Thoracic Pain

Heart

The nerve endings that transduce the chemical and mechanical state of the heart and relay that information to the brain are heterogeneous histologically and with respect to receptor type ( ). Activation of fibers traveling with the vagus is generally associated with hypotension, bradycardia, and nausea, whereas activation of fibers with sympathetic paths evokes hypertension, tachycardia, and most importantly, anginal pain. A large variety of substances released during thrombus formation, myocardial ischemia, and myocardial reperfusion have been implicated in the activation of cardiac afferents signaling ischemic pain ( ). Blockade of the capsaicin receptor, also known as vanilloid receptor 1 (VR1) or transient receptor potential vanilloid 1 (TRPV1), attenuates the activity of sympathetic afferents during myocardial ischemia ( ). Apart from its role in sensing myocardial ischemia, TRPV1 may also contribute to myocardial protection through release of multiple neurokinins from sensory nerve terminals ( ).

Sensation to the heart is provided by afferent fibers of the vagus nerve and sympathetic chain that intermingle in the cardiac plexuses ( Fig. 52-1 ). Three larger cardiac nerves and multiple smaller ones arise from the superficial (ventral) and deep (dorsal) cardiac plexuses ( ). From the cardiac plexuses, seven cardiopulmonary nerves arise and project bilaterally to the superior, middle cervical, and stellate ganglia ( ). Fibers from these plexuses also join the vagus. Afferent fibers from sympathetic ganglia enter the spinal cord at the posterior horn of the upper thoracic segments ( ) and, sometimes, the cervical segments ( ). This is consistent with the observation that phrenic stimulation above the heart can excite the upper cervical segments of the spinal cord ( ). In addition to its innervation of the pericardium, a small branch of the phrenic nerve innervates the right atrium ( ). Moreover, the phrenic nerve may receive branches from the stellate ganglion or ansa subclavia ( ).

After entering the dorsal horn of the spinal cord, sensory fibers traveling with sympathetic nerves synapse on neurons of the spinothalamic tract, whereas vagal sensory fibers converge on the nucleus of the solitary tract ( ). Sensory input from both sympathetic and parasympathetic nerves then project to the thalamus, hypothalamus, periaqueductal gray matter, and cerebrum ( ). When innervation to the heart is disrupted after cardiac transplantation, anginal sensation is not possible but is often restored to some degree after several years ( ). Consistent with the thalamic projection of afferent nerves subserving the heart, the sensation of angina can be evoked by thalamic stimulation ( ). Cortical projections include the insular cortex, anterior cingulate cortex, prefrontal cortex, and primary somatosensory cortex ( ). Functional imaging of the brain during induced ischemia reveals activation of cortical and subcortical structures when angina is experienced, and activation of subcortical structures persists even after the anginal pain resides. For those with “silent” ischemia, only subcortical structures are activated. In those who experience anginal pain without clinical evidence of coronary artery disease (cardiac syndrome X, see below), cortical activation is often greater than in those with known coronary artery disease experiencing myocardial ischemia ( ; ). Thus, cortical activation appears to be necessary to experience anginal pain, might not take place despite subcortical activity, and may be exaggerated in those with cardiac syndrome X.

Pericardium

The pericardium consists of an outer fibrous layer and visceral and parietal serous layers, with the visceral layer also known as the epicardium ( ). Innervation of the pericardium is provided by the vagus, phrenic, anterior intercostal, and sympathetic nerves that pass through the cardiac plexus ( ). Along their course the phrenic nerves are joined by fibers from the cervical sympathetic ganglia ( ). Collectively, these nerves richly innervate the fibrous and serous portions of the parietal pericardium ( ). The parietal pericardium ( ) and visceral pericardium ( ) appear to be sensitive to both chemical and mechanical stimuli. In these studies, the chemical sensitivity of the parietal pericardium was found to be mediated by sympathetic afferents, whereas both chemical and mechanical stimuli of the epicardium produced activity in the vagus, with chemical stimuli being considerably more effective than mechanical stimuli.

Great Vessels

In addition to the specialized baro- and chemoreceptors of the aortic arch with afferent pathways in the vagus, the aorta contains afferent sympathetic nerve fibers that render it sensitive to dilatation and chemical stimulation of the adventitia ( ). The clinical correlate of these experimental observations is the pain experienced during balloon angioplasty performed for aortic coarctation ( ). The afferent sympathetic nerve fibers conveying these sensations pass through the cardiac plexus to the sympathetic chain, primarily on the left side and, eventually travel to the upper thoracic segments of the spinal cord ( ). Mechanical, thermal, and chemical stimuli applied to the proximal pulmonary artery will activate sympathetic fibers of the cardiac plexus ( ). Relatively little is known about the innervation of the great veins. However, vena cava stretch at the junction of the atria produces tachycardia through a vagally mediated afferent limb ( ). Although this demonstrates the presence of stretch receptors in portions of the vena cava, this particular observation may be more related to homeostasis than to nociception.

Lungs, Diaphragm, Pleura, and Tracheobronchial Tree

The visceral pleura covers the surface of each lung and its interlobular fissures but not the hilar region, whereas the parietal pleura extends over the thoracic wall and the majority of the diaphragm and midline structures. The visceral pleura is supplied by nerves coursing with the bronchial vessels. Intercostal nerves supply the costal and peripheral portions of the diaphragmatic pleura, whereas the phrenic nerve supplies sensation to the central portion of the diaphragmatic pleura and the mediastinal pleura ( ). The phrenic nerve receives contributions from the cervical sympathetic ganglia and possibly the thoracic sympathetic plexuses. The intercostal nerves are all joined by fibers from the corresponding sympathetic ganglion ( ). The visceral pleura has generally been considered to be insensitive to noxious stimuli, but this may not explain the pain associated with many disease processes of the thorax that involve the pleura ( ). An explanation may lie in the identification of “visceral pleural receptors,” which reside only on the interlobular and mediastinal lung surface and exhibit histochemical characteristics linked to transduction of mechanical and/or chemical stimuli ( ). These nerve fibers appear to be non-vagal in origin and probably arise from the dorsal root ganglia of the thorax ( ). In contrast, the parietal pleura is clearly sensitive to mechanical and chemical stimuli ( ), with the acid-sensitive ion channels being important contributors to the transduction of noxious stimuli ( ). Apart from any discomfort produced by noxious stimulation of the parietal pleura, mechanical and chemical stimulation of it can lead to decreases in output to phrenic motor neurons and sympathetic outflow ( ). The importance of the afferent component of the phrenic nerve is reflected by the fact that blockade of this nerve alleviates the shoulder pain often experienced after thoracotomy ( ) whereas suprascapular nerve block does not ( ).

Information from a variety of receptor types located in the tracheobronchial tree and lung parenchyma is conveyed centrally along the vagus nerve and contributes to defensive and homeostatic mechanisms. The chemical and mechanical information provided can initiate cough, modulate bronchial diameter, and refine the depth and pattern of the ventilatory cycle ( ). A complex interplay involving local interaction and central integration of receptor activity can lead to seemingly paradoxical responses to tussive stimuli ( ). Although coughing is usually thought to originate along the airway ( ), other organs with vagal innervation, such as the esophagus, can initiate coughing in response to chemical or mechanical stimulation ( ).

The unpleasant sensation of dyspnea can be evoked by chemical and mechanical input from a large variety of sensors, not all of which reside within the thorax ( ). Chemical input includes that of the peripheral (via the carotid sinus nerve) and central (medullary) chemoreceptors, which signal oxygen and carbon dioxide tension, and possibly metaboreceptors within exercising muscle ( ) and the diaphragm ( ). The sense of gas movement within the upper airway as reflected by cooler temperatures detected by vagally mediated cold receptors in the upper airway may be an important modulator of dyspnea ( ). Stretch receptors in the lung ( ) and muscle spindles of the chest wall ( ) signal the adequacy of inspiratory effort. The pathways by which the foregoing signals ascend and are integrated to generate the sensation of dyspnea are not well understood ( ). However, as with many other unpleasant sensations, functional imaging reveals activation of the anterior cingulate cortex and insular cortex when dyspnea is experienced ( ).

Hiccups are another unpleasant symptom that originate in the thorax and can be triggered by afferent input from the phrenic or vagus nerve, particularly with stimulation at the diaphragm, mediastinum, or distal portion of the esophagus, as well as by central mechanisms ( ). Apart from the discomfort that they produce, hiccups may be significant because mechanical or chemical stimuli that would otherwise be perceived as pain at other locations are instead manifested as hiccups through irritation of afferent components of the aforementioned nerves.

Esophagus

Like the heart and pericardium, the esophagus is innervated by both vagal and sympathetic afferents. Sympathetic fibers supplying the upper portion of the esophagus travel with those innervating the heart and pericardium. Both vagal and sympathetic afferents are sensitive to mechanical and chemical stimuli, although the sympathetic system is thought to encode the majority of noxious input. The sympathetic afferents enter the spinal cord in the region of C2–6, T2–4, and T8–12; synapse with fibers of the spinothalamic tract and posterior columns; and project to the thalamus, sensory cortex, prefrontal cortex, insula, and anterior cingulate cortex ( ). Pain can be generated by acid exposure, distention, and sustained muscle contraction ( ). TRPV1 receptors and other acid-sensing channels are found in the gastrointestinal tract, and activation of these receptors may be a source of pain and inflammation ( ).

Breast and Chest Wall

Cutaneous innervation of the breast is provided by the anterior (T1–6) and medial (T2–7) branches of the intercostal nerves. Supply to the nipple–areola complex is derived primarily from the anterior and medial branches of the fourth intercostal nerve with varying contributions from the third and fifth intercostal nerves ( ). Innervation of the chest wall is provided by the intercostal nerves of the corresponding dermatome with supplementation by the nerves above and below. Some additional input is provided to the two upper thoracic dermatomes by the third and fourth cervical nerve roots. In addition, sensation to portions of the upper extremities is supplied by the first two thoracic nerves ( ). The intercostobrachial nerve arises from T1 and T2. Its upper branch provides sensation to the breast and anterior aspect of the chest, and its two lower branches supply sensation to the axilla and arm. TRP channels such as the TRPV1 receptor appear to play an important role in human breast pain and its variability ( ).