Nociceptive 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.

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.