Introduction
Clinically, the most commonly referenced definition of pain initially described by Harold Merskey in 1964, and as adopted by the International Association in the Study of Pain in 1979, defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” In this chapter, we will give an overview of the pathways involved in pain processing as it occurs in both the central and peripheral nervous systems as is currently conceived. This overview will include: anatomy involved in the processing of nociceptive stimuli; the fundamentals of systems underlying acute nociception and persistent pain states; and the linkage to chronic pain and how the immune system plays a role in this processing.
Peripheral Anatomy
Primary Afferents
The signal of acute nociceptive pain is propagated along sensory neurons, which have cell bodies (somas) that lie in the dorsal root ganglia (DRG) and send one of their axon projections to the periphery and the other to the dorsal horn of the spinal cord in the central nervous system. The axons of peripheral afferents can be classified by anatomical characteristics (Erlanger-Gasser), Conduction Velocity (Lloyd-Hunt), and by their respective thresholds for activation. Most commonly, they are known by anatomical classification into two types of A fibers (β and δ) and C fibers.
C fibers are small, unmyelinated, and therefore, slow conducting fibers (<2 m/s). These primary sensory afferent neurons represent the majority of afferent fibers found in the periphery and are most commonly high threshold fibers, meaning they are not activated unless the stimulus (thermal, mechanical, or chemical) is at an intensity sufficiently high enough to potentially cause tissue injury. As nociceptors, or receptors that detect noxious stimuli, they are triggered to discharge when the range of temperature or pressure corresponds to what would be considered painful. The distal terminals of these small C fibers display large branching dendritic trees and are characterized as being “free” nerve endings. These nerve endings can be activated further by many specific agents in the periphery in response to tissue injury, inflammation, or infection in a concentration-dependent fashion. Table 1.1 depicts the source and nature of these agents as well as the eponymous receptor on C fibers that is activated with each agent. The fact that there are multiple stimulus modalities for these C fibers that can lead to a signal of pain is the reason they are known as C-polymodal nociceptors. In fact, C fibers can be characterized further 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 afferents (MIAs), only respond to very high levels of nonphysiologic mechanical stimulation and/or heat. However, they can acquire sensitivity in the face of pathology, such as inflammation, which leads to a sensitized state and activation by relatively low-intensity mechanical/thermal stimuli.
| Agents | Tissue Source | Receptors |
|---|---|---|
| Amines | Mast cells (histamine) Platelets (serotonin) | H1 5HT3 |
| Bradykinin | Clotting factors (bradykinin) | BK 1, BK2 |
| Lipidic acids | Prostanoids (PGE2), leukotrienes | EP |
| Cytokines | Macrophages (interleukins, tumor necrosis factor) | IL-1, TNFR |
| Primary afferent peptides | C fibers [substance P (SP), calcitonin gene-related peptide (CGRP)] | NK1, CGRP |
| Proteinases | Inflammatory cells (thrombin, trypsin) | PAR3, PAR1 |
| Low pH or hyperkalemia | Tissue injury [(H+), (K+), adenosine] | ASIC3/VR1, A2 |
| Lipopolysaccharide (LPS), formyl peptide | Bacteria (LPS, formyl peptide) | TLR4, FPR1 |
Like C fibers, A-δ fibers are small and can be high threshold. But, A-δ fibers are myelinated, and therefore, faster, with conduction velocity between 10 and 40 m/s. As such, A-δ fibers act as nociceptors and mediate “first” or “fast” pain, whereas C fibers are responsible for “second” or “slow” pain. To put this in context, consider what happens when you touch a hot object. Your immediate reaction is to pull your hand away, which is mediated by noxious thermal sensation activating fast conducting A-∂ afferents. Typically, there is also a slower sensation of pain traveling over the slowly conducting C fibers, which relay tissue damage in the form of a burning sensation. Some populations of A-δ fibers can also be lower threshold at times, meaning they begin to discharge when the range of temperature or pressure corresponds to what would be nontissue damaging. In the case of thermal stimulus, it would be considered a mildly noxious warm/hot sensation. In the case of mechanical stimulus, it would be considered touch or pressure that is borderline painful. A-δ fibers also differ from C fibers in that they express specialized nerve endings that serve to define their response characteristics. This relationship will be delineated further in the peripheral physiology section.
In contrast, A-β fibers are large, myelinated fibers with the fastest conduction velocity (>40 m/s) of primary afferent neurons. They are low threshold afferent fibers that fire in response to low threshold mechanical stimulation, such as touch or pressure. Under normal physiologic states, activation of these afferents does not generate a noxious sensation. However, there are certain conditions in which these afferents initiate a pain sensation, or allodynia. The definition of allodynia is low-intensity tactile or thermal stimuli causing a pain state. This can occur in scenarios where there is nerve damage (for example, carpal tunnel or sciatic nerve lesions).
All of the afferent nerve fibers share the following important characteristics related to the pattern in which they respond to a stimulus and the manner in which they fire:
- i)
Afferent nerve fibers display little or no spontaneous firing. They do not spontaneously discharge like other nerve cells of the brain or heart;
- ii)
Peripheral afferents typically display a monotonic increase in discharge frequency that covaries with stimulus intensity. This means that if the thermal or mechanical intensity increases, there will be a monotonic increase in discharge frequency because there will be a greater depolarization of the terminal, which will increase frequency of axon discharge; and
- iii)
Afferents serve to encode modality by being able to transduce thermal, mechanical, and/or chemical signals into a depolarization based on their individual nerve ending transduction properties. For the larger A-β fiber afferents, the nerve endings are highly specialized, e.g., Pacinian corpuscle, and only respond to specific low threshold stimuli, whereas the free nerve endings of the small C fibers respond to a more diverse array of signals at higher threshold.
Somatic and Visceral Afferents ,
The location of peripheral afferents is also important when it comes to the type of pain sensation. Peripheral afferent axon projections to the periphery are found throughout the body. The axon projections to the skin, joints, and muscles are involved in somatic pain. The axon projections to the organs are involved in visceral pain. The main functional differences between afferents in the viscera and somatic systems are that there is little distinction between nociceptive afferents and nonnociceptive afferents, and there is significant prevalence of MIAs in the viscera. The visceral afferents only exist as high threshold and low threshold afferents, the latter of which responds to a range of stimulation intensities. The main anatomical difference between afferents in the viscera and afferents in the somatic system is that there are significantly fewer afferents in the viscera. Less than 10% of the total spinal cord afferent input comes from the visceral afferents. This often means that visceral input travels to its more central projections along with somatic input. The concept of referred pain, whereby organ pathology causes a concomitant dermatomal spread of pain, is thought to be caused by convergence of somatic and visceral afferents onto the same wide dynamic range neurons (WDRs) at the dorsal horn level (see Fig. 1.1 ). This leads to the message generated by a visceral afferent being conflated with the input generated by a particular somatic region, thereby accounting for the “referred pain” profile of a visceral stimulus. WDR neurons will be discussed further in the central anatomy section.
Central Anatomy
First-Order Neurons: Spinal Dorsal Horn Projections ,
If the signal generated by an acute nociceptive stimulus is followed anatomically, from distally to proximally, the peripheral afferents extend through the DRG, where the afferent cell body lies, to the axon terminals of the spinal cord. Then, they terminate at the dorsal horn, where the dorsal root entry zone (DREZ) is found. The smaller afferents tend to enter the DREZ more laterally, and the larger afferents tend to enter the DREZ more medially. The small and large afferents collectively enter the dorsal horn as the fascicles that make up the nerve root. Nerve roots are divided into cervical, thoracic, lumbar, and sacral segments in a rostrocaudal distribution and enter on the ipsilateral side of the dorsal horn.
High threshold, small, unmyelinated afferents (C fibers) project to the more superficial regions of the dorsal horn: Lamina I (marginal layer), Lamina II (substantia gelatinosa), and the central canal (Lamina X). These segmental penetrating axons also send axons rostrally and caudally, traveling in the lateral tract of Lissauer, up to the level at which they enter the dorsal horn. This collateralization can be up to several segments above or below the entry point into the dorsal horn. Low threshold, large, myelinated afferents (A-β fibers) project deeper into the dorsal horn (Laminae IV, V, and VI), a region known as the nucleus proprius. Smaller myelinated afferents (A-δ fibers) project to the marginal layer and substantia gelatinosa layers (Laminae I and II) as well as the deeper layer of the nucleus proprius (Lamina V). Larger A type fibers also collateralize up to 1 to 2 segments rostral or caudal to their entry point, but they collateralize in the dorsal columns to travel up to the dorsal column nuclei (see Fig. 1.2 ).
Second-Order Neurons: Dorsal Horn Anatomy and Functional Organization ,
The dorsal horn is made up principally of second-order neurons that will send projections into the ascending spinal tracts to transmit sensory information to the brainstem and cortex. These second-order neurons can be classified according to their functional characteristics as well as their anatomic location within the dorsal horn itself. Cross-sectional anatomy of the gray matter of the dorsal horn has been well characterized and is a way to organize the types of second-order neurons that give rise to the tracts of the spinal cord (See Fig. 1.2 ). As discussed earlier, specific sensory afferents project to specific locations within the dorsal horn.
The most superficial, dorsal level of the dorsal horn is known as the marginal zone or Lamina I, according to the Rexed Lamina(e) classification. The marginal zone is where C fibers and A-δ fibers terminate. As such, neurons in this layer respond selectively to high threshold stimulation and send projections into the spinal tracts located in the ventrolateral (or anterolateral) section of the cord on the contralateral side of entry. These tracts will eventually project to the various nuclei in the contralateral brainstem and thalamus, more formally known as the spinothalamic tracts. As discussed before, some of the neurons in the marginal zone project ipsilaterally for a few segments in the white matter along the dorsolateral tract of Lissauer before entering the gray matter on the contralateral side and joining the tracts in the ventrolateral quadrant of the spinal cord. These projections are otherwise known as part of the intersegmental system.
Lamina II, also known as the substantia gelatinosa, is where C fibers and A-δ fibers terminate. However, it is also where many local interneurons are located. Interneurons are second-order neurons that project from the more superficial dorsal horn layers to the deeper layers of the Nucleus Proprius (Laminae III, IV, V, and VI). These interneurons are classified as excitatory or inhibitory and serve to locally regulate the excitability of dorsal horn projection neurons. The complexity of this layer is due in part to the fact that second-order interneurons are in direct communication with second-order neurons, which make up the ascending spinal tracts that are all in communication, either directly or indirectly, with the original primary afferents, including C fibers and A-δ fibers.
The nucleus proprius (Laminae III, IV, V, and VI), where large, myelinated, primary afferents (A-β fibers) terminate, has large-soma neurons, which send their dendrites up into the upper lamina to make contact with small, high threshold afferent input. Large, low threshold afferents make synaptic contact on the cell bodies and the ascending dendrites. Thus, they receive convergent low and high threshold input. This enables them to respond to low threshold and show increasing discharge rates with increasing stimulus intensities as small afferents are engaged. Accordingly, these cells are referred to as WDR neurons.
The central canal (Lamina X) is the deepest layer of the dorsal horn. This location is where a large amount of visceral afferent input occurs and where smaller somatic afferents (C fibers and A-δ fibers) also terminate. Signals received here are high threshold temperature and noxious mechanical stimulation. The tracts located here are the second-order neurons that are crossing midline and ascending to form the anterolateral portion of the spinothalamic tracts.
Organization of the dorsal horn is not strictly based on anatomic location of the second-order neurons. Second-order neurons can also be organized by how they respond to stimuli and, therefore, by their function. There are high threshold neurons in Lamina I and II that are nociceptive specific and respond only to highly intense stimulation. The other type of second-order neuron, described above, which is based on how it responds is the WDR neuron (see Table 1.2 ). As the name suggests, these neurons respond to a wide range of stimulus intensities and they are able to respond with increased frequency based on how intense the stimulation is that they are receiving. This concept of a graded response to stimulation is how innocuous light touch is differentiated from a noxious pinch or squeeze. The location of these neurons is principally in the nucleus proprius (Laminae III, IV, V, and VI).
| Primary Afferents | Secondary Projections | Tertiary Projections | Results |
|---|---|---|---|
| C fibers | Dorsal horn—Laminae I and II | Spinothalamic tracts to mediodorsalis nucleus of thalamus | Anterior cingulate cortex—emotional pain response |
| A-δ fibers | Dorsal horn—Laminae II and V | Spinothalamic tracts to ventrobasal thalamus | Somatosensory cortex—precision mapping of pain response |
| A-β fibers | Dorsal columns collateralization | Dorsal columns to medial lemniscus | Somatosensory cortex—tactile sensation and proprioception |
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