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.

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 recordings5 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.610 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, cutaneous2,3 and corneal24,25 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).3342 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

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

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