Chapter 22 Unlike other senses, such as vision, receptors for tissue damage do not return to their prestimulus state after activation but remain “switched on” for a period of time. It is now known that not only is the sensitivity of damage-detecting sensory nerve endings altered after injury, but their synaptic connections inside the central nervous system may be significantly modified and reorganized. The ability of the pain-sensing system to change in response to input is referred to as plasticity. The end result of these plastic changes is heightened activity and responsiveness of the system, making it easier for a signal to get through and be perceived as painful (hyperalgesia); stimuli that would not normally have been felt as painful (both from the site of surgery and from other areas) may be felt as painful when the animal regains consciousness (allodynia). Changes that occur in the peripheral and central nervous systems are known as peripheral and central sensitization. This sensitization can occur very quickly after surgery.46,47 The clinical implications of this sensitization include the following: (1) once “pain” is established, analgesic drugs, for a given dose, are much less effective (i.e., pain is more difficult to control), and (2) for a constant input over time, the “pain” felt by the animal increases. Most nociceptors are relatively nonselective ion channels gated not by voltage but by the stimulus (temperature, chemicals, mechanical forces). Once activated, the channels open and the inward flux of Na+ and Ca2+ ions produces an inward current that depolarizes the membrane. The presence, specificity, and threshold of these transducers define the different classes of primary afferent fibers. Most fibers are considered polymodal, responding to multiple types of noxious stimuli, whereas some are unimodal and respond to only one form of stimulus. Almost all C-fibers are high-threshold and polymodal. Considerable progress has been made over the past decade in identifying the molecular structure and function of various nociceptor ion channels.5 Most C-fibers are polymodal, being both heat and mechanically sensitive (C-fiber nociceptors).63 Certain C-fiber nociceptors, called silent nociceptors, are heat responsive but mechanically insensitive, and are not normally active. These develop mechanical sensitivity only in the setting of injury and become more responsive when the so-called “inflammatory soup” alters their properties. Subsets of these C-fiber nociceptors afferents are also responsive to a variety of itch-producing substances. Approximately 10% of all C-fiber nerve endings respond to low-intensity stimuli, such as stroking, and may mediate pleasant touch. Nociceptors can also be distinguished according to their differential expression of channels that confer sensitivity to heat (transient receptor potential vanilloid-1 [TRPV1]), cold (transient receptor potential menthol-8 [TRPM8]), acid environment (acid-sensing ion channels), and a host of chemical irritants [TRPA1])5,41 (Figure 22-2). The human pain threshold to heat, which typically rests around 43° C, parallels the heat sensitivity of C and type II Aδ nociceptors described earlier. Capsaicin and related vanilloid compounds produce burning pain by depolarizing specific subsets of C and Aδ nociceptors through activation of the capsaicin (or vanilloid) receptor, transient receptor potential vanilloid-1—one of approximately 30 members of the greater transient receptor potential (TRP) ion channel family.13 Recent studies indicate that TRPV1 is not solely responsible for heat transduction but plays an important role. Current data indicate that both TRPV1-dependent and TRPV1-independent components of noxious heat sensitivity are mediated via TRPV1-expressing nociceptors. This is an important concept, because targeting TRPV1-expressing neurons (e.g., molecular neurosurgery) may have greater utility than selective targeting of TRPV1 receptors. Recent unpublished data from human patients support this. The somatosensory system detects diverse mechanical stimuli, ranging from a light brush of the skin to distention of viscera. High-threshold mechanoreceptors include C-fibers and slowly adapting Aδ mechanoreceptor fibers, both of which terminate as free nerve endings in the skin. Low-threshold mechanoreceptors include Aδ hair fibers that terminate on down hairs in the skin and detect light touch. Aβ fibers that innervate Merkel cells, Pacinian corpuscles, and hair follicles detect texture, vibration, and light pressure. Very little is known about the molecular basis of mechanosensation. Suggested candidate mechanotransducers include mec-4 and mec-10, members of the degenerin/epithelial Na+ channel (DEG/ENaC) families, possibly involving the MEC-2 orthologue, SLP3.86 Acid-sensing ion channels 1, 2, and 3 have been proposed as mechanotransduction channels; however although these channels appear to play a role in musculoskeletal and ischemic pain, their contribution to mechanosensation is controversial. TRPV2 and TRPV4 have also been proposed to be involved in mechanotransduction. In addition to the transduction elements, other molecules are considered to play a role in transduction by tuning or altering sensitivity of the transduction elements. These are far from being well characterized but include voltage-gated sodium channels and voltage-gated potassium channels (KCNK2 [TREK-1] and KCNK4 [TRAAK]1,61 and KCNK18).7 If the depolarizing current initiated during transduction is of sufficient magnitude, voltage-gated ion channels are activated, further depolarizing the membrane and causing a burst of action potentials. Voltage-gated Na+ and K+ channels are critical to the generation of action potentials. Several isoforms of Na+ channels have been recognized for their specific role in nociception. The tetrodotoxin (TTX)-sensitive Na+ channel, Nav1.7, and the TTX-resistant Na+ channels, Nav1.8 and Nav1.9,5,14 have attracted the most attention. The Nav1.7 has received attention because of the finding that altered activity in this channel leads to a variety of human pain disorders,24,33,67 and the finding that Nav1.7 is upregulated in a variety of rodent inflammatory pain models.60 The Nav1.8 is also highly expressed by most C-fiber nociceptors and is not inactivated at low temperatures, making it the predominant action potential generator under cold conditions. Much of the analgesic effect of cold is considered to be due to inactivation of sodium channels. These voltage-gated sodium channels are the targets of local anesthetics and are the focus of intense development of specific channel blockers (such as Nav1.7 blockers). Additionally, many drugs have some sodium channel blocking activity. For example, the analgesic effects of serotonin and norepinephrine reuptake inhibitors may result in part from their ability to block sodium channels.25 It is important to recognize that powerful descending pathways are able to modulate the pain response. Descending modulation is controlled from three main sources: the periaqueductal gray matter of the midbrain; the rostroventral medulla and pons of the brainstem; and the thalamocortical structures (see Figure 22-4).52 Descending neurons from the neocortex and hypothalamus activate enkephalinergic interneurons in the periaqueductal gray matter. The caudate nucleus and the amygdala, two other forebrain structures, have also been implicated in antinociception. Projections from the periaqueductal gray matter terminate in various brainstem structures in the rostroventral medulla, including the nucleus raphe magnus, the reticularis magnocellularis, and the nucleus paragigantocellularis. Descending serotonergic fibers originate in the nucleus raphe magnus; serotonergic, noradrenergic, enkephalinergic and joint enkephalinergic, and serotonergic fibers originate in the nucleus paragigantocellularis; and noradrenergic axons originate from cell groups lateral to the nucleus paragigantocellularis. These fibers descend in the dorsal lateral funiculus and synapse onto thalamic projection neurons in lamina I, and local opioid-containing inhibitory interneurons in lamina II (the substantia gelatinosa). These descending pathways are often activated by stressful events (pain, fear, hypoxia), and opioid-like analgesic effects are produced. Within the rostroventral medulla are populations of cells referred to as on and off cells.53 Off cells hyperpolarize in response to spinothalamic tract input and reduce the transmission of nociceptive signals through the brainstem. On cells are excited by nociceptive input from the spinothalamic tract and facilitate nociceptive transmission to areas involved in arousal and aversive reactions to pain. Activity of these neurons can also affect local spinal cord modulation of nociceptive processing. Control of these rostroventral medulla neurons is being investigated. 1. Gate control theory55: inhibitory interneurons normally inhibit output of projection neurons. Input from large myelinated Aβ fibers encoding non-noxious information can increase inhibitory interneuron activity, and limit the amount of noxious sensory information going to the brain. 2. Endogenous opioids: endogenous opioids inhibit the release of local excitatory neurotransmitters, including glutamate and substance P. 3. Other local modulators of excitatory and inhibitory spinal cord transmission: these substances are under local control or control via projections from higher centers. A surgical procedure, trauma, or disease results in direct stimulation of afferent nociceptors (Aδ and C-polymodal) or stimulation via the “inflammatory soup” that is produced. Neurotransmitters (glutamate), peptides (substance P, calcitonin gene-related peptide, bradykinin), eicosanoids and other lipids (prostaglandins, thromboxanes, leukotrienes, endocannabinoids), neurotrophins (nerve growth factor), cytokines, chemokines, proteases, and protons are all components of the so-called inflammatory soup. These substances are released from activated nociceptors, damaged tissue cells, or non-neuronal cells that reside in the local area or are recruited in platelets, neutrophils, lymphocytes, macrophages, and mast cells.49,54 Direct tissue damage results in local release and spread of adenosine triphosphate (ATP), ions (H+, K+), prostaglandins, bradykinin, and nerve growth factor. Lymphocytes, neutrophils, and macrophages release cytokines (interleukin [IL]-1, IL-6, tumor necrosis factor [TNF]-α). Mast cell degranulation increases the local concentration of 5-HT and histamine. These chemicals will directly activate or will sensitize nociceptors to different types of stimuli, such as thermal, mechanical, and chemical.49,54 The processes are complex and interrelated (Figure 22-5).
Surgical Pain
Pathophysiology, Assessment, and Treatment Strategies
Transduction (Peripheral Nociceptors)
Heat Transduction
Mechanical Transduction
Local Modulation of Transduction
Transmission and Projection
Supraspinal Modulation of Sensory Input
Local Modulation of Sensory Input at the Spinal Cord
Plasticity of Nociception and Pain
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Surgical Pain: Pathophysiology, Assessment, and Treatment Strategies
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