Molecular Basis of Nociception

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CHAPTER 155 Molecular Basis of Nociception

This chapter describes the cellular and molecular substrate of nociception. Nociception comprises the afferent activity that is produced in the peripheral and central nervous systems by stimuli of sufficient intensity to (potentially) damage tissue.¹ Nociception is initiated by a subset of primary afferent (dorsal root ganglion and trigeminal ganglion) neurons that is specialized for the detection of tissue damage. This specialized subset (commonly referred to as nociceptors) was first identified and its very existence documented in neurophysiologic experiments performed in the late 1960s.^2,³ Nociceptors innervate all tissues of the body except for the neuraxis. The cornea, teeth, internal surface of the tympanic membrane, dura, and venous and bony sinuses within the cranium are innervated mainly, if not exclusively by nociceptors. Other tissues of the body are innervated by both nociceptive and non-nociceptive (low-threshold mechanoreceptor and thermoreceptor) primary afferent neurons. Innervation of the body surface by peripheral nerves follows the well-known pattern of radicular dermatomes.

Table 155-1 provides a breakdown of the various nociceptive and non-nociceptive fiber groups in peripheral nerves and the velocities at which they conduct action potentials along their axons. It can be seen that conduction velocity varies as a function of both axon diameter and extent of myelination. The vast majority of nociceptors conduct action potentials relatively slowly because they have small-diameter, thinly myelinated (group III/Aδ fiber), or unmyelinated (group IV/C fiber) axons, as do low-threshold thermoreceptors. Low-threshold, non-nociceptive mechanosensitive primary afferent neurons tend to have large-diameter, myelinated (Aβ) axons. Contrary to general belief, nociceptors with large-diameter, myelinated axons do exist⁴ but are much less numerous than nociceptors with small-diameter myelinated or unmyelinated fibers, and their input may not reach consciousness. Consequently, input from nociceptors with thinly myelinated (Aδ) axons is typically responsible for the “first pain” felt after sudden stimulation of the foot (by stepping on a nail or a hot surface), whereas nociceptors with unmyelinated (C) fibers are responsible for the “second pain” evoked by such stimuli.

TABLE 155-1 Classification of Sensory Fibers in Peripheral Nerves

Under normal circumstances, nociceptors produce action potential discharge only in response to tissue-damaging stimuli and have the ability to code the intensity of a noxious stimulus by proportionally varying the frequency of action potential discharge. In contrast, non-nociceptive afferents (sensory receptors specialized for the detection of low-intensity, innocuous stimuli) are unable to signal the intensity of noxious stimuli because the firing frequency of these neurons becomes saturated at noxious levels of stimulation. Microneurographic recordings ⁵ and microstimulation with microelectrodes inserted into the fascicles of peripheral nerves make possible a direct correlation between action potential discharge in identified primary afferent neurons and concomitant reports of sensations in humans.⁶^–¹⁰ Skin is densely innervated by nociceptors, and the sensory pathways preserve a high degree of somatotopic organization, as shown by the small projected receptive fields of the sensations that are evoked by electrical stimulation of nociceptors through the microneurography electrodes. The electrical receptive fields agree rather well with the receptive fields determined by natural stimulation of nerve endings.⁸ Electrical activation of very few, perhaps even a single peripheral nociceptor, is sufficient to produce a pain sensation. Initiation of the sensation in these circumstances requires temporal summation of several action potentials. Above the threshold level, the intensity of the sensation is proportional to the stimulus frequency. The quality of pain evoked by electrical stimulation of nociceptors depends on the target tissue and the subtype of nociceptor that is stimulated. Activation of cutaneous Aδ nociceptor afferents typically evokes sharp, prickling pain, whereas stimulation of C-fiber nociceptors causes dull or burning pain (and in some cases itching).⁸ Recordings in humans have demonstrated that the intensity of burning pain evoked by heat applied to the skin is best matched by the frequency of action potential discharge in mechanoheat and heat-specific nociceptors with C fibers.¹¹ In contrast, the intense burning pain felt after intracutaneous injection of capsaicin is best matched by the level of discharge in mechanoinsensitive (chemospecific) and heat-specific nociceptors with C fibers.¹² Activation of nociceptive C fibers that innervate muscle gives rise to cramping pain.¹³

Properties of Nociceptors That Innervate Different Peripheral Organs

Visceral Nociceptors

Viscera are particularly sensitive to distention but may be quite insensitive to cutting or burning. The peripheral basis of visceral pain differs from that in other body regions.^14,¹⁵ The distinction between responses to innocuous and noxious stimulation has been more difficult to make for visceral neurons because there is a much wider overlap in their response properties and some neurons are spontaneously active even in the absence of obvious sensitization or intentional stimulation.¹⁶ When compared with cutaneous tissues, pain from visceral tissues is more difficult to localize, most likely because of lower innervation density.

Deep Nociceptors of Muscles and Joints

Muscle pain occurs during sustained muscular contraction and ischemia, after trauma, or after eccentric exercise.^17,¹⁸ Slightly less than half of the group III and IV fibers in muscle are thought to be nociceptors; the remainder are low-threshold afferents thought to signal deep pressure and thermosensitive afferents believed to be involved in thermoregulation (for an extensive review see Mense¹⁹). Pain is the major sensation that is ascribed to the joint.²⁰ Joints are frequently affected by inflammatory and degenerative disorders and by injury. Experimentally induced arthritis causes dramatic changes in the response properties of joint afferent fibers.²¹ Sensitization has been directly documented in long-term electrophysiologic recordings from single identified afferent fibers during the development of acute inflammation.²² These experiments have shown that joints receive substantial innervation by the so-called silent (or mechanically insensitive) nociceptors, which only begin to respond to moderate-strength stimuli once inflammation becomes established.

Nociceptors at the Body Surface

Because of easy accessibility to experimental manipulation, cutaneous ^2,³ and corneal^24,²⁵ nociceptive neurons have been studied extensively. Much of the information on nociceptors provided later is based on studies of cutaneous nociceptors.

Physiologic Subtypes of Cutaneous Nociceptors

Collectively, nociceptive primary afferent neurons are able to sense three (thermal, mechanical, and chemical) submodalities of noxious stimulation, whereas individual nociceptors are inhomogeneous and respond to various combinations of the three submodalities. Most common are polymodal nociceptors that respond to mechanical and heat stimuli. These include A-fiber type II mechanoheat nociceptors (AMHs), which have a heat threshold of approximately 45°C, and type I AMHs, which have a heat threshold that is higher (>51°C). The latter become sensitized to heat by brief (≈30-second) exposure to high temperatures. Polymodal nociceptors in the C-fiber group are referred to as type 1A nociceptors.²⁶ Type 1A nociceptors are typically excited by moderately intense mechanical and heat stimuli in excess of 42°C. Approximately half of type 1A nociceptors also respond to noxious cold (near-freezing) temperatures. A second major group of C-fiber nociceptors is the type 1B afferents,²⁶ which respond with a vigorous discharge to noxious chemical stimuli but are essentially insensitive to mechanical and thermal stimulation. Mechanically insensitive C-fiber nociceptors that react only to noxious heat or cold are known to also exist.¹² The existence of different subtypes of nociceptor, some that respond to all submodalities of noxious stimulation and others that respond to only some, implies that the nociceptors express different, more or less specialized, transducer molecules.

Nociceptive Transduction Mechanisms

As in other sensory receptors, signaling by nociceptors starts with transduction, a process in which environmental stimuli evoke conformational changes in protein molecules located at nociceptor terminals that directly (or indirectly via cellular signaling cascades) trigger the opening of excitatory or the closing of inhibitory ion channels (or both). The resulting change in ionic flow across the plasma membrane (the generator current) leads to a depolarization that (if the generator potential exceeds a threshold) causes discharge of action potentials by the axon. If as recently postulated (see later), nociceptive transduction is initiated by accessory (non-neuronal) cells (e.g., keratinocytes), the generator potential in the nociceptor (in the absence of electrotonic coupling) would have to be triggered by transmitter molecules (released by the accessory cells) acting on the sensory nerve ending.

Thermosensitivity

A major breakthrough in the search for molecules that may be responsible for the transduction of noxious stimuli arrived with the cloning of a membrane ion channel called TRPV1 (for transient receptor potential vanilloid subtype 1).²⁷ TRPV1 responds to heat with a threshold of about 42°C, a temperature comparable to the heat threshold of most heat-sensitive C-fiber nociceptors. Additional thermosensitive channels (members of the TRP superfamily) were cloned soon thereafter: TRPV2, a membrane channel with a higher threshold for heat activation (>52°C²⁸) that is comparable to the temperature threshold of some mechanoheat nociceptors with Aδ fibers (the type I AMHs); TRPA1, which may mediate response to noxious cold stimuli (with a threshold for activation of around 15°C); the warm-sensitive TRPV3 and TRPV4 (apparent thresholds of 32°C to 39°C and 27°C to 34°C, respectively),²⁹ and TRPM8, an ion channel that is activated by gentle cooling from neutral skin temperature (≈32°C). All of these channels are excellent candidates for thermal transduction by non-nociceptive thermoreceptors (the so-called warm and cold fibers, respectively). Responses of TRPV3 receptors continue to increase as the stimulus temperature is increased into the noxious range,³⁰ thus suggesting that in addition to sensing warmth, TRPV3 receptors may contribute to nociception. Three additional TRP channels, TRPM2, TRPM4, and TRPM5, can also be activated by warm temperatures; however, evidence for their expression in skin is still lacking.²⁹ All thermosensitive TRP molecules are nonselective cation channels with a high temperature coefficient (Q₁₀ ≈ 20) governing the kinetics of opening and closing of the channel pore. Other molecules, such as the highly mechanosensitive and thermosensitive channels TREK-1 (a “TWIK-related potassium channel,” where TWIK stands for “tandem P domain in a weak inward rectifier K⁺ channel”) and TRAAK (TWIK-related arachidonic acid–stimulated K⁺ channel), may contribute to the thermosensitivity of primary afferent neurons.³¹ Although these known thermosensitive channels cover the entire temperature range from 0°C to higher than 50°C,³² behavioral studies on transgenic mice, pharmacologic studies on native sensory nerve endings in vitro, and patch-clamp recordings from cultured dorsal root ganglion neurons indicate that additional thermosensitive ion channels remain to be cloned.

Chemosensitivity

Chemonociceptors (Fig. 155-1) express a multitude of specific molecular receptors for the endogenous inflammatory mediators bradykinin (both B2 and B1 receptors), serotonin (5-HT₃ receptors), prostaglandin E₂ (EP receptors), histamine, and protons (the acid-sensitive ion channels ASIC 1, 2, and 3).³³^–⁴² Sensitivity of nociceptors to these inflammatory mediators plays a central role in many forms of inflammatory pain.^43,⁴⁴ Nociceptive neurons also express receptors for extracellular adenosine triphosphate (ATP), which is released in large quantities from neighboring cells when they are damaged. Most prominent among the receptors for ATP are metabotropic receptors made of P2Y subunits and ionotropic receptors consisting of P2X2 and P2X3 subunits. Administration of P2X3 antagonist drugs or antisense oligonucleotides to animals reduces both inflammatory hyperalgesia and neuropathic pain.⁴⁵

FIGURE 155-1 Overview of the factors and cells involved in the activation and sensitization of nociceptive neurons after tissue damage and inflammation. Note that substances released by inflammatory cells act on the nerve ending. Substances released by the nerve ending (e.g., substance P) may in turn facilitate the inflammatory response. ATP, adenosine trisphosphate; diHETE, 8(R),15(S)-dihydroxyeicosatetraenoic acid; H⁺, protons; 5-HT, 5-hydroxytryptamine; LTB₄, leukotriene B₄; LTD₄, leukotriene D₄; NGF, nerve growth factor; PGI₂, prostacyclin; PGs, prostaglandins E₁, E₂, or F_2α.

(From Rang HP, Bevan S, Dray A. Chemical activation of nociceptive peripheral neurones. Br Med Bull. 1991;47:534-548.)

Confounding the concept of thermal, mechanical, and chemical submodality specificity of nociception, many thermosensitive TRP channels are polymodal molecular receptors in the sense that besides being gated by temperature, they are also gated by a number of exogenous chemicals and endogenous inflammatory mediators. Among the exogenous chemicals that gate TRP channels are certain phytochemicals that are well known for the particular thermal sensation that they elicit: capsaicin, piperine, and resiniferatoxin (which when applied to skin or mucosa produce the sensation of burning) gate open TRPV1; menthol (which produces the sensations of cooling and occasionally stinging or burning) gates TRPV3, TRPM8, and TRPA1; and camphor (which when rubbed into the skin gives rise to the sensation of warmth) gates TRPV3 (which is also gated by carvacrol, thymol, eugenol, and vanillin).

A wide spectrum of inflammatory mediators that sensitize or activate nociceptors have been found to gate or sensitize TRP channels. TRPV1 is gated by metabolites of 12- and 15-lipoxygenase (leukotriene B₄ and 15(S)-hydroxyeicosatrienoic acid), N-arachidonyl dopamine, and protons. Other phytochemicals that activate TRPV1 include piperine and resiniferatoxin. Activation of phospholipase C (removal of phosphatidylinositol 4,5-bisphosphate from the membrane) facilitates the activation of TRPV1, and so does phosphorylation of TRPV1 by protein kinase C. Phosphorylation of TRPV1 by protein kinase A slows the time course of TRPV1 desensitization. Therefore, activation of G protein–coupled receptors (e.g., protease-activated receptors, bradykinin receptors, P2Y purinergic receptors, prostaglandin receptors, metabotropic glutamate receptors) strongly upmodulates TRPV1 channel activity in primary afferent neurons. TRPV4 is activated by several endogenous chemicals: anandamide, arachidonic acid, and 5′,6′-epoxyeicosatrienoic acid. TRPM8 responds to not only menthol but also icilin and eucalyptol. Interestingly, the cold-activated channel TRPM8 is modulated by phosphatidylinositol 4,5-bisphosphate in a direction that is opposite that of the heat-activated TRPV1 (TRPM8 requires phosphatidylinositol 4,5-bisphosphate for activity).

TRPA1 stands out by being activated by environmental pollutants and acrid chemicals such formaldehyde, acrolein, and the tear gases CN, CR, and CS.⁴⁶ Other exogenous chemicals that activate TRPA1 are allicin, mustard oils (allyl isothiocyanates) in wasabi and horseradish, cinnamaldehyde, eugenol, gingerol, carvacrol, 2-pentenal, icilin, low concentrations of menthol (<100 µM, higher concentrations cause an open channel block), and Δ9-tetrahydrocannabinol. TRPA1 is also activated by chemicals originating from within the body such as arachidonic acid, bradykinin, 15-deoxy-Δ12,14-prostaglandin J₂ (a cyclopentane prostaglandin D₂ metabolite), and products of oxidative stress, including hydrogen peroxide, 4-hydroxynonenal, 4-oxononenal, and 4-hydroxyhexenal.⁴⁷ Most compounds known to activate TRPA1 are able to covalently bind cysteine residues.⁴⁸

Mechanosensitivity

There are good reasons to believe that noxious mechanical stimuli are transduced by ion channels that are gated open or closed by stretch or a change in curvature of the membrane. Such channels were recorded with patch-clamp methods, but the molecular identities of these channels remain largely to be elucidated. On the basis of sequence similarity to mechanosensitive molecules found in Caenorhabditis elegans, certain mec-related proteins have been tested in mammals. Mutant mice lacking a mec-2–related protein, stomatin-like protein 3 (SLP3), show a marked loss of touch sensitivity. SLP3 appears to be essential for mechanotransduction in a subset of cutaneous touch receptors. By contrast, similar studies indicate that three neuronal degenerin/epithelial sodium channel isoforms (the acid-sensing ion channels ASIC 1, 2, and 3) are not indispensable for mechanotransduction.²⁹ It therefore appears that several families of mechanosensitive molecules contribute to low-threshold mechanotransduction, but the ion channels involved in high-threshold mechanotransduction (mechanonociception) remain to identified.

Some thermosensitive TRP channels have a dual function as mechanotransducer molecules. In animal models of painful peripheral neuropathy associated with vincristine chemotherapy, alcoholism, diabetes, and human immunodeficiency virus/acquired immunodeficiency syndrome therapy, mechanical hyperalgesia (hypersensitivity to mechanical stimuli) was markedly reduced by spinal intrathecal administration of oligodeoxynucleotides antisense to TRPV4 mRNA.⁴⁹ (This treatment of mechanical hyperalgesia is effective because the dorsal root ganglia that harbor the cell bodies of primary afferent neurons reside within the intrathecal space and are therefore accessed directly by compounds injected intrathecally.) Two additional thermosensitive TRPV channels (TRPV1 and TRP2) have been implicated in mechanosensory signaling. TRPV2 is a candidate mechanotransduction channel because it can be activated by hypotonic and stretch stimuli in vitro.²⁹ TRPV1 might contribute to mechanotransduction in visceral organs.²⁹ It is unclear whether TRPV2 participates in mechanonociception because TRPV2 is expressed in large-diameter somatosensory neurons, most of which are not nociceptive (see earlier). TRPA1 has likewise been proposed to be involved in mechanotransduction. Recent work has demonstrated that inhibition of TRPA1 function reduces the mechanical hypersensitivity produced by inflammation. Acute application in a nerve-skin preparation of HC-030031, a selective TRPA1 antagonist, markedly reduced mechanically evoked action potential firing in rodent C fibers, particularly at high-intensity forces, but had no effect on the mechanical responsiveness of Aδ-fiber nociceptors.⁵⁰ Another recent study demonstrated that ND-C cells (a hybrid cell line derived from neonatal rat dorsal root ganglion neurons that expresses mechanosensitive ion channels and provides a useful expression system for testing candidate mechanosensitive ion channels), when transfected with the candidate mechanotransducer channel TRPA1, does not show an increase in mechanoactivated currents.⁵¹ Together, these perplexing and controversial results indicate that many types of molecules (yet to be identified) must work in concert to control the sensitivity of mechanonociceptors.

Sensitization of Nociceptors (Primary Hyperalgesia)

“Mechanically insensitive” afferents ⁵²^–⁵⁴ can be quite insensitive in normal healthy tissue but become markedly sensitized to mechanical stimuli by exposure to inflammatory mediators⁵² released by resident mast cells or by immune cells (macrophages, others) attracted to the site of tissue injury. Inflammatory mediators tend to lower the threshold for nociceptor excitation (causing allodynia, or pain evoked by normally innocuous stimuli) and increase nociceptor responses to suprathreshold stimuli (causing primary hyperalgesia, or more intense pain evoked by normally less painful stimuli).⁴³ Among the compounds that sensitize nociceptive neurons are eicosanoids (the cyclooxygenase products prostaglandins E₁ and E₂ and the 15-lipoxygenase product 8[R],15[S]-dihydroxyeicosatetraenoic acid^55,⁵⁶), kinins (bradykinin⁵⁷ and T-kinin⁵⁸), 5-hydroxytryptamine (5-HT), low pH,^59,⁶⁰ and ATP (see Fig. 155-1).⁶¹ Nociceptors are also sensitized by extracellular enzymes acting on the G protein–coupled protease-activated receptor 2 (PAR-2). Mast cell tryptase, trypsin, and trypsin-like proteases and coagulation factors VIIa and Xa are considered endogenous agonists of PAR-2. Inflammatory mediators control nociceptor action potential discharge by modulating voltage-gated ion channels through intracellular pathways that involve second messenger molecules such as inositol 1,4,5,-triphosphate, diacylglycerol, or cyclic adenosine monophosphate.^33,⁶²

Epithelial Cells as Sensory Receptor Cells

The previous description of nociceptive cells is based on the traditional view that nociceptive transduction in mammals occurs in the terminals of primary sensory neurons. In this traditional view, the surrounding cells (e.g., skin keratinocytes) are thought to provide only physical and trophic support to the nerve terminals. An emerging alternative view is that rather than being mere bystanders in the transduction process, non-neuronal cells are involved actively by providing function as primary transducers of physical and chemical stimuli and communicating excitatory events to neighboring somatosensory afferent fibers by releasing certain chemical messenger molecules. Keratinocytes express a number of receptor molecules that have been implicated in nociception or temperature sensation. In fact, some of these receptor molecules (e.g., TRPV3 and TRPV4) are more readily detected in keratinocytes than in primary somatosensory neurons. When tested in culture, keratinocytes generate measurable membrane currents after thermal or chemical stimulation that lead to changes in intracellular free calcium concentration. Thus, keratinocytes possess the transduction mechanism that would be required for stimulated release of chemical substances (e.g., ATP) for which nociceptive neurons express molecular receptors. Although such a mode of transduction of mechanical stimuli was demonstrated recently in vitro, direct evidence of keratinocyte to sensory neuron signaling in vivo is thus far lacking.²⁹ It is worth noting in this context that specialized epithelial (non-neuronal) cells in the nasal epithelium (called solitary chemoreceptor cells) appear to play an active role in the transduction of sensory irritant stimuli by relaying nociceptive information to the adjacent nerve endings of trigeminal ganglion neurons.⁶³

Neurogenic Inflammation

Some small-diameter primary afferent neurons, when activated by stimuli in the noxious range, play a major efferent function in inflammatory processes through the release of proinflammatory (calcitonin gene–related peptide [CGRP], substance P) molecules via the so-called axon reflex.⁶⁴ “Axon reflex” implies action potential conduction in the efferent direction (which happens when an action potential conducted in the orthodromic direction along one terminal branch in the periphery splits or is deflected at the axonal branch point and then, after being propagated in the antidromic direction, invades the other sensory terminal branch). Depolarization at the terminal causes the influx of calcium, which leads to release of neuropeptides (see Fig. 155-1). There is some evidence that neurogenic release of substance P contributes to the severity of arthritis.⁶⁵ It has been suggested that neurogenic release of CGRP is one of the driving forces in migraine, but this issue remains controversial.^66,⁶⁷ In addition to the proinflammatory action of substance P and CGRP, there is also experimental evidence for the anti-inflammatory action of other neuropeptides (e.g., somatostatin) released from the sensory nerve endings of primary afferent neurons.⁶⁸

Centripetal Transfer of Information

Molecules Responsible for Generation and Conduction of Action Potentials in Peripheral Nerve Fibers

Activation of mechanosensitive, thermosensitive, or chemosensitive molecules leads to depolarization of the sensory nerve ending. This process is highly modulated by intracellular messenger molecules (Fig. 155-2). Depolarization of the nerve ending above a certain threshold causes the generation of action potentials and their conduction along the axon. This process is mediated by voltage-gated sodium channels in conjunction with voltage-gated calcium and voltage-gated potassium channels. Primary afferent neurons use a variety of voltage-gated Na⁺ channels that differ in their sensitivity to tetrodotoxin (TTX). Some voltage-gated sodium channels are highly sensitive to TTX, some are resistant to TTX, and some are insensitive to TTX. TTX-resistant Na⁺ currents are mediated by the NaV1.8 and NaV1.9 protein subunits, TTX-insensitive currents by NaV1.5, and TTX-sensitive currents by the NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7 subunits. The prevailing view is that NaV1.8-mediated currents are mainly responsible for spike initiation in nociceptor terminals and cell bodies whereas axonal conduction is mediated by the TTX-sensitive channels NaV1.6 and NaV1.7. NaV1.7 subunits no doubt play a central role because mutations in NaV1.7 have been found to be responsible for a spectrum of pain disorders ranging from erythermalgia to complete insensitivity to painful stimuli.⁶⁹ However, the exclusion of NaV1.8 channels from axonal conduction in nociceptors may have to be revised in view of a recent study⁷⁰ in which it was documented that activity-dependent slowing^26,⁷¹ in meningeal C-fiber nociceptors is mediated by use-dependent entry of TTX-resistant Na⁺ channels into the inactivated, slow-recovery state. Mechanosensitive and mechanoinsensitive nociceptors probably use a somewhat different mix of voltage-gated ion channel subunits for conduction of action potentials because these two major classes of nociceptors differ in the pattern of activity-dependent slowing of conduction velocity,²⁶ but the particular ion channel subunits and ion pumps that contribute to this biophysical difference remain to be identified.

FIGURE 155-2 Simplified scheme showing some of the extracellular and intracellular processes involved in control of the excitability of nociceptive nerve terminals. Left, Cation channels gated extracellularly by pain-producing compounds such as capsaicin, protons, adenosine triphosphate (ATP), and serotonin (5-HT). Right, Receptors for inflammatory mediators such as bradykinin (BKN) and prostaglandin (PG). Activation of phospholipase-linked receptors (by BKN) and adenylate cyclase–linked receptors (by PG) results in the production of intracellular messengers (DAG, cAMP) that activate kinases, which then modulate the excitability of voltage- or calcium-gated ion channels. The generation of IP₃ causes an increase in calcium coming from intracellular stores, which facilitates the release of neuropeptides by the nerve ending. AA, arachidonic acid; AC, adenyl cyclase; cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP₃, inositol 1,4,5-trisphosphate; NSAIDs, nonsteroidal anti-inflammatory drugs; PKA, cAMP-dependent protein kinase; PKC, protein kinase C; PLA₂, phospholipase A₂; PLC, phospholipase C. SC19220 is a PG antagonist. The figure is a composite scheme of the excitatory pathways within the nociceptive terminal. The reader should keep in mind that any given nociceptive terminal may express receptors for only a subset of the chemical mediators.

(From Rang HP, Bevan S, Dray A. Chemical activation of nociceptive peripheral neurones. Br Med Bull. 1991;47:534-548.)

Axonal Projections

The cell bodies of all nociceptors are located in either the dorsal root ganglia or the trigeminal ganglia, where they are mixed with the cell bodies of non-nociceptive neurons and arranged in a loosely somatotopic fashion. Each cell body is connected to the peripheral and central branches of its axon via a short branch forming a T-shaped connection. Axons of nociceptive neurons project through the peripheral nerves, through the dorsal root ganglia (or the trigeminal ganglia), and through the dorsal roots accompanied by axons of non-nociceptive neurons (Fig. 155-3). The axons of visceral nociceptive neurons project through visceral nerves along with the axons of sympathetic and parasympathetic neurons (see Fig. 155-3). The central branch projects through the dorsal root to the spinal cord (or in the case of trigeminal nociceptors to the brainstem). As the spinal nerve root approaches the spinal cord, it splits into smaller rootlets. Axons with a larger diameter tend to aggregate in the medial and central rootlets, whereas small-diameter axons congregate in the more lateral rootlets, but the separation is not absolute. Early workers reported that cutting the lateral rootlets abolishes some behavior and reflexes that are normally triggered by nociceptive input,⁷² thus suggesting that chronic pain of peripheral origin could be treated by selective rhizotomy. However, subsequent studies showed that it is probably impossible to destroy nociceptive fibers selectively by cutting the lateral rootlets. Modern interpretation of the classic experiments is that the nociceptive deficits were due to vascular damage associated with cutting the dorsal roots.⁷³ As nociceptive axons in the dorsal roots enter the superficial root entry zone of the spinal cord, they bifurcate into short ascending and descending branches to form Lissauer’s tract, which caps the dorsal horn. From Lissauer’s tract, the nociceptors enter particular layers (laminae) of the dorsal horn (Fig. 155-4), where they synapse with local interneurons and projection neurons.

FIGURE 155-3 Schema of a spinal nerve and the different types of low- and high-threshold afferent fibers that it contains.

(From Bonica JJ. Anatomic and physiological basis of nociception and pain. In: Bonica JJ, ed. The Management of Pain, vol 1. Philadelphia: Lea & Febiger; 1990:28-94.)

FIGURE 155-4 Schematic diagram of primary afferent terminals in a transverse cross section of the lumbar spinal cord. Left, Terminal arbors of nociceptive fibers in the dorsal horn; right, typical terminal arbors of several subtypes of low-threshold mechanoreceptors. Note the difference in the shape of the terminal arbors and their location relative to laminae I to V.

(From Fitzgerald M. The course and termination of primary afferent fibres. In: Wall PD, Melzack R, eds. Textbook of Pain, 2nd ed. Edinburgh, Churchill Livingstone, 1989.)

There are some exceptions to the general rule that sensory information enters the spinal cord via the dorsal roots.⁷⁴ Some afferent axons enter via the ventral root.⁷⁴ About 30% of axons in the ventral root are unmyelinated, even in segments that contribute little to autonomic outflow. These unmyelinated axons might carry nociceptive information. Figure 155-5 shows the two possibilities for the ultimate course of these aberrant axons. Most fibers that enter the ventral root turn back and then enter the spinal cord through the dorsal root as usual (Fig. 155-5B). A few fibers also probably penetrate the cord from the ventral root and traverse the ventral horn to terminate in superficial layers of the dorsal horn (see Fig. 155-5A). These findings have been cited as one reason why dorsal rhizotomy frequently fails to relieve pain⁷⁵ and why dorsal root ganglionectomy may be a better surgical strategy for the elimination of all nociceptive afferent fibers to a spinal segment.

FIGURE 155-5 Aberrant course of some dorsal root ganglion neurons. A, Dorsal root ganglion neuron with an axon projecting through the ventral root and ventral horn and terminating in the dorsal horn of the spinal cord. B, Dorsal root ganglion neuron whose axon loops in the ventral root.

(From Bonica JJ. Anatomic and physiological basis of nociception and pain. In: Bonica JJ, ed. The Management of Pain, vol 1. Philadelphia: Lea & Febiger; 1990:28-94.)

Synaptic Transmission and Segmental Facilitatory Mechanisms

Primary afferent neurons synthesize excitatory amino acids and a wide variety of neuropeptides, any of which could potentially act as a synaptic neurotransmitter/neuromodulator.⁷⁶ The excitatory acid glutamate is the substance responsible for the fast excitatory synaptic actions of primary nociceptive neurons on second-order neurons in the spinal cord or trigeminal brainstem nuclei. Fast excitation is mediated by ion currents flowing through the membrane-spanning pore of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Substance P in conjunction with kinin receptors appears to mediate some of the slower synaptic actions. Other neuropeptides that are released from small-diameter primary afferent neurons (e.g., CGRP, vasoactive intestinal polypeptide, and somatostatin) may modulate synaptic transmission.⁷⁷