CHAPTER 1 Basic Science of Pain CASEY J. FISHER, MD • TONY L. YAKSH, PHD • KELLY BRUNO, MD • KELLY A. EDDINGER, BS, RVT INTRODUCTION detect noxious stimuli, they are triggered to discharge Clinically, the most commonly referenced definition of when the range of temperature or pressure corresponds pain initially described by Harold Merskey in 1964, and to what would be considered painful. The distal termi- as adopted by the International Association in the Study nals of these small C fibers display large branching den- of Pain in 1979, defines pain as “an unpleasant sensory dritic trees and are characterized as being “free” nerve and emotional experience associated with actual or po- endings. These nerve endings can be activated further tential tissue damage, or described in terms of such by many specific agents in the periphery in response damage.”1 In this chapter, we will give an overview of to tissue injury, inflammation, or infection in a the pathways involved in pain processing as it occurs concentration-dependent fashion. Table 1.1 depicts in both the central and peripheral nervous systems as the source and nature of these agents as well as the is currently conceived. This overview will include: anat- eponymous receptor on C fibers that is activated with omy involved in the processing of nociceptive stimuli; each agent. The fact that there are multiple stimulus the fundamentals of systems underlying acute nocicep- modalities for these C fibers that can lead to a signal tion and persistent pain states; and the linkage to of pain is the reason they are known as C-polymodal chronic pain and how the immune system plays a role nociceptors. In fact, C fibers can be characterized further in this processing. by what provokes them to fire. There are some C fibers that do not respond to mechanical stimulation. These so-called silent nociceptors, or mechanically insensitive PERIPHERAL ANATOMY afferents (MIAs), only respond to very high levels of e Primary Afferents2 4 nonphysiologic mechanical stimulation and/or heat. The signal of acute nociceptive pain is propagated However, they can acquire sensitivity in the face of pa- along sensory neurons, which have cell bodies (somas) thology, such as inflammation, which leads to a sensi- that lie in the dorsal root ganglia (DRG) and send one tized state and activation by relatively low-intensity of their axon projections to the periphery and the mechanical/thermal stimuli. other to the dorsal horn of the spinal cord in the Like C fibers, A-d fibers are small and can be high central nervous system. The axons of peripheral affer- threshold. But, A-d fibers are myelinated, and there- ents can be classified by anatomical characteristics fore, faster, with conduction velocity between 10 and (Erlanger-Gasser), Conduction Velocity (Lloyd-Hunt), 40 m/s. As such, A-d fibers act as nociceptors and and by their respective thresholds for activation. Most mediate “first” or “fast” pain, whereas C fibers are commonly, they are known by anatomical classification responsible for “second” or “slow” pain. To put this into two types of A fibers (b and d) and C fibers. in context, consider what happens when you touch a C fibers are small, unmyelinated, and therefore, slow hot object. Your immediate reaction is to pull your conducting fibers (<2 m/s). These primary sensory hand away, which is mediated by noxious thermal afferent neurons represent the majority of afferent fibers sensation activating fast conducting A-v afferents. found in the periphery and are most commonly high Typically, there is also a slower sensation of pain trav- threshold fibers, meaning they are not activated unless eling over the slowly conducting C fibers, which relay the stimulus (thermal, mechanical, or chemical) is at tissue damage in the form of a burning sensation. an intensity sufficiently high enough to potentially Some populations of A-d fibers can also be lower cause tissue injury. As nociceptors, or receptors that threshold at times, meaning they begin to discharge Pain Care Essentials and Innovations. https://doi.org/10.1016/B978-0-323-72216-2.00001-6 Copyright © 2021 Elsevier Inc. All rights reserved. 1 2 Pain Care Essentials and Innovations TABLE 1.1 allodynia is low-intensity tactile or thermal stimuli causing a pain state. This can occur in scenarios where Summary of Agents, Tissue Source, and there is nerve damage (for example, carpal tunnel or Receptors Found at C Fibers12. sciatic nerve lesions). Agents Tissue Source Receptors All of the afferent nerve fibers share the following Amines Mast cells H1 important characteristics related to the pattern in which (histamine) 5HT3 they respond to a stimulus and the manner in which Platelets they fire: (serotonin) i) Afferent nerve fibers display little or no sponta- fi Bradykinin Clotting factors BK 1, BK2 neous ring. They do not spontaneously discharge (bradykinin) like other nerve cells of the brain or heart; Lipidic acids Prostanoids EP ii) Peripheral afferents typically display a monotonic (PGE2), increase in discharge frequency that covaries leukotrienes with stimulus intensity. This means that if the thermal or mechanical intensity increases, there Cytokines Macrophages IL-1, TNFR (interleukins, will be a monotonic increase in discharge fre- tumor necrosis quency because there will be a greater depolari- factor) zation of the terminal, which will increase frequency of axon discharge; and Primary afferent C fibers NK1, peptides [substance P (SP), CGRP iii) Afferents serve to encode modality by being able calcitonin gene- to transduce thermal, mechanical, and/or chemi- related peptide cal signals into a depolarization based on their (CGRP)] individual nerve ending transduction properties. b fi Proteinases Inflammatory cells PAR3, For the larger A- ber afferents, the nerve endings (thrombin, trypsin) PAR1 are highly specialized, e.g., Pacinian corpuscle, and fi þ only respond to speci c low threshold stimuli, Low pH or Tissue injury [(H ), ASIC3/ fi hyperkalemia (Kþ), adenosine] VR1, A2 whereas the free nerve endings of the small C bers respond to a more diverse array of signals at higher Lipopolysaccharide Bacteria (LPS, TLR4, threshold. (LPS), formyl formyl peptide) FPR1 peptide Somatic and Visceral Afferents4,5 The location of peripheral afferents is also important when it comes to the type of pain sensation. Peripheral when the range of temperature or pressure corresponds afferent axon projections to the periphery are found to what would be nontissue damaging. In the case of throughout the body. The axon projections to the thermal stimulus, it would be considered a mildly skin, joints, and muscles are involved in somatic pain. noxious warm/hot sensation. In the case of mechanical The axon projections to the organs are involved in stimulus, it would be considered touch or pressure that visceral pain. The main functional differences between is borderline painful. A-d fibers also differ from C fi- afferents in the viscera and somatic systems are that bers in that they express specialized nerve endings there is little distinction between nociceptive afferents that serve to define their response characteristics. This and nonnociceptive afferents, and there is significant relationship will be delineated further in the periph- prevalence of MIAs in the viscera. The visceral afferents eral physiology section. only exist as high threshold and low threshold afferents, In contrast, A-b fibers are large, myelinated fibers the latter of which responds to a range of stimulation with the fastest conduction velocity (>40 m/s) of pri- intensities. The main anatomical difference between mary afferent neurons. They are low threshold afferent afferents in the viscera and afferents in the somatic sys- fibers that fire in response to low threshold mechanical tem is that there are significantly fewer afferents in the stimulation, such as touch or pressure. Under normal viscera. Less than 10% of the total spinal cord afferent physiologic states, activation of these afferents does input comes from the visceral afferents. This often not generate a noxious sensation. However, there are means that visceral input travels to its more central certain conditions in which these afferents initiate a projections along with somatic input. The concept of pain sensation, or allodynia. The definition of referred pain, whereby organ pathology causes a CHAPTER 1 Basic Science of Pain 3 WDR Visceral Afferent Somatic Afferent Coronary Left Arm Pain Ischemia FIG. 1.1 Viscerosomatic convergence. (Credit: Kelly A. Eddinger.) concomitant dermatomal spread of pain, is thought to CENTRAL ANATOMY be caused by convergence of somatic and visceral affer- First-Order Neurons: Spinal Dorsal Horn ents onto the same wide dynamic range neurons Projections6,7 (WDRs) at the dorsal horn level (see Fig. 1.1). This leads If the signal generated by an acute nociceptive stimulus is to the message generated by a visceral afferent being followed anatomically, from distally to proximally, the fl con ated with the input generated by a particular so- peripheral afferents extend through the DRG, where the “ matic region, thereby accounting for the referred afferent cell body lies, to the axon terminals of the spinal ” fi pain pro le of a visceral stimulus. WDR neurons will cord. Then, they terminate at the dorsal horn, where the be discussed further in the central anatomy section. dorsal root entry zone (DREZ) is found. The smaller 4 Pain Care Essentials and Innovations afferents tend to enter the DREZ more laterally, and the a way to organize the types of second-order neurons larger afferents tend to enter the DREZ more medially. that give rise to the tracts of the spinal cord (See The small and large afferents collectively enter the dorsal Fig. 1.2). As discussed earlier, specific sensory afferents horn as the fascicles that make up the nerve root. Nerve project to specific locations within the dorsal horn. roots are divided into cervical, thoracic, lumbar, and The most superficial, dorsal level of the dorsal horn sacral segments in a rostrocaudal distribution and enter is known as the marginal zone or Lamina I, according to on the ipsilateral side of the dorsal horn.