Systems Physiology
Management of Perioperative Pain
Despite significant progress in our mechanistic understanding of the nociceptive system, inadequately treated perioperative pain remains a significant problem. A third of patients undergoing surgery continue to suffer from moderate to severe pain, resulting in personal suffering, protracted recovery including persistent pain after surgery, delayed hospital discharge, and increased morbidity and mortality. Improving the management of postoperative pain remains an important clinical challenge. Although opioids are the most efficacious drugs, their pharmacologic profile does not allow adequate pain control in all patients. The occurrence of adverse effects can conflict with opioid dosing strategies required to alleviate pain. This has led to the widely embraced concept of multimodel analgesia, the combined use of different drug classes and regional anesthesia techniques, for the treatment of postoperative pain. The liberal use of opioids is also associated with significant abuse potential and drug diversion, which contributes to the current opioid epidemic in the United States, a serious public health issue costing many lives. As such, identifying novel analgesic drug classes that exploit alternative targets in the nociceptive system remains a high priority.
This chapter primarily covers the fundamental neuroanatomy, molecular biology, and physiologic functions of the nociceptive system as they pertain to the processing of acute pain and the practice of anesthesia. The objective is to provide a framework that facilitates the understanding of current and novel analgesic drug targets and management strategies for the treatment of acute pain . Given the focus of this book on the practice of anesthesia rather than the management of chronic pain, functional alterations of the nociceptive system in the context of chronic pain are not discussed in depth. However, it is noteworthy that the protective function of postoperative pain can be lost, as pain becomes maladaptive in patients who develop persistent postoperative pain (PPP).
Several clinical factors are associated with PPP, including type of surgery, severity of postoperative pain, young age, female sex, preexisting chronic pain conditions, and underlying psychosocial vulnerability. However, the molecular mechanisms underlying PPP remain poorly understood. Polymorphism of certain genes, including genes coding for catecholamine- O -methyltransferase, Na V 1.7, and K V 1.9, have been linked to the propensity for developing chronic pain. Whether these polymorphisms contribute to PPP in clinically relevant ways remains to be determined. Conceptionally, PPP reflects a shift in the balance between pronociceptive and antinociceptive processes, owing either to an exaggerated amplification of nociceptive input (central sensitization) or the deficient activation of endogenous central inhibitory pathways. Accordingly, several drugs classes counteracting central sensitization and/or enhancing central inhibitory control have been examined for reducing the incidence of PPP. They include α 2 -adrenergic agonists, calcium channel α 2 δ ligands (gabapentin and pregabalin), and N -methyl- d -aspartate (NMDA)-type glutamate receptor antagonists. Among them, efficacy is best documented for the NMDA receptor antagonist ketamine.
Overview of the Nociceptive System
The nociceptive system is a sensory component of the peripheral and central nervous systems devoted to signal input that is potentially harmful. The system controls involuntary defensive and adaptive responses to injurious stimuli and mediates the perception of pain. Nociception typically starts by activation of peripheral nerves tuned to respond to potentially harmful thermal, mechanical, or chemical stimuli. Physical or chemical input is transduced into transmembrane potential changes that can trigger action potentials (see Chapter 8 ). Primary sensory afferents consisting of nonmyelinated slow-conducting C-fibers and thinly myelinated faster-conducting Aδ fibers propagate action potentials to the dorsal horn of the spinal cord, where they synapse with spinal neurons. The neuronal architecture of the dorsal horn is complex and consists largely of interneurons that either amplify or inhibit transmission of incoming signals. Processed nociceptive input is relayed to supraspinal sites by projection neurons ascending in the spinothalamic and spinomedullary tracts, but the input is also transmitted to spinal sites serving autonomic and motor functions. Integration of nociceptive information in supraspinal brain regions results in complex somatic, emotional, autonomic, and endocrine responses. Finally, descending fibers emerge from supraspinal sites, including the cerebral cortex, hypothalamus, and brainstem, and project to the spinal cord where they facilitate or inhibit transmission of nociceptive signals and regulate behavior.
Peripheral Nociception
Nociceptor Classification
Nociceptors are a specific set of primary afferent nerve fibers that conduct noxious signals from peripheral somatic and visceral tissue to the spinal cord. They are pseudo-unipolar in architecture with distal and proximal projections arising from their cell bodies located in dorsal root and other sensory (e.g., trigeminal) ganglia. The peripheral nerve endings of nociceptors exhibit significant arborization and cover receptive fields from a few square millimeters to a few square centimeters, contingent on body location and fiber type. At the unmyelinated nerve endings, membrane ion channels and receptors convert nociceptive input into changes in transmembrane potential, ultimately triggering the propagation of action potentials if nociceptive input is of sufficient magnitude.
An important characteristic of nociceptors is their ability to become sensitized in injured tissue, requiring less input to initiate action potentials. Nociceptor sensitization is the neurophysiologic correlate of primary hyperalgesia, the increased sensitivity to nociceptive stimuli in injured and inflamed tissue. The term primary indicates that hyperalgesia is due to local events at the site of injury rather than central processes that can also amplify nociceptive input (secondary hyperalgesia is discussed later in this chapter).
Pain signals are conducted to the dorsal horn of the spinal cord via two distinct populations of peripheral nociceptors that are characterized by their fast and slow conduction velocities: small myelinated Aδ fibers (5–25 m/sec) and unmyelinated C-fibers (<2 m/sec). Aδ fibers transmit “fast” pain that is typically well localized and causes a rapid withdrawal of the affected body region, whereas C-fibers transmit “slow-onset” pain that is diffuse in character, intensifies over time, and often elicits a guarding response. These divergent responses are partially due to the difference in conduction velocities but also reflect differential neuronal integration of Aδ and C- fiber signals in the central nervous system (CNS).
Aδ fibers can be further subdivided into type I high-threshold mechanical (HTM) nociceptors that are activated by mechanical and chemical stimuli but exhibit a high threshold for activation by noxious heat (>50°C), and type II Aδ fibers that conversely exhibit low thresholds for activation by noxious heat (~43°C) but high thresholds for mechanical stimuli. Type I fibers are generally thought to conduct “fast” pain triggered by mechanical input (e.g., pinprick), whereas type II fibers conduct “fast” pain triggered to noxious heat.
C-fibers are classified as peptidergic or nonpeptidergic. Peptidergic fibers constitute the largest group of nociceptors and contain the neuropeptides substance P (SP) and/or calcitonin gene-related peptide (CGRP). Upon their release after tissue injury, SP and CGRP activate receptors on capillaries and terminal arterioles, causing vasodilation (CGRP) or plasma extravasation (SP). They also trigger the release of inflammatory and nociceptive mediators by neighboring cells, which amplifies inflammation and pain. Clinically, this phenomenon is known as neurogenic inflammation, which is thought to underlie chronic pain states with prominent vasomotor components such as fibromyalgia and complex regional pain syndrome.
Peptidergic C-fibers also express tropomyosin receptor kinase A (TrkA), the high-affinity receptor for nerve growth factor (NGF). The critical importance of peptidergic C-fibers, TrkA, and NGF in normal neuronal development is highlighted by the rare autosomal recessive disease congenital insensitivity to pain with anhidrosis, which is caused by loss of TrkA receptor function. Patients with this disorder retain touch perception and proprioception but lack any sensory response to heat, cold, and nociceptive input (including visceral input). TrkA loss of function has wide-ranging clinical consequences, including self-mutilation and bone fractures owing to lack of nociception, frequent fevers owing to lack of adequate thermoregulation (anhidrosis), autonomic abnormalities, and cognitive impairment.
Nonpeptidergic C-fibers are stimulated by glial cell line–derived neurotrophic factors (GDNFs, neurterin, artemin, and persephin) and can be identified by the expression of the target for GDNF, the c-RET tyrosine kinase receptor. Nonpeptidergic fibers also frequently express the purinergic P2X 3 receptor, which is thought to mediate signals initiated by ATP released from damaged tissues, ultimately causing pain and itch.
Although fiber size and molecular markers provide some basis to differentiate nociceptive neurons, mapping specific pain modalities (heat, chemical, and mechanical) onto specific nociceptors is a challenge because of the significant heterogeneity among nociceptive neurons. Some nociceptors respond to multiple noxious modalities, whereas others are modality-specific or remain silent until activated by tissue injury or inflammation. Examples of well-characterized nociceptors are “polymodal” mechanical and heat-sensitive C-fibers (CMH) , and mechano-insensitive afferent (MIA) C-fibers, which respond only to heat and chemical stimuli. MIA C-fibers constitute up to 20% of nociceptors in human skin. They may play a particularly important role in the development and maintenance of hyperalgesia, as these mechanically silent nociceptors become responsive to mechanical stimulation in inflamed tissue.
Identification of ion channels and receptors responding to specific nociceptive modalities has provided further means to group nociceptors into subpopulations that roughly correlate with their functional roles. For example, the transient receptor potential vanilloid 1 (TRPV1) receptor is the predominant sensor of noxious heat. Although genetic deletion studies in mice suggest that TRPV1 is not the sole channel responsible for transmission of nociceptive heat, chemical ablation of TRPV1-expressing neurons eliminates the response to nociceptive heat without altering responses to other nociceptive modalities. This finding implicates TRPV1 as an excellent molecular marker for nociceptors responsive to noxious heat. Similar approaches targeting nociceptors that express the Mas-related G-protein–coupled (MRG) receptor demonstrate that MRG is a specific marker for nociceptors that transmit noxious mechanical input.
Nociceptor Activation
The peripheral terminals of nociceptive neurons contain a mosaic of receptors responsive to both endogenous ligands and exogenous physical or chemical stimuli. A complex set of excitatory and inhibitory signals originating from these receptors ultimately governs the degree to which a nociceptive stimulus is transduced from the periphery to the CNS. This is illustrated schematically in Fig. 16.1 for a TRPV1-expressing nociceptor. TRPV1 is directly activated by exogenous input, including noxious heat, acidosis, and the pungent agent capsaicin derived from “hot” chili peppers, whereas endogenous ligands, including bradykinin 2, prostaglandin E 2 , and 5-hydroxytryptamine, modulate TRPV1 indirectly via second-messenger systems. Endogenous ligands are derived from nonneuronal neighboring cells, including resident cells (e.g., keratinocytes and mast cells) and migrating immune cells (e.g., neutrophils and lymphocytes). Nociceptive signaling thus involves a complex integration of exogenous cues acting directly on the nociceptor and endogenous modulators that communicate the state of the surrounding nonneuronal tissue.
The cell surface proteins responsible for encoding nociceptive signals fall into three general classes: ion channels, metabotropic G-protein–coupled receptors (GPCRs), and receptors for neurotrophins or cytokines. Although significant progress has been made in elucidating the basic biophysical properties of individual channels and receptors involved in nociception, it is the complex integration of multiple channels and receptors in vivo that results in nociceptive signaling. The scale of this complexity is further amplified by variations in channel expression and activity in different tissue types (e.g., skin vs. viscera) and contexts (e.g., type and time course of injury). Processing of specific noxious inputs can also often involve multiple redundant channels, receptors, and second-messenger systems, further complicating our ability to a priori predict the efficacy of promising drug candidates acting at novel targets. Recent attempts to attenuate the activity of peptidergic C-fibers illustrate this well. Although TrkA receptor and CGRP antagonists are both promising novel analgesic agents (discussed in later text), neurokinin-1 (SP) receptor antagonists exhibit a surprising lack of analgesic efficacy for treatment of acute pain.
Ion Channels
Table 16.1 lists representative ionotropic receptors that regulate nociceptive signaling. Particularly relevant examples of ion channels, including members of the TRP-family, isoforms of the voltage-gated sodium ion (Na + ) channel, and two-pore potassium (K 2P ) leak K + channels, are discussed in more detail.
| Abbreviation | Name | Stimulus Transduction | Activation | Sensitization |
|---|---|---|---|---|
| ASIC 1-4 | Acid-sensing ion channels, subtypes 1-4 | Chemical | Protons | Ischemia-induced pain, muscle hypersensitivity |
| TRPV1 | Transient receptor potential vanilloid 1 receptor (URI) | Thermal Chemical | Heat, protons, vanilloids, fatty acids, arachidonic acid derivatives | Heat hyperalgesia |
| TRPV4 | Transient receptor potential vanilloid 4 receptor | Mechanical | Osmotic challenge, stretching | Visceral and cutaneous hypersensitivity in inflammation and nerve injury |
| TRPA1 | Transient receptor potential subfamily A1 receptor | Chemical Mechanical | Mustard oil, cinnamaldehyde, acrolein, formalin | Chemically induced hyperalgesia Mechanical hyperalgesia |
| TRPM8 | Transient receptor potential subfamily M8 receptor | Thermal | Cold | Cold hyperalgesia |
| P2X3 | P2X purinoceptor 3 | Mechanical (indirect) | Adenosine triphosphate | Visceral and somatic pain in inflammation and nerve injury |
| P2X1-6 | P2X purinoceptor 1-6 | Chemical | Adenosine triphosphate | Pain and hypersensitivity associated with injury in various tissues |
| TREK 1 | TWIK-related potassium channel 1 | Mechanical Thermal Chemical | Stretching Heat Protons, arachidonic acid | Inflammatory hyperalgesia, mechanical hyperalgesia |
| TRAAK | TWIK-activated arachidonic acid potassium channel | Mechanical Thermal Chemical | Stretching Heat Protons arachidonic acid | Mechanical hyperalgesia |
| TMEM16A | Anoctamin calcium-activated chloride channel | Chemical Thermal | Heat Bradykinin | Roles in thermal, mechanical, and inflammatory hyperalgesia |
| 5-HT3 | 5-Hydroxytryptamine receptor | Chemical | Serotonin | Most prominent role in visceral pain |
| nACh (multiple subunits) | Nicotinic acetylcholine receptor | Chemical | Acetylcholine | May be pronociceptive at peripheral terminals, antinociceptive at central terminals |
| Glutamate (GluR1-5 and NR1-2) | Ampakine (GluR1-4), kainate (GluR5), and NMDA (NR1-2) receptors | Chemical | Glutamate and subtype specific agonists | Evidence for peripheral role in pain, but most compelling evidence for role at central terminals |
| GABA (multiple subunits) | Gamma-aminobutyric acid receptor | Chemical | GABA and subunit specific agonists | May be inhibitory or excitatory |
a Metabotropic receptors exist in large numbers on nociceptive neurons and are not included in this table.
The family of transient receptor potential (TRP) ion channels is characterized by a conserved structural architecture consisting of a tetrameric assembly of six transmembrane-domain subunits that form a nonselective cation channels with high calcium ion (Ca 2+ ) permeability. The early discovery of the key role of TRPV1 receptors in encoding nociceptive heat and the burning pain sensation triggered by the vanilloid compound capsaicin from hot chili peppers laid the groundwork for the effective use of natural chemical compounds to probe the nociceptive sensory system. Subsequent work has elucidated the role of the TRPM8 receptors, activated by the natural “cooling” compound menthol, as a critical target for transducing noxious cold stimuli. TRPA1 receptors transduce the effects of numerous pungent natural agents, including the isothiocyanate compounds found in mustard, horseradish, and wasabi, and thiosulfinate found in garlic. TRPA1 is also potently activated by proalgesic agents including bradykinin and formalin, suggesting that TRPA1 is important in nociceptive signaling associated with inflammation including a wide range of exogenous and endogenous irritant compounds.
Voltage-gated Na + channels (Na v ) play an essential role in initiating and propagating action potentials. They are large, multimeric complexes that consist of an α subunit and one or more auxiliary β subunits (see Chapter 20 ). The α subunit contains the ion-conducting aqueous pore that is the essential element of Na + channel function. The β subunits modify kinetics and voltage dependence and are involved in channel localization via interaction with cell adhesion molecules, extracellular matrix, and the intracellular cytoskeleton. Nine isoforms of Na v α subunits have been identified (Na v 1.1 through Na v 1.9), each with specific physiologic and pharmacologic functions. Numerous Na + channels have been found to play a role in inflammatory and neuropathic pain, including Na v 1.1, Na v 1.3., Na v 1.7, Na v 1.8, and Na v 1.9. Three isoforms, Na v 1.7, Na v 1.8, and Na v 1.9, are expressed nearly exclusively in the peripheral nervous system, with Na v 1.7 expressed in sensory, sympathetic, and myenteric neurons, Na v 1.9 expressed in sensory and myenteric neuron, and Na v 1.8 expression solely in sensory neurons. The importance of Na v 1.7 in nociception has been highlighted by the discovery of multiple inherited pain syndromes that derive from mutations in the SCN9A gene encoding Na v 1.7, including a dominant gain-of-function mutation that causes inherited erythromyalgia, and a recessive loss-of-function mutations that causes congenital insensitivity to pain. Gain-of-function mutations in the Na v 1.7, Na v 1.8, and Na v 1.9 channels underlie various forms of painful small fiber neuropathy, further highlighting the importance of these sodium channels in human pain processing. Upregulation of Na v 1.3 expression on peripheral axons after nerve damage or in dorsal horn neurons after spinal cord injury leads to increased neuronal excitability and likely contributes to the genesis of neuropathic pain after nerve injury. While Na v 1.1 has not historically been considered a contributor to nociception, a recent study demonstrated that Na v 1.1 plays an important role regulating activity of HTM Aδ fibers.
The inhibitory function of K + channels in nociceptive signal transduction is well established. Many GPCR ligands, including opioids and endocannabinoids, exert their antinociceptive effects by activating K + channels via their respective second-messenger systems. Of particular recent interest are members of the K 2P channel family, as these channels can be directly activated by nociceptive input, including mechanical, thermal, and chemical stimuli. The numbing and tingling sensation produced by ingestion of Chinese peppercorns has been attributed to inhibitory effects on TASK K 2P channels in peripheral nociceptive fibers, whereas volatile anesthetic agents activate TASK and TREK K 2P channels. A human pain syndrome, familial migraine with aura, has been linked to a dominant negative mutation in the TRESK K 2P channel, further emphasizing the role of these channels in pain signaling. Although K 2P channels represent potential novel analgesic targets, expression of the K 2P family is not limited to the sensory nervous system. The wide distribution and functional importance of these channels throughout the body may complicate efforts to target these channels for the treatment of pain.
Metabotropic G-Protein–Coupled Receptors
Many excitatory and inhibitory GPCRs modulate nociceptor excitability by activating or inhibiting ion channels via second-messenger systems. Examples of excitatory receptors include the receptors for CGRP, bradykinin (B1 and B2), endothelin A (ET A ), protease (PAR 1-4), and prostaglandin (EP1, EP3C, and EP4). Although these GPCRs would appear to be suitable targets for novel analgesic compounds, their relative abundance and heterogeneity within nociceptors seems to account for the fact that specific receptor antagonists mostly lack efficacy. CGRP antagonists and antibodies are a notable exception as they are effective for the treatment of migraine headache. By contrast to the pronociceptive receptors, several inhibitory GPCRs are effective drug targets, including opioid receptors (µ, δ, κ), cannabinoid receptors (CB1, CB2), and serotonin receptors (5HT-1B and -D). While opioids exert broad analgesic effects, the efficacy of serotonergic antagonists is limited to migraine. Cannabinoids have been used extensively for their anxiolytic, antiemetic, and antinociceptive properties. The development of nonpsychogenic cannabinoid derivative for use in clinical pain management is an area of active study.
Receptors for Neurotrophins
Nociceptors express one of two distinct classes of neurotrophic factor receptors that are infrequently coexpressed in a specific nociceptor. Neurotrophins belong either to the NGF family expressed (NGF, brain-derived neurotrophic factor [BDNF], and neurotrophin 3 and 4) mainly in C-peptidergic fibers or the GDNF family (neurturin, artemin, and persephin) expressed in nonpeptidergic nociceptors. Neurotrophins promote the survival, growth, and maintenance of discrete populations of neurons by altering transcriptional and translational regulation of neuronal proteins, including key ion channels and GPCRs relevant for nociceptive signaling. Considering that neurotrophic factors are derived from nonneuronal tissues, they critically link tissue inflammation and nociception. Inflammation-induced surges of neurotrophic factors during tissue injury can profoundly affect nociceptor excitability and result in hyperalgesia.
NGF is the most widely studied neurotrophic factor with regard to pain physiology. It is released from a host of inflammatory and resident cells upon tissue injury and binds to its high-affinity receptor TrkA on nociceptors. TrkA is a receptor tyrosine kinase able to activate multiple downstream second-messenger signaling cascades and promote nociceptor excitability via sensitization of several ion channels, including TRPV1, ASIC3, P2X3, and Na V . The TrkA/NGF complex is also internalized within the nociceptor and transported in retrograde fashion to the cell body, where is exerts transcriptional control on numerous nociceptive pathways over the course of hours or even days. This longer-lasting action triggers the release of the neuroinflammatory peptides CGRP and SP. It also induces central sensitization via the synthesis of the centrally released neurotrophic factor BDNF. In contrast to inflammatory states with elevated NGF levels, the loss of basal NGF or GDNF signaling after peripheral nerve or spinal cord injury appears to play a prominent role in the upregulation of Na v 1.3 that drives neuropathic pain after neuronal injury. Based on the role of NGF in regulating key components of the nociceptive pathway, it has become an important drug target. Approaches sequestering NGF or antagonizing TrkA receptors are in development to target chronic pain in patients with osteoarthritis, diabetic neuropathy, cancer, or back pain.
Signal Processing in the Dorsal Horn
Nociceptors transmit pain signals from the periphery to the dorsal horn of the spinal cord. The dorsal horn should not be considered a simple relay station but rather a region of complex signal processing. Incoming nociceptive signals are processed through a neuronal network built by primary nociceptive and nonnociceptive afferents, inhibitory and excitatory interneurons, and descending neurons originating in the brainstem. These neuronal circuits are ultimately linked to projection neurons, which relay nociceptive output from the dorsal horn to various supraspinal structures, including nuclei of the brainstem and the thalamus. Some processed nociceptive signals are also distributed locally within the spinal cord and underlie spinally mediated autonomic and motor responses to painful stimuli. Knowledge regarding the synaptic circuitry and function of dorsal horn neuronal structures is still quite incomplete, although some basic circuitry has been defined.
Structural Components
The spinal cord gray matter has historically been defined by 10 cyto-architecturally distinct layers ( Fig. 16.2 ). The majority of nociceptive fibers terminate in the most superficial lamina I (the marginal layer) and lamina II (the substantia gelatinosa). The peptidergic C-fiber population that expresses TRPV1 and underlies noxious thermal responses projects to the most superficial layers of the dorsal horn (lamina I and the outer region of lamina II), whereas MRG-expressing nonpeptidergic C-fibers that mediate mechanical pain project to a deeper region within inner lamina II. This spatially distinct mapping of nociceptive modalities and specific nociceptive fibers within the dorsal horn is important to discriminate among different nociceptive modalities. Although many nociceptive Aδ fibers also terminate within lamina I, a subset project to lamina V, where they overlap with the projections of nonnociceptive low-threshold mechanosensitive Aβ and Aδ fibers within the deeper lamina (III-V). This allows for the integration of nociceptive and nonnociceptive sensory inputs.
In the simplest arrangements, primary nociceptive afferents form simple axosomatic or axodendritic synapses with projection neurons, which then carry nociceptive signals forward to the brain. However, these arrangements represent only a small fraction of the neuronal network in the dorsal horn. More commonly, incoming nociceptive primary afferent fibers terminate at various excitatory and inhibitory interneurons, allowing for the complex modulation of incoming sensory information. The major neurotransmitter of excitatory interneurons is glutamate, while gamma-aminobutyric acid (GABA) and glycine are the main transmitters of inhibitory interneurons. Lamina II is enriched with interneurons, which have been studied in great detail and are classified based on morphologic criteria, as islet, central, vertical, and radial cells ( Fig. 16.3 ). Islet and central cells tend to arborize solely within the lamina that contains their cell body. Vertical cells exhibit dendritic trees that extend over multiple laminae and thus are able to integrate multiple incoming afferent signals. Vertical cells receive afferent input from C, Aδ, and Aβ fibers, whereas islet and central cells tend to receive input only from C-fibers. Islet cells are virtually all inhibitory and invariably release GABA or glycine, whereas radial and most vertical cells are excitatory and release glutamate. Central cells can be either excitatory or inhibitory. It should be noted that the relationship between morphology and neurochemical function is not strict. Nearly 30% of interneurons do not fall into a strict morphologic category.
Projection neurons carry nociceptive output from the dorsal horn to higher CNS structures. These efferent neurons are most densely present in lamina I, are virtually absent in interneuron-rich lamina II, and are scattered throughout the remaining laminae. Projection neurons belong to two general classes, nociceptive-specific projection neurons that exclusively transmit noxious signals, and wide-dynamic-range (WDR) projections neurons able to code for both noxious and nonnoxious signals. Nociceptive-specific projection neurons are concentrated within lamina I and are marked by the expression of the neurokinin-1 receptor (NK1R), the receptor targeted by the neuropeptide SP. SP-rich C-peptidergic nociceptors known to terminate within lamina I project to NK1R-expressing efferent neurons. While lamina III is not a significant target for nociceptive afferent fiber projections, a population of lamina III efferent neurons also expresses the NK1 receptor and receive nociceptive input by extending dendritic projections into the nociceptor-rich regions of laminae I and II. WDR projection neurons are concentrated within the deeper dorsal lamina V, where they receive inputs from nonnociceptive touch-coding Aβ fibers, nociceptive Aδ fibers, and interneurons originating in more superficial laminae. WDR neurons are unique in that they receive simultaneous input from somatic and visceral structures, allowing for the convergence of viscera-somatic signal, the neuronal substrate underlying the perception of referred pain (e.g., myocardial ischemia causing shoulder pain). Projection neurons ascend to numerous supraspinal structures, including nuclei in the brainstem and the thalamus, to mediate behavioral and emotional responses to pain.
Neurochemistry
Virtually all nociceptive afferents are excitatory and signal to postsynaptic structures through the release of glutamate. Fast transmission of excitatory signals within the dorsal horn is mediated by the binding of glutamate to postsynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and kainate receptors. The AMPA and kainate receptors are glutamatergic cation-permeable ion channels that exhibit fast activation and inactivation kinetics underlying the rapid depolarization of the postsynaptic membrane. Glutamate also activates NMDA receptors, but these glutamatergic channels are activated more slowly as they are potently blocked by magnesium ions at resting hyperpolarized membrane potentials. In the setting of high-strength synaptic input, activation of AMPA and kainate receptors produces sufficient membrane depolarization to relieve the voltage-dependent magnesium ion (Mg 2+ ) block of NMDA receptors, which results in activation of these channels. NMDA receptors are permeable for calcium. The influx of calcium through NMDA receptors in the setting of high-strength synaptic signaling is a hallmark of long-term potentiation (LTP), the long-lasting use-dependent enhancement of synaptic signal transmission. LTP in the dorsal horn is one of a number of mechanisms underlying spinally mediated hyperalgesia (discussed later in this chapter)and the importance of NMDA receptors to this process is the rationale for the use of NMDA receptor antagonists like ketamine to prevent persistent pain after surgery. NMDA receptors exhibit complex pharmacologic regulation and varied subunit distributions, as further detailed in Fig. 16.4 .
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