a similar

dose of adenosine infused into the right atrium did not evoke any pain.

Excitation of sympathetic afferent fibers with adenosine strongly supports

the results of human and receptor studies. The first report of the excitatory ef-fects of adenosine on cardiac sympathetic afferents of the third thoracic rami or

the sympathetic chain was done by Uchida & Murao (48). In a more detailed

study, afferent fibers responding to coronary artery occlusion are excited when

adenosine is applied to the epicardium (73). These results show that adenosine

activates afferent fibers that very likely are important for transmitting informa-

tion that leads to pain perception. In contrast, Pan & Longhurst (74) show that

afferent fibers cannot be activated by adenosine but only by bradykinin; there-

fore, they argue that other mechanisms account for activation of the receptors

by adenosine. Differences in anesthesia, animal preparation for exposing theheart, length of coronary occlusion, and sites for recording afferent activity

might contribute to the conflicting results between these two studies. Support

for activation of cardiac sympathetic afferent fibers with adenosine also comes

from the work of Huang et al (24), who show that adenosine also excites dorsal

root ganglion cells that respond to coronary occlusion. Thus, there is strong evi-

dence to suggest that sympathetic afferent pathways are activated by adenosine

and can play an important role in generation of angina pectoris.

Surface membrane P1 receptors have at least two subtypes (A1 and A2)

that adenosine stimulates to produce cardiac effects (75). Several studies sug-gest that A1 receptors are the primary mediators of the effects of endogenous

adenosine on pain (76, 68); however, Huang et al (24) suggest that A1- and A2-

receptor effects and substance P receptors are present on sensory nerve endings

in the epicardium of the ventricle.

SPINAL CORD PROCESSING OF VISCERALINFORMATION

Sympathetic afferent fibers from the heart and coronary arteries have their cellbodies generally in the dorsal root ganglia of the C8 to T9 spinal segments.

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The major concentration, however, is found between the T2 and T6 segments

(77, 78). These dorsal root ganglion cells have axons entering the tract of

Lissauer and terminating in the same segment or ascending and descending a

few segments before they penetrate into the spinal cord (77). Axons course over

the dorsal rim of the gray matter and terminate primarily in lamina I, whereasothers slide along the lateral edge of the gray matter and terminate primarily in

laminae V, VII, and X. It should be noted that the density of visceral termination

sites is much less than those of the somatic afferent fibers. Diffuse pain expe-

rienced with cardiac ischemia may occur because sympathetic afferent axons

are a small percentage of the fibers that enter the spinal cord, and they have

a broad rostral to caudal distribution. This extensive and diffuse arrangement

of visceral afferent fibers innervates second-order neurons in several segments,

thus contributing to the diffuse and poorly localized nature of angina pectoris.

Central Sensitization of Visceral Afferent Information

Continual bombardment of neurons in the gray matter of the spinal cord can ac-

tivate mechanisms in cells of the spinal cord that provide a functional substrate

for hyperalgesic states resulting from injury to visceral organs. The primary

focus of the previous studies was to study central sensitization for somatic

components, but the visceral effects lagged behind (79). Studies of other vis-

ceral organs provide insight into the changes that may occur in the thoracic

segments of the spinal cord during angina pectoris. Repeated noxious balloon

distensions of the colorectal region in humans evoke painful responses thatincrease pain sensitivity and expand the area of pain referral to the overlying

somatic areas of the body (80). Animal models support the findings observed

in human studies. Recordings made from neurons in the lower thoracic gray

matter during gall bladder distension show that some neurons respond only

to somatic input and not to the visceral stimulus whereas another population

responds to both somatic input and distension (81). The somatic receptive field

enlarges only for spinal neurons that receive input from noxious stimulation of

the gall bladder. Thus, the conditioning visceral stimulus is selective because

only those neurons responsive to a visceral afferent input change their sensi-tization to the somatic input. An additional important characteristic of these

responsive neurons is that the somatic referral of visceral pain that produced

the changes tends to outlast the duration of the noxious visceral stimulus. This

observation correlates well with the clinical experience that hyperalgesia is felt

after the painful episode has passed. These results raise the possibility that

central sensitization of spinothalamic tract (STT) cells and neurons in the gray

matter can intensify the pain experience resulting from cardiac pain.

ASCENDING PATHWAYS TRANSMITTING NOXIOUS CARDIAC INFORMATION Thegray matter is made up of cells serving as interneurons and as the origin of

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CARDIAC PAIN 151

ascending pathways that transmit visceral information to areas of the brain

processing sensory information and participating in pain perception (Figure 1).

Of the ascending pathways, the STT is the most studied system for transmitting

visceral afferent information to the brain. Axons of STT cells generally cross

over to the contralateral side within one or two segments and then ascendgenerally in the anterolateral quadrant. Recent studies, however, have shown

that some axons remain on the ipsilateral side and some are in the dorsolateral

quadrant (82). Visceral information from the upper thoracic segments usually

converges with input from somatic structures and ascends to the lateral and

medial thalamus (8386).

Spinothalamic Tract Organization and Characteristics

of Angina Pectoris: Chest and Arm

Patients with angina pectoris express three main clinical characteristics to de-scribe their symptoms: (a) Pain from the heart is generally referred to somatic

structures innervated by the same spinal segments that innervate the heart (87);

(b) pain of angina pectoris is referred to proximal and axial body areas but gen-

erally not to distal limbs (88); and (c) angina pectoris is generally felt as deep

and not superficial or cutaneous pain (89). In this section, neurophysiological

mechanisms are described to support the patient observations of the referred

pain associated with myocardial ischemia and other cardiac diseases.

VISCEROSOMATIC CONVERGENCE Electrophysiological studies showthat elec-trical stimulation of cardiopulmonary afferent fibers excites STT cells in the

T1 to T6 segments of the spinal cord (90). Approximately 80% of the cells

recorded in these segments are strongly activated with cardiopulmonary af-

ferent stimulation, and all these cells receive convergent input from somatic

structures. It is interesting that cardiopulmonary afferent stimulation has little

effect on the activity of cells in the C7 and C8 segments, where the major inner-

vation is to the distal forelimb and hand. This fits with the clinical observations

that anginal pain is usually not referred to the hand and distal forelimb (9193).

Thus, lack of responsiveness of these cells agrees with clinical observations.Once past the cervical enlargement, STT cells of the C5C6 segments are

again primarily excited by cardiopulmonary sympathetic afferent and somatic

stimulation. In these segments, cardiopulmonary afferent stimulation excited

approximately 60% of the cells and inhibited 16%. Somatic fields for these cells

are primarily from the chest. An interesting feature of these segments is that

they do not receive cardiac input directly from their dorsal root ganglion cells;

in fact, the afferent input is a few segments away. Some evidence suggests

that cardiopulmonary afferent fibers may activate cell bodies of a propriospinal

path where it directly or indirectly makes synaptic connection with STT cells inthe cervical region (94). It is also possible that afferent branches of the T2 and

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CARDIAC PAIN 153

T3 sympathetic fibers may travel in the zone of Lissauer for several segments

(95). Thus, convergence of visceral and somatic input onto a common pool of

STT cells provides a substrate for explaining the referral of pain to somatic

structures.

PROXIMAL AND AXIAL SOMATIC INVOLVEMENT Neurophysiological mecha-nisms also provide a basis for the proximal nature of the referred pain of angina

pectoris. Electrophysiological studies of the STT show that cardiopulmonary

afferent input most commonly excites cells with proximal somatic receptive

fields (90). Cardiopulmonary input strongly excites approximately 80% of

the STT cells with proximal somatic receptor fields but only weakly excites

35% of the cells with distal somatic input. Thus, the relationship of cells with

excitatory visceral input and proximal axial fields is highly significant. These

neurophysiological observations support the human studies that angina pectoris

is most commonly felt in the proximal and axial regions of the left arm and

chest. The frequency distribution of angina pectoris shows that the chest is in-

volved more than 95% of the time, and the pain radiates 3060% of the time to

the left proximal shoulder and less involvement occurs down the arm (92, 96).

DEEP, DULL, DIFFUSE, ACHING PAIN The final characteristic of angina pectoris

is the deep, diffuse, dull nature of the symptoms. These sensations are com-

parable to muscle pain. That is, the pain is typically deep and aching and is

often associated with referred muscle hyperalgesia. The similarity of muscle

pain and visceral pain was shown in patients who suffer frequently from anginapectoris referred unilaterally to the chest and radiating down the inner aspect

of the left arm (89). These patients were asked to compare their sensations

of angina pectoris with those provoked when a hypertonic saline solution was

injected into the interspinus ligament of the left eighth cervical or first thoracic

spinal segment. These patients explained that the pain was felt in the upper in-

terscapular region, over the left chest, and then radiated down the inside aspect

of the left arm. These patients stated that the onset, continuation, segmental

Figure 1 Schematic diagram showing functional organization to explaincharacteristics of referred

pain of angina pectoris in the chest and arm (C5C6, T1T5) and the neck and jaw (C1C2). The

spinothalamic tract (solid line) ascends from each of the spinal segments to the lateral (VPLc,

caudal ventral posterolateral nucleus) and medial (CL, nucleus centralis lateralis; CM-Pf, centrum

medianum-parafascicularis nucleus) nuclei of the thalamus. Afferent pathways from the somatic

structures (dashed line) and the cardiopulmonary sympathetic afferent fibers (dotted line) and vagal

fibers (dotted/dashed line) converge on cell bodies of the spinothalamic tract. Blackened regions on

the figures represent somatic fields. NTS, nucleus tractus solitarius; VPM, ventral posteromedial

nucleus; VPI,ventral posteroinferior nucleus; VPMpc, ventral posteromedial nucleus, parvocellular

part.

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154 FOREMAN

localization, and character closely mimicked their anginal pectoris. The pain

is diffuse, continuous, and difficult to describe, although it can be identified as

causing suffering (89).

Human studies show that referred muscle hyperalgesia resulting from a dis-

eased visceral organ is a common presentation in the clinic (97). Although thissection focuses on the results of hyperalgesia from different visceral organs,

the possibility of hyperalgesia resulting from angina pectoris should also be

considered. Patients suffering pain caused by calculosis of the upper urinary

tract experience muscular hyperalgesia with less involvement of overlying cu-

taneous structures (98, 99). Experimental studies also show that stimulation

of the ureter results in muscular hyperalgesia and central sensitization of dor-

sal horn cells (100102). Their results show that muscle and deep structures

make contributions to referred pain resulting from visceral diseases, and cu-

taneous pain plays a much smaller role. Muscle hyperalgesia associated withvisceral pain leads to the suggestion that the STT plays a role in processing

sensations associated with muscle changes resulting from cardiac pain. This

led to the hypothesis that STT cells excited by visceral stimulus are more likely

to be excited with deep, i.e. muscle, input than cutaneous input (90, 103).

This hypothesis was tested by recording STT cell activity during stimulation of

cardiopulmonary afferent fibers and pinching the skin and muscle of somatic

receptor fields in the hands and the proximal arm and chest (90). In the hand

and fingers, the strongest response of STT cells is elicited when the skin alone is

pinched and does not increase when skin and muscle are stimulated together. Inthese neurons, cardiopulmonary afferent fiber stimulation minimally increases

cell activity to approximately 10% of the maximal response to cutaneous stimu-

lation. When STT cells receive their input primarily from the proximal arm and

chest region, they are most often excited powerfully during muscle stimulation.

Their overall response reaches 88% of the maximal somatic response that can

be elicited from all neurons with proximal somatic input. Cutaneous stimula-

tion alone only achieves less than 33% of the maximal somatic response. These

muscle responsive cells are strongly excited during cardiopulmonary afferent

stimulation, with their activity reaching 68% of the maximal somatic response.These observations provided support for our hypothesis that muscle and vis-

ceral afferent fiber input converged most commonly onto the same STT cells,

whereas cells with primarily cutaneous input were not very responsive to the

visceral stimulus. Thus, converging input from deep tissue and visceral affer-

ent fibers onto STT cells may provide a basis for explaining why visceral pain,

such as that resulting from myocardial ischemia, is felt predominantly as a deep

or localized suffering pain, generally in proximal structures such as muscles,

tendons, and ligaments. It also supports the idea that some hyperalgesia may

remain after episodes of angina pectoris.

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CARDIAC PAIN 155

Spinothalamic Tract Organization and Characteristics

of Angina Pectoris: Neck and Jaw Pain

Surgical sympathectomy reduces the incidence of refractoryangina pectoris, but

pain referred to the neck and jaw sometimes remains or appears after extensive

sympathectomy. This pain led to the suggestion that vagal afferent fibers,which commonly are thought to transmit non-nociceptive sensory information,

may produce referred pain associated with myocardial ischemia (9, 12, 10). A

particularly interesting study would be one that noted the incidence of jaw or

neck pain in patients who are quadriplegic because of a lower cervical segment

injury and who have coronary artery disease. Presumably these patients would

not have sympathetic afferent input to the upper cervical segments, thereby

eliminating the sympathetic component as a factor in jaw pain. Stimulation of

the vagal or sympathetic afferent fibers and chemical stimulation of the heart

excites STT neurons in the C1C3 segments (104, 105). Thus, these afferentpathways are candidates for transmitting noxious cardiac information to these

segments. Vagal stimulation serves as a more potent stimulus than the input

from cardiopulmonary afferent fibers. Vagal stimulation markedly increases

cell activity with C-fiber input more often than does cardiopulmonary afferent

stimulation. Somatic receptive fields for these C1C3 STT neurons are found

most commonly on the neck, jaw, ear, and upper arm. Overlapping terminations

of primary afferent fibers from different regions could explain why the receptive

fields of the head and upper body have variable locations. Somatic fields from

the ipsilateral neck and/or shoulder regions enter the spinal cord at the uppercervical dorsal root ganglia (106). The more caudal somatic fields may result

from projections of somatic afferent fibers from the C5C7 segments on the

upper cervical segments (107, 108). Although cardiopulmonary afferent input

seems to play a subordinate role, this pathway nevertheless excites neurons

in the C1C3 segments. These cells are far removed from the entry zone of

the cardiac afferent fibers, which is primarily in the T2T6 dorsal root ganglia

(109, 77). Most likely, cardiac afferent input enters the spinal cord and ascends

in a pathway in the ventrolateral quadrant and synapses on these C1C3 neu-

rons (110). Such a pathway likely exists in monkeys as well as in rats. Thissuggestion is based on information that excitation of the T1T5 STT cells by

splanchnic nerve stimulation is abolished when the ventrolateral part of the cord

is cut rostral to the T7 segment (111). The splanchnic nerve has its primary point

of entry in the T9T11 segments of the spinal cord. Thus, it is likely that this

pool of neurons in the C1C3 segments of the spinal cord provides a neural

substrate for referred pain originating from the heart and being perceived in the

neck and jaw region. The exact mechanism has not been defined to explain

why some patients feel neck and jaw pain with angina and others do not.

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OTHER ASCENDING PATHWAYS FORTRANSMITTING VISCERAL INFORMATION

The Anterolateral Pathways

Other ascending tracts besides the STT in the anterolateral quadrant of the spinalcord may be important for transmission of noxious information that ascends to

the brain and leads to the perception of pain (112114). A prominent pathway

is the parabrachial region of the pons, which that may serve as an important

relay for processing visceral somatic nociceptive information. A major projec-

tion of axons originates from lamina I and enters the lateral parabrachial area

(115118). This information is relayed to the amygdala (119), the ventromedial

nucleus, and the retrochiasmatic area of the hypothalamus (120). This system

might contribute to the emotional-affective behavioral and autonomic reactions

to noxious events. Future studies need to address similarities and differences ofinformation transmitted via the parabrachial relay versus the medial thalamic

relay nucleus for cardiac input.

Other pathways, including the spinoreticular pathway (121) and the spino-

mesencephalic (122, 123), spinosolitary (124), and spinohypothalamic tracts

(125), may all be involved with conveying visceral information from the heart,

but much less is known about the visceral responsiveness of these pathways.

Future studies will help to determine how these particular pathways contribute

to the overall cardiac pain experience during myocardial ischemia.

The Dorsal Column Pathway

Recent studies also suggest that the dorsal column pathways play an important

role in transmitting nociceptive visceral information, particularly from pelvic

organs (126130). The role of the dorsal columns became known when it was

shown that eight patients were successfully relieved of their pelvic cancer pain

following a midline lesion of the dorsal column at the T10 spinal level (131).

This limited myelotomy only penetrated the dorsal columns and not other areas

of the spinal cord. In animal studies, gentle or noxious stimulation of repro-

ductive organs or noxious colorectal distension excited gracile nucleus neuronsthat most likely reach this pathway via the postsynaptic dorsal column pathway

(126, 130). The limited dorsal column lesion also reduced their response of

cells in the ventroposterolateral nucleus of the thalamus in rats, showing that

visceral input could be transmitted via the dorsal columns (127). Less work

has been done for the afferent input from the heart. Recordings from neurons

of the ventroposterolateral nucleus of the thalamus show that both STT and

dorsal column pathways play a role in transmitting information from the heart

and thoracic region to the thalamus (132). Thus, multiple ascending pathways

transmit visceral information, but the content of the coded visceral messages in

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CARDIAC PAIN 157

the somatic information that each pathway contributes to the processing of the

thalamus must be evaluated to understand their respective roles in sculpting vis-

ceral sensation. In comparison to the STT tract neurons, a smaller percentage

of cells of the cuneothalamic neurons respond with significantly fewer evoked

action potentials and a shorter latency to activation (133). Furthermore, mostcuneothalamic neurons respond primarily to innocuous somatic stimuli whereas

STT neurons respond primarily or solely to noxious pinches of somatic fields.

Neurons that responded to cardiopulmonary input most often have somatic

fields on the proximal arm and chest. Thus, differences in neuronal responses

to noxious stimulation of the cardiopulmonary afferent fibers suggest that a dor-

sal column pathway and the ventrolateral pathways to the ventroposterolateral

thalamus may play different roles in the transmission and integration of pain

associated with coronary artery disease. Much more work needs to be done to

understand how these different contributions can explain the characteristics ofcardiac pain.

SUPRASPINAL PROCESSING OF CARDIACNOCICEPTIVE INFORMATION

Thalamus

LATERAL THALAMUS The lateral thalamus is composed primarily of the ven-

troposterolateral and posteromedial nuclei. Cells of the lateral thalamus relay

information to the primary somatosensory cortex and possibly to the secondarysomatic cortex (Figure 2). Little information exists about processing of vis-

ceral information in the somatosensory cortex, but there is some evidence to

suggest that this information can project to this region (134136). This region

is important for processing information that would be interpreted as sensory

discriminative because it refers to the capacity to analyze location, intensity,

and duration of the nociceptive stimulus (137, 138).

MEDIAL THALAMUS Ascending pathways carrying visceral and somatic in-

put also project to the medial thalamus (Figure 2). The medial thalamus isprimarily the centralis lateralis and centrum medianum-parafascicularis nuclei

(139, 140). These nuclei send information to the association cortex, including

the insular cortex, amygdala, and cingulate gyrus (141144). These nuclei may

be primarily responsible for the motivational affective components of pain,

including autonomic adjustments (145147, 137).

Higher Central Integration

Information on higher central integration is sketchy. Much less is known

about processing of noxious visceral information in cortical structures. The

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158 FOREMAN

Figure 2 Generalization of supraspinal organization of cardiac nociceptive (solid line) and other

noxious visceral (dashed line) afferent inputs in the cortex from the lateral and medial thalamus.

This organization is based primarily on positron emission tomography studies (151, 148150, 152).

Brodmanns Area (BA) 2,1,3, postcentral gyrus; 10, medial orbitofrontal cortex; 13/14, anterior

insula; 24, anterior cingulate gyrus; 25, ventral cingulate gyrus; and 47, lateral basal frontal cortex.

Post., posterior; Ant., anterior. Abbreviations for the thalamus are defined in the legend of Figure 1.

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CARDIAC PAIN 159

information described here resulted from positron emission tomography (PET)

studies and functional magnetic resonance imaging in patients. To date, few

laboratories have used PET studies to determine the cortical areas that are in-

volved with angina pectoris (148, 149, 150). In addition, these techniques were

used to study brain blood flow changes resulting from gastrointestinal disten-sion in healthy volunteers (151) and patients with irritable bowl syndrome (152).

Far more studies with PET have been done to examine brain responses during

noxious somatic stimulation (153).

Ascending pathways transmit noxious somatic and cardiac information to the

lateral and medial thalamus (83) as well as to both the reticular formation and

the thalamus (121). In addition, convergent input from the dorsal column post-

synaptic pathway transmits information at least to the lateral thalamus (127).

Cells of the lateral thalamus respond to cardiac afferent input (132, 154). Other

visceral stimuli, such as colorectal distension and urinary bladder distension,also excite the VPL neurons (136, 128). Human studies also suggest that tha-

lamic nuclei are activated during angina pectoris (149).

Cells of the lateral thalamus project primarily to somatosensory cortex, par-

ticularly areas 1 and 3 (Figure 2). This region of the cortex is activated during

painful esophageal distension in healthy patients (151). Nonpainful distension

produces bilateral activation of the central sulcus, and the response is intensi-

fied during painful esophageal distension. Activation of these areas contributes

to the spatial localization and encoding intensity discrimination of the stimu-

lus. It should be noted that this area did not show changes in patients withirritable bowel syndrome and angina pectoris (152, 149). Because visceral in-

formation changes cell activity, it is possible that angina pectoris reaches the

region, but the effects are not observed because excitation of one pool of neurons

is counterbalanced by inhibition of another pool of neurons. Thus, activity of

visceral input from myocardial ischemia cannot be ruled out for this region of

the cortex.

The medial thalamus projects its information to those areas of the cortex

that are important for cognitive-evaluative and affective-motivational aspects

of the pain experience (Figure 2). Angina pectoris increases thalamic blood flowbilaterally, but the sensitivity of PET is not sufficient to identify the specific

nuclei involved. Based on previous studies, angina pectoris most likely acti-

vates the medial thalamus. Noxious visceral information resulting from angina

pectoris projects bilaterally to the ventral cingulate cortex (BA 25) [BA stands

for Brodmanns areas (see 155157 for a description of these areas) and the

numbers identify surface regions of the cortex], the lateral basal frontal cortex

(BA 47), and the mesial orbitofrontal cortex (BA 10) (149). The ventral cingu-

late gyrus increases its blood flow [in the 1994 study of Rosen et al (148), the

increase occurred only in the left gyrus, but a bilateral increase was reported

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160 FOREMAN

in their 1996 study (149)]. Other visceral studies have shown that the anterior

cingulate gyrus (BA 24) is strongly activated by a visceral stimulus (151, 152).

The 1994 study of Rosen et al (148) shows a decrease in regional blood flow in

BA 24 whereas the later study shows that blood flow in this region increased,

although the change was substantially less than for BA 25. These results, ingeneral, show that the anterior cingulate gyrus appears to be activated during

noxious visceral stimulation. This region of the gyrus is most closely related

to visceromotor responses (158). In rats, this general area connects with the

nucleus of the solitary tract (159), dorsal motor nucleus of the vagus, and sym-

pathetic thoracic intermediolateral cell columns (160). This region generates

affective and cognitive responses to pain (161).

Angina pectoris also activates the prefrontal (BA 47) and mesial orbitofrontal

(BA 10) cortices. This general area is also activated in patients with irritable

bowel syndrome (152). In general, noxious cardiac information may causeresponses in these regions as a consequence of planning that has resulted

from behavioral and attentional organization (153, 162164). This general area

may also be associated with emotional vocalization and verbalization (158),

as well as recall of negative affectively charged memories (152). In contrast,

esophageal pain in healthy volunteers did not activate this region (151). The

reason for this difference is unclear, but one difference may be that chronic

pain patients use this region to plan a strategy that helps them to cope with

their pain whereas healthy patients are not required to evoke these behavioral

patterns.The insular cortex is another important association area for coordinating

visceral sensory and motor information that project from thalamic nuclei, the

nucleus of the solitary tract, via the parabrachial nucleus and via reciprocal

efferent projections to these areas (165167). Painful esophageal distention

activated the insular cortices (151). It is therefore somewhat surprising that

angina pectoris did not evoke activity in this region, even though angina is a

visceral stimulus and cardiovascular afferent fibers innervate the insula (165).

One reason for the difference may be that esophageal pain is an acute stimulus

and angina pectoris is a chronic condition.A number of discrepancies and differences exist among the studies that have

been done using PET and magnetic resonance imaging scans to examine the

effects of visceral input. Future studies must be done to elucidate the spa-

tial and temporal processing of neural mechanisms that underlie the changes

observed with this technology. These studies, however, have provided an im-

portant catalyst to study these areas in the future using electrophysiological,

neuroanatomical, and inmunocytochemical techniques as well as refined PET

scans and other research strategies. Elucidation of how these areas function

will facilitate ways to treat chronic pain of visceral origin.

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CARDIAC PAIN 161

ACKNOWLEDGMENTS

I thank Ms. Carrie Hulka for typing the manuscript and Mr. Patrick Whelan

for preparing the figures. This work was supported by the National Institutes

of Health grants HL22732, HL52986, and NS35471 and by the Presbyterian

Health Foundation.

Visit theAnnual Reviews home page at

http://www.AnnualReviews.org

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Annual Review of Physiology

Volume 61, 1999

CONTENTS

Pulling the Cart and Enjoying the Ride, Carlton C. Hunt 1

Cellular and Molecular Basis for Electrical Rhythmicity in

Gastrointestinal Muscles,Burton Horowitz, Sean M. Ward, Kenton M.Sanders

19

Ionic Conductances in Gastrointestinal Smooth Muscles and Interstitial

Cells of Cajal, G. Farrugia45

Excitation-Contraction Coupling in Gastrointestinal and Other Smooth

Muscles, T. B. Bolton, S. A. Prestwich, A. V. Zholos, D. V. Gordienko85

THE ENTERIC NERVOUS SYSTEM AND REGULATION OF

INTESTINAL MOTILITY, W. A. A. Kunze, J. B. Furness117

Mechanisms of Cardiac Pain,R. D. Foreman 143

Desensitization of G Protein-Coupled Receptors in the Cardiovascular

System,M. Bnemann, K. B. Lee, R. Pals-Rylaarsdam, A. G. Roseberry,

M. M. Hosey

169

Regulation of Natriuretic Peptide Secretion by the Heart, G. Thibault, F.

Amiri, R. Garcia193

Myoblast Cell Grafting into Heart Muscle: Cellular Biology and Potential

Applications, P. D. Kessler, B. J. Byrne219

Heat-Shock Proteins, Molecular Chaperones, and the Stress Response:

Evolutionary and Ecological Physiology, Martin E. Feder, Gretchen E.

Hofmann

243

Genetic Diseases and Gene Knockouts Reveal Diverse Connexin

Functions, Thomas W. White, David L. Paul283

Localized Intracellular Calcium Signaling in Muscle: Calcium Sparks and

Calcium Quarks,Ernst Niggli311

ATP-Sensitive Potassium Channels: A Model of Heteromultimeric

Potassium Channel/Receptor Assemblies, Susumu Seino 337Adrenomedullin and the Control of Fluid and Electrolyte Homeostasis,

Willis K. Samson363

Pathophysiology of Endothelin in the Cardiovascular System, Takashi

Miyauchi, Tomoh Masaki391

Gene Interactions in Gonadal Development, Keith L. Parker, Andreas

Schedl, Bernard P. Schimmer417

Synchronous Activity in the Visual System, W. Martin Usrey, R. Clay

Reid435

Timing in the Auditory System of the Bat,Ellen Covey, John H.

Casseday457

Synaptic Mechanisms for Coding Timing in Auditory Neurons,Laurence

O. Trussell

477

The Role of Timing in the Brainstem Auditory Nuclei of Vertebrates, D.

Oertel497

TIMING OF SYNAPTIC TRANSMISSION, B. L. Sabatini, W. G.

Regehr521

Structure, Strength, Failure, and Remodeling of the Pulmonary Blood-Gas

Barrier, J. B. West, O. Mathieu-Costello543

Evolution of Vertebrate Cardio-Pulmonary System, C. G. Farmer 573


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Mouse Models of Airway Responsiveness: Physiological Basis of

Observed Outcomes and Analysis of Selected Examples Using These

Outcome Indicators,J. M. Drazen, P. W. Finn, G. T. De Sanctis

593

Sodium Channels in Alveolar Epithelial Cells: Molecular

Characterization, Biophysical Properties, and Physiological Significance,

Sadis Matalon, Hugh O'Brodovich

627

Sodium-Coupled Transporters for Krebs Cycle Intermediates,Ana M.

Pajor 663

Modulation of Vasopressin-Elicited Water Transport by Trafficking of

Aquaporin2-Containing Vesicles,Donald T. Ward, Timothy G.

Hammond, H. William Harris

683

Electrogenic Na+/HCO3- Cotransporters: Cloning and Physiology,

Michael F. Romero, Walter F. Boron699

Electrophysiology of Synaptic Vesicle Cycling,Henrique von Gersdorff,

Gary Matthews725

Genetics of Synaptic Vesicle Function: Toward the Complete Functional

Anatomy of an Organelle,Rafael Fernndez-Chacn, Thomas C. Sdhof753

RECONSTITUTION OF REGULATED EXOCYTOSIS IN CELL-FREE

SYSTEMS: A Critical Appraisal,Julia Avery, Reinhard Jahn, J. MichaelEdwardson

777

Mechanisms of Hair Cell Tuning,R. Fettiplace, P. A. Fuchs 809

Ion Channels of Nociception,Edwin W. McCleskey, Michael S. Gold 835

Controversial Issues in Vertebrate Olfactory Transduction, Geoffrey H.

Gold857

Cellular Mechanisms of Taste Transduction,M. Scott Herness, Timothy

A. Gilbertson873

mechanisms of cardiac pain.pdf

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