Keywords

FormalPara Key Concepts

  • Physiological pain is an adaptive protective mechanism.

  • Nociceptors are primary sensory neurons specialized to detect environmental threatening or damaging inputs to initiate a protective response.

  • The pain perception is a cascade of events starting with transduction, followed by conduction, transmission, and eventually modulation and perception.

  • Endogenous attenuation of the nociceptive pain signal involves segmental inhibition, the endogenous opioid system, and the descending inhibitory system.

Introduction

Nociception and pain perception comprise two different events. Nociception is the activation of sensory neuronal pathways upon stimulation by noxious stimuli, while pain refers to one’s perception of this experience after the brain processes the transmitted signal. Nociception may lead to pain, yet a person may experience pain without activation of the nociceptive pathway. Noxious perception is a complex process that begins in periphery, extends along the neuraxis, and terminates in supraspinal regions responsible for perception, interpretation, and reaction. This process includes nociceptor activation, neural conduction, spinal transmission, and modulation of the stimuli and ultimately spinal and supraspinal responses (Fig. 3.1).

Fig. 3.1
figure 1

General schematic diagram showing nociception from the site of injury to the spinal cord (CNS). Transmission occurs in the blue boxes, which are discussed in more detail in Fig. 3.3 (With permission from Nature Publishing Group, GLIA: Watkins LR, Maier SF. A novel drug discovery target for clinical pain. Nat Rev Drug Discov. 2003;2(12), fig 1)

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Transduction

Transduction is the process by which potential harmful mechanical, chemical, or thermal stimuli are converted by peripheral nociceptors into action potential within the distal fingerlike nociceptor endings.

Nociceptors

Sherrington first described nociceptors about a century ago. These are sensory neurons with free nerve endings consisting of receptor subtypes that can be excited by mechanical, temperature, and chemical stimuli applied to skin, muscles, joints, bone, viscera, and dura. Yet, they are not excited by innocuous stimuli (e.g., gentle warming or light touch). The intensity of the stimulus determines the initial response. Nociceptors have a high threshold and normally respond only to stimuli of sufficient energy to potentially or actually damage tissue. There are two categories of nociceptors: (a) thinly myelinated (Aδ fibers) and (b) unmyelinated (C fibers). These primary sensory neurons have their cell bodies in dorsal root ganglia [DRG] and give rise to a single axon that bifurcates into a peripheral branch that innervates peripheral target tissue and a central axon that enters the CNS to synapse on nociceptive second-order neurons in the dorsal horn of the spinal cord. As such the unit components of the nociceptor include:

  • Peripheral terminal that innervates target tissue and transduces noxious stimuli

  • Axon that conducts action potentials from the periphery to the central nervous system

  • Cell body in the dorsal root ganglion

  • Central terminal where information is transferred to second-order neurons at central synapses.

Following their origin from the neural crest, nociceptors undergo a distinct differentiation pathway that leads to formation of two characteristic subgroups:

  1. (a)

    “Peptidergic”: Express CGRP and substance P. Calcitonin gene-related protein [CGRP ] is a 37-amino acid peptide found in peripheral and central terminal of nearly 50% of the C fibers and 35% of Ad fibers. Substance P is an 11-amino acid peptide found in a subset of nociceptive neurons.

  2. (b)

    “Non-peptidergic”: Do not express peptides but express signaling components to respond to glial cell-derived growth factor [GDNF ].

Nociceptor Activation

Noxious stimuli are converted into an ion flux. A heterogeneous group of receptors is present on the surface of nociceptors, and they are responsive to various stimuli [polymodal] primarily due to the presence of polycationic channels. Tissue injury mediators activate transducer molecules such as transient receptor potential [TRP] ion channel. TRP channels are a diverse family of ion channels that respond to thermal [TRPV1], traumatic, and chemical [TRPA and TRPM] stimuli. TRPV1/capsaicin receptor is the best-described member of the family. It is a 4 subunit receptor which upon stimulation by H+ ions, heat, or capsaicin permits an inward flux of Ca2+ and Na+. This inward flux is responsible for generation of action potential by causing membrane depolarization and lowering the activation threshold (Fig. 3.2).

Fig. 3.2
figure 2

This is an illustration of a close-up area of the circle in Fig. 3.1. A heterogeneous group of receptors on nociceptors respond to various stimuli, leading to an influx and calcium and sodium, generating an action potential. While TRP channels respond to trauma, heat, and chemical stimuli, there are other channels that may be expressed. Na 1.8/1.9, TRPM8, and ASIC channels respond to mechanical, cold/menthol, and protons, respectively. P2X3 channels respond to ATP released from inflamed cells (Adapted from Macmillan Publishers Ltd., Scholz J, Woolf CJ. Can we conquer pain? Nat Neurosci. 2002;5:1062–7, fig 2)

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Tissue injury and cellular damage are associated with the release of noxious mediators such as arachidonic acid [AA] from lysed cell membranes as well as intracellular H+ and K+ ions. Furthermore, active metabolites of AA such as PGE2 PGG2 bradykinin play a significant role in the activation of peripheral nociceptor. They bind G-protein receptor proteins and activate intracellular signaling cascade such as extracellular-regulated kinase and adenylate cyclase which in turn a) activate ion channels by phosphorylation [e.g., TrpV1 phosphorylation] and b) increase the cell membrane ion channel turnover from internal stores. The net result is activation of Ca2+ and Na+ influx and membrane depolarization. There are different sodium channels expressed in somatosensory neurons. These include tetrodotoxin (TTX)-sensitive channels (Nav 1.1, 1.6, and 1.7) and TTX-insensitive channels (Nav 1.8 and 1.9). Of particular note, Nav 1.7 is largely involved with pain perception, as patients with loss-of-function mutations of this gene cannot detect noxious stimuli. The C nociceptors express both Nav 1.7 and Nav 1.8 sodium channels. These voltage-gated sodium channels are targets of local anesthetic drugs.

Conduction

The action potentials generated by activated nociceptors are conducted through different types of nociceptive fibers: thinly myelinated afferent nociceptors (Αδ nociceptors) and smaller diameter unmyelinated afferent nociceptors (C nociceptors) (Table 3.1). The Aδ fibers mediate the “first” wave of pain (acute, sharp pain), while the C fibers mediate the “second” wave of pain (delayed, diffuse, dull) perceived by the brain. These fibers conduct pain signals through the cell bodies, which are located in the dorsal root ganglia and the trigeminal ganglion for the body and face, respectively, and continue toward the dorsal horn of the spinal cord, where the nociceptive fibers synapse with second-order neurons.

Table 3.1 Classification of primary sensory neurons
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While it is anticipated to think of the nociceptive pathway as a one-way process, in reality it is more complicated. Primary afferent fibers are described as “pseudounipolar,” where the nociceptor can send and receive input from either the periphery or central terminals. Both ends serve as targets for endogenous regulatory factors and pharmacotherapy that alter the neuron’s threshold to fire in order to regulate pain.

Nociceptive signals are transduced to synapses in the dorsal horn through action potentials mediated mostly through voltage-gated sodium and potassium channels. Voltage-gated calcium channels facilitate neurotransmitter release at the dorsal horn synapse of nociceptor terminals to transmit pain signals. The activation of the various nociceptors and ion channels leads to the propagation of action potentials from peripheral nociceptive endings via myelinated and unmyelinated nerve fibers, in a process termed conduction.

A heterogeneous group of voltage-gated calcium channels are also expressed on nociceptors. All calcium channels are heteromeric proteins, consisting of α1 pore-forming subunits and modulatory subunits α2δ, α2β, or α2γ. In C nociceptors, the α2δ subunit is upregulated in nerve injury and contributes to hypersensitivity and allodynia. This is the target of gabapentin and pregabalin, used to treat neuropathic pain.

Transmission

Transmission refers to the transfer of noxious impulses from primary nociceptors to cells in the spinal cord dorsal horn. Both Αδ and C fibers conduct nociceptive input via first-order neurons, which upon entering the spinal cord travel up or down for one to two vertebral levels in Lissauer’s tract before synapsing with second-order neurons in the dorsal horn of the spinal cord. When the signal arrives at the central terminals of nociceptors, depolarization leads to activation of the N-type calcium channel. The influx of calcium leads to the release of the predominant excitatory neurotransmitters at the level of the dorsal horn, glutamate, and substance P (see Fig. 3.3).

Fig. 3.3
figure 3

This is a close-up of the area in the smaller square of Fig. 3.1. The release of vesicles containing excitatory neurotransmitters, substance P, and glutamate is Ca dependent (With permission from Springer, Rodger IW. Analgesic targets: today and tomorrow. InflammoPharmacology 2009;17(3))

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Glutamate activates postsynaptic AMPA and kainate subtypes of ionotropic glutamate receptors. Substance P activates postsynaptic NK1 receptors (Table 3.2). The activation of these receptors generates excitatory postsynaptic currents (EPSCs) in the second-order neurons located in the dorsal horn. The summation of subthreshold EPSCs results in action potential firing and transmission of pain signals to higher-order neurons. Transduction of pain is also modulated by neurotransmitters and neuropeptides that influence nerve transmission threshold, thus affecting one’s increased or decreased sensitivity of pain perception.

Table 3.2 Receptors associated with dorsal horn noxious signals
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Of note, glutamate and substance P lead to activation of glial cells. Microglia function as macrophages and are homogeneously dispersed in the gray matter of the spinal cord. These are presumed to function as sentinels of injury or infection. Glia found outside of the spinal cord may be involved in pain enhancement. Their expression is upregulated in pain conditions while they produce proinflammatory and neuroexcitatory substances, including interleukin-1β, tumor necrosis factor-α, and IL-6, among others. Glial activation increases neuronal excitability while opposing opioid analgesia and enhancing opioid tolerance and dependence.

In the dorsal horn, primary nociceptor afferent nerve fibers synapse into specific laminae (Table 3.3). Predominantly, second-order cells are located in Rexed’s laminae II (substantia gelatinosa) and V (nucleus proprius). Spinal cord neurons within lamina I and II are generally responsive to noxious stimulation, while neurons located in laminae III and IV are responsive to non-noxious stimuli (Aβ fibers). Neurons in lamina V receive both non-noxious and noxious inputs via direct Aδ/Aβ inputs and non-direct C fiber inputs through interneurons in lamina II.

Table 3.3 Functional classification of dorsal horn neurons
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The second-order neurons in lamina V are collectively referred to as wide dynamic range (WDR) neurons as they respond to a wide range of stimulus intensities. It is also the location of where some visceral inputs occur. The convergence of somatic and visceral inputs explains the phenomenon of referred pain, where pain from an injury to a visceral tissue is referred to a somatic structure (e.g., shoulder discomfort with a heart attack). Second-order neurons conducting nociceptive stimuli cross the spinal midline and ascend via the spinothalamic tract to the thalamus where a synapse occurs with the third-order neurons. This pathway describes how pain information is transmitted as well as how normal thermal stimuli <45°C are transmitted. Thalamic stroke patients may have a dysfunctional thalamus which may be a source of pain without involvement of the spinothalamic pathway. This is referred to as “thalamic pain.”

In the facial area , noxious stimuli are transmitted through nerve cells in the trigeminal ganglion and cranial nuclei VII, IX, and X. These travel to the medulla, cross the neural midline, and ascend to the thalamic nerve cells on the contralateral side. Spontaneous firing of the trigeminal nerve ganglion may give rise to “trigeminal neuralgia.” This is commonly caused by local trigeminal nerve damage as a result of a mechanical compression by the cerebellar artery.

Perception

The thalamic region receiving pain transmission from the spinal cord and the trigeminal nuclei also receives normal sensory stimuli (i.e., touch and pressure). From the thalamic nuclei, the third-order neurons conduct impulses to the somatosensory cortices. This is where sensory-discriminative component of pain is processed. By having both nociceptive and normal somatic sensory information converging in the same area of the brain, location and intensity of pain can be processed into a localized perception of pain. The cortical representation of the body (described by Penfield’s homunculus) may change after limb amputations, causing “phantom pain” as well as non-painful sensations like “telescoping phenomena.”

The third-order neurons also project the pain signal to the limbic structures, namely, the anterior cingulate cortex and the insula. Here, the emotional and cognitive components of pain are processed.

Modulation

The concept of modulation refers to pain-suppressive mechanisms within the spinal cord dorsal horn and at the higher levels of brain stem and midbrain. Studies of endogenous inhibition of pain started around the time of World War II when Dr. Beecher noted injured soldiers often experience little or no pain despite sustaining severe battle wounds. There have been studies on the dissociation between body injury and pain, and three mechanisms have been described in literature: segmental inhibition, the endogenous opioid system, and the descending inhibitory nerve system.

Segmental Inhibition

In 1965, Melzack and Wall proposed the “gate theory of pain control,” which describes the ability of the transmission of pain signals from the Aδ and C nerve fibers to the dorsal horn be blocked or diminished. This led to the development of the TENS unit. The activation of large myelinated Aβ fibers (touch/proprioception) stimulates an inhibitory nerve that inhibits synaptic pain transmission (Fig. 3.4).

Fig. 3.4
figure 4

The gate control theory of pain (Melzack and Wall). Nociceptive signals from the peripheral C fibers inhibit the inhibitory interneuron while propagating excitatory signals to the spinothalamic tract. When mechanoreceptors are activated, the inhibition from the C fiber at the inhibitory interneuron is lessened, and the nociceptive signal to the spinothalamic tract is in competition with proprioceptive signals from the mechanoreceptors. + Excitatory synapse, − inhibitory synapse

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Endogenous Opioid System

Since the 1960s, opioid receptors have been found to be concentrated in the periaqueductal gray matter, lamina II of the dorsal horn of the spinal cord, as well as the ventral medulla. Studies have shown that mammals produce enkephalins, endorphins, and dynorphin, three endogenous compounds that bind to these opioid receptors. Along with the descending inhibitory nerve system, this serves as a pain modulatory system that may partly explain the subjective variability in pain perception among individuals.

Descending Inhibitory System

The periaqueductal gray matter in the upper brain stem, the locus coeruleus, the nucleus raphe magnus, and the nucleus reticularis gigantocellularis in the rostroventral medulla contribute to the descending pain suppression pathway. This inhibits ascending nociceptive information from the nociceptive pain pathway (Fig. 3.5). The axons involved in this pathway descend down the bilateral dorsolateral funiculus and synapses in laminae I, II, and V of the spinal cord. Some of the common inhibitory neurotransmitters are serotonin as well as norepinephrine. Drugs that serve to block reuptake of these neurotransmitters prolong their inhibitory action on the spinal cord neurons involved with pain transmission, leading to pain relief. This explains the use of serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants for their analgesic properties.

Fig. 3.5
figure 5

Diagram showing the descending inhibitory pathway . Pain signals from the peripheral sensory nerves are transmitted rostrally via the spinothalamic tract. At the thalamus, descending inhibition is initiated, and the inhibitory signals descend down and synapse in the dorsal horn of the spinal cord (With permission from Elsevier, Livingston A, Chambers P. Pain management in animals. 2000. p. 9–19, fig 2.2)

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Conclusion

The nociceptive pain pathway is complex, and this chapter provides for a broad overview to simplify for easier understanding. It is important to learn this system well in order to understand targeted pharmacological therapies to alleviate the perception of nociceptive pain as well as to understand pathologies described in later chapters that lead to dysfunction of this nociceptive pain pathway through peripheral and central sensitization.