Mechanisms of Pain in Thoracic Surgery

Jessica A. Boyette-Davis
Patrick M. Dougherty

Pain is a sensation that is normally associated with the application of noxious or injurious stimuli. In the context of thoracic surgery, pain can develop in multiple ways. Acute pain occurs as a direct result of physical trauma sustained during thoracic surgery. This trauma can include tissue damage from surgical incisions or manipulation, fractures to ribs, and hematomas.¹ As will be discussed in this chapter, this acute pain may then develop into a chronic pain state in approximately half of all patients. Damage to nerves, most often the intercostal nerves, during surgery also contributes significantly to pain, as this damage manifests as a distinct form of chronic pain termed neuropathy. Thus, pain in thoracic surgery patients involves multiple components and mechanisms including those mediating acute somatic pain, hyperalgesia, and neuropathic pain. In the instance where these multiple components are all observed in a patient, the condition is referred to as chronic post-thoracotomy pain. To explain this condition in part or in its entirety, this chapter will review the basic physiology of pain, including pain pathways and neurochemistry, the neural mechanisms and neurochemical mediators of primary and secondary hyperalgesia, and the unique mechanisms of neuropathic pain.

OVERVIEW OF PAIN PATHWAYS AND NEUROCHEMISTRY

Peripheral Neural Mechanisms

In general, pain begins in a distinct class of primary afferent fibers that respond selectively to noxious stimuli. These nociceptors are located in the periphery, with the cell bodies located in dorsal root ganglia (DRG) outside the spinal cord, and terminate in the dorsal horn. Nociceptors respond to a number of different stimulus modalities including thermal, chemical, and mechanical stimuli.^2,3 However, there are different classifications of nociceptors, generally based on the conduction velocity of the axons of these nociceptive neurons. The C fibers are generally unmyelinated fibers that conduct at velocities of less than 2 m/s and constitute over 75% of afferent fibers present in peripheral nerves. Several lines of evidence indicate that C-fiber nociceptors are essential for the normal perception of pain. For instance, intraneural electrical stimulation of identified C-fiber nociceptors in humans elicits the sensation of pain, and blockade of C-fiber transmission prevents thermal pain perception at the normal heat pain threshold.⁴ Absence of C fibers, either via capsaicin ablation⁵ or as is seen in patients with congenital insensitivity to pain,⁶ results in diminished or altogether absent pain sensation. Recordings from C fibers in humans suggest that C-fiber activity is associated with a prolonged burning sensation. In contrast, activation of faster conducting (5 to 20 m/s) myelinated Aδ fibers evokes a sharp, intense, tingling sensation. Combined, Aδ- and C-fiber nociceptors encode and transmit information to the central nervous system concerning the intensity, location, and duration of noxious stimuli.

Following transduction by peripheral afferents, nociceptive information is transmitted via nerves to the central nervous system. Within the thoracic cavity, it is the intercostal nerves of the peripheral nervous system that transmit pain signals to the spinal cord. These nerves, which are located with the intercostal space, are often damaged during thoracic surgery, leading to symptoms of neuropathic pain. The mechanisms of this pain are discussed below.

Central Neural Mechanisms

The axons of primary afferents terminate at the ipsilateral side of the dorsal horn of the spinal cord in a highly organized manner.^7,8 As can be seen in Figure 6–1, the cells of the dorsal horn are arranged in layers, or laminae,⁹ with C fibers terminating primarily in the most superficial lamina (I and II outer) and Aδ fibers ending in lamina I, and in laminae III to V. Because both C and Aδ fibers terminate in lamina I, in addition to C fiber termination into lamina II, neurons within these laminae respond almost exclusively to noxious inputs¹⁰ and are often termed nociceptive specific (NS) or high-threshold neurons.^11,12

In addition to these NS neurons, two other classes of sensory spinal neurons make synapse with nociceptive neurons. These cells, the wide dynamic range (WDR) and the multi-receptive (MR) cells, respond to both noxious and non-noxious stimuli with the difference being that WDR cells show a discharge rate that is graded with stimulus intensity whereas the MR cells do not.^13,14 The WDR and MR cells in laminae III to V show responses to both cutaneous mechanical and heat stimuli, but rarely show responses from deep tissues, while cells in laminae VI and VII tend to show responses from deep tissue and visceral receptors.

Figure 6–1. Laminae distribution and primary afferent termination within the spinal cord. The histological section on the left is labeled to show the location of the dorsal horn within the spinal cord. In the enlarged segment to the right, the layers of laminae I through VI are outlined. Primary afferent innervation to the various laminae is depicted in the schematic at the bottom. (From: Raja, SN & Dougherty, PM. Anatomy and physiology of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 1-1, pg 3. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)

Unlike for touch where information ascends ipislaterally up the spinal cord via the dorsal column medial lemniscal system, almost all nociceptive information is transmitted to the contralateral side of the body at the level of primary afferent innervation. There the axons of WDR and NS neurons cross the midline of the spinal cord, gather into bundles and then ascend toward targets in the brainstem and diencephalon via the antereolateral system. This system is further divided into distinct tracts based primarily upon the location of projection neurons within dorsal horn laminae (Figure 6–2). For instance, the axons of WDR and NS cells that make synapse within laminae I and V-VII ascend to the medial thalamus, thus forming the spinothalamic tract.

Figure 6–2. Summary of the central nociceptive pathways. Information ascends from primary afferent fibers via either the dorsal column medial lemniscal column (touch) or the anterolateral system (nociception). Projections of various nociceptive specific tracts are also depicted. (From: Raja, SN & Dougherty, PM. Anatomy and physiology of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 1-4, pg 5. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)

Within the brain, several areas are especially involved in processing nociceptive information.¹⁵ In response to pain, six brain areas are consistently recruited: the primary and secondary somatosensory cortices, the insular cortex, the anterior cingulate cortex, the prefrontal cortex (PFC), and several nuclei of the thalamus. The somatosensory cortices provide information regarding where in the body pain originates, and there is evidence that S2 contains a somatotopic map for nociceptive input. The insular and rostral anterior cingulate cortices are part of the limbic system, and an abundance of literature suggests these brain structures modulate the affective or emotional aspect of pain. The PFC aids not only in making a decision as to what actions should be taken to alter pain, but this part of the brain also is useful in controlling input from the limbic system. Interestingly, some research suggests that the pattern of brain activation changes during chronic pain from more limbic-related activity to significantly more activation in the PFC. Further, thalamic activation tends to be lower in chronic versus acute pain. Finally, other key areas of the brain are involved in the descending modulation of pain, primarily via serotonin-related mechanisms. These areas include the rostral ventromedial medulla, the nucleus raphe magnus, the locus ceruleus, and the periaqueductal gray matter.

Neurochemistry

Within the periphery, numerous chemicals are released following insult to tissue (Figure 6–3). These chemicals, which can directly activate nociceptors or increase the general excitability of nociceptors, are frequently referred to as an “inflammatory soup.” Following injury, both bradykinin¹⁶ and serotonin¹⁷ directly activate nociceptors. The neuropeptides histamine, substance P, and calcitonin gene-related peptide (CGRP) are derived from activated nociceptors and produce a variety of responses, including vasodilation and edema. Further, histamine excites polymodal visceral nociceptors and potentiates the responses of nociceptors to bradykinin and heat.¹⁸ Eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, directly activate and sensitize afferents.^19,20 Nitric oxide (NO) released by damaged afferents can further sensitize nearby neurons, augmenting pain and inflammation.²¹ Cytokines released by a variety of cells¹⁹ can also serve to directly excite and sensitize nociceptive afferent fibers to thermal and mechanical stimuli. Cytokines also lead to increased production of nerve growth factor (NGF),²² which in turn stimulates mast cells to release histamine and serotonin, leading to the aforementioned primary afferent fiber activation and sensitization. Proteinases such as thrombin, trypsin, and tryptase, although not traditionally considered part of the inflammatory soup, are gaining increasing attention as mediators of pain and inflammation.²³ Activation of proteinase receptors PAR1 and PAR2, which are located on primary afferent nerve fiber endings, leads to a cascade effect of histamine, substance P, CGRP, prostaglandin, bradykinin, and cytokine release.

Figure 6–3. Summary of the neurochemical mediators in the periphery. Tissue injury provokes the release of numerous chemical mediators of pain. Pro-nociceptive mediators augment pain via multiple mechanisms, including directly activating nociceptors, sensitizing primary afferents, and causing the release of other known mediators. (Adapted from Dougherty, PM & Raja, SN. Neurochemistry of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia 2nd ed., Figure 2-1, pg 8. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)

In addition to these pro-nociceptive mediators, anti-nociceptive chemicals are also present in the periphery. For instance, opioids, which are known for their analgesic properties, are also a component in inflammatory soup.²⁴ The peripheral terminals of afferent fibers contain receptors for opioids, and the number of receptors is upregulated following tissue injury. Acetylcholine modulates pain primarily via its effects on muscarinic receptors. This is supported by the findings that muscarinic agonists desensitize C-fiber nociceptors to mechanical and heat stimuli.²⁵ Finally, somatostatin (SST) may also serve as an antinociceptive agent. The SST receptor type 2a has been identified in a small percentage of unmyelinated primary afferent fibers,²⁶ and administration of the SST receptor agonist octreotide attenuates bradykinin-induced nociceptor sensitization. SST also inhibits the release of cholecystokinin, which has been shown to have nociceptive properties.

Within the central nervous system, pain is modulated via a host of chemical mediators (Figure 6–4). The amino acids glutamate and aspartate constitute the main excitatory neurotransmitters within the central nervous system. Of particular interest is the glutamate receptor N-methyl-D-aspartate (NMDA). In the spinal cord, the NMDA receptor is recruited only by intense and/or prolonged stimuli, and persistent activation of NMDA receptors leads to sensitization of dorsal horn neurons that includes an increase in receptive field size, decreased activation threshold, and prolonged depolarization. The impact of spinal NMDA-mediated changes will be discussed again in regards to hyperalgesia. In the brain, NMDA receptors are also important for pain²⁷ and are upregulated following injury. This upregulation is associated with augmented sensitivity to inflammatory pain, excessive excitation of the brainstem, and increased expression of the transcription factor c-Fos. A multitude of research implicates c-Fos as an important facilitator of pain. Adenosine triphosphate (ATP) also serves to enhance pain. ATP receptors, especially the P2X family of receptors are present on the central terminals of primary afferent fibers innervating neurons in lamina V and II of the dorsal horn where they function to increase the release of glutamate. Like many other chemical mediators, the effects of ATP are not limited to neurons. The binding of ATP to P2 receptors on microglia activates these cells, which then begin to secrete inflammatory mediators such as cytokines, nerve growth factor, and NO. These factors then serve to sustain pain and inflammation.²⁸

Figure 6–4. Summary of the neurochemical mediators in the spinal cord. As is seen in the periphery, many modulators are present in the spinal cord which work to increase pain transmission. In addition to these factors, nociceptive mediated changes within the spinal cord also include changes to ion channel expression and glial cell activation. These changes play a role in the transition from acute to chronic pain. (Adapted from Dougherty, PM & Raja, SN. Neurochemistry of somatosensory and pain processing. In HT Benzon, SN Raja, RE Molloy, SS Liu, & SM Fishman (eds). Essentials of Pain Medicine and Regional Anesthesia. 2nd ed. Figure 2-2, pg 10. Philadelphia, USA: Elsevier, Churchill, Livingstone; 2005, with permission.)

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