16 May


Abstract Pain research has uncovered important  neuronal mechanisms that underlie clin- ically relevant pain states such as inflammatory  and neuropathic  pain. Importantly,  both the peripheral and the central nociceptive system contribute significantly to the generation of pain upon inflammation  and nerve injury. Peripheral nociceptors are sensitized during inflammation, and peripheral nerve fibres develop ectopic discharges upon nerve injury or disease. As a consequence a complex neuronal response is evoked in the spinal cord where neurons become hyperexcitable, and a new balance is set between excitation and inhibition. The spinal processes are significantly influenced by brain stem circuits that inhibit or facil- itate spinal nociceptive processing. Numerous mechanisms are involved in peripheral and central nociceptive processes including rapid functional changes of signalling and long- term regulatory changes such as up-regulation  of mediator/receptor systems. Conscious pain is generated by thalamocortical  networks that produce both sensory discriminative and affective components of the pain response.

Keywords  Nociceptive system · Nociceptors · Inflammatory pain · Neuropathic pain · Peripheral sensitization · Central sensitization · Ectopic discharges ·

Descending inhibition · Descending facilitation

Introduction on Pain

Types of Pain

In daily life the sensation pain is specifically evoked by potential or actual nox- ious (i.e. tissue damaging) stimuli applied to the body such as heat, squeezing a skin fold or over-rotating  a joint. The predictable correlation  between the noxious stimulus  and the pain sensation  causes us to avoid behaviour  and situations  that  evoke pain. Pain during  disease is different  from “normal” pain. It occurs in the absence of external noxious stimuli, during mild stimu- lation or in an unpredictable  way. Types of pain have been classified accord- ing to their pathogenesis, and pain research intends to define their neuronal mechanisms.

Cervero and Laird (1991) distinguish between three types of pain. Applica- tion of an acute noxious stimulus to normal tissue elicits acute physiological nociceptive pain. It protects tissue from being (further) damaged because with- drawal reflexes are usually elicited. Pathophysiological nociceptive pain occurs when the tissue is inflamed or injured.  It may appear  as spontaneous  pain (pain in the absence of any intentional stimulation) or as hyperalgesia and/or allodynia. Hyperalgesia is extreme pain intensity felt upon noxious stimula- tion, and allodynia is the sensation of pain elicited by stimuli that are normally below pain threshold. In non-neuropathic pain, some authors include the low- ering of the pain threshold in the term hyperalgesia. While nociceptive pain is elicited by stimulation  of the sensory endings in the tissue, pain!neuropathic results from injury or disease of neurons in the peripheral or central nervous system. It does not primarily signal noxious tissue stimulation and often feels abnormal. Its character is often burning or electrical, and it can be persistent or occur in short episodes (e.g. trigeminal neuralgia). It may be combined with hyperalgesia and allodynia. During allodynia even touching the skin can cause

Peripheral and Central Mechanisms of Pain Generation

intense pain. Causes of neuropathic  pain are numerous,  including axotomy, nerve or plexus damage, metabolic diseases such as diabetes mellitus, or her- pes zoster. Damage to central neurons (e.g. in the thalamus) can cause central neuropathic  pain.

This relatively simple classification of pain will certainly be modified for several reasons. First, in many cases pain is not strictly inflammatory or neuro-

pathic because neuropathy may involve inflammatory components and neuro- pathic components may contribute to inflammatory pain states. Second, pain research now addresses other types of pain such as pain during surgery (inci- sional pain), cancer pain, pain during degenerative diseases (e.g. osteoarthri-

tis), or pain in the course of psychiatric diseases. This research will probably lead to a more diversified classification that takes into account general and disease-specific neuronal mechanisms.

An important aspect is the distinction  between acute and chronic  pain. Usually pain in patients is called “chronic” when it lasts longer than6 months (Russo and Brose 1998). Chronic pain may result from a chronic disease and

may then actually result form persistent nociceptive processes. More recently the emphasis with chronic pain is being put on its character. In many chronic pain states the causal relationship  between nociception and pain is not tight and pain does not reflect tissue damage. Rather psychological and social factors

seem to influence the pain, e.g. in many cases of low back pain (Kendall 1999). Chronic pain may be accompanied by neuroendocrine dysregulation, fatigue, dysphoria,  and impaired  physical and even mental performance  (Chapman

and Gavrin 1999).


The Nociceptive System: An Overview

Nociception is the encoding and processing of noxious stimuli in the nervous system that can be measured  with electrophysiological techniques. Neurons involved in nociception form the nociceptive system. Noxious stimuli activate primary nociceptive neurons with “free nerve endings” (Aδ and C fibres, no-

ciceptors) in the peripheral nerve. Most of the nociceptors respond to noxious mechanical (e.g. squeezing the tissue), thermal (heat or cold), and chemical stimuli and are thus polymodal (cf. in Belmonte and Cervero 1996). Nocicep-

tors can also exert efferent functions in the tissue by releasing neuropeptides [substance P (SP), calcitonin gene-related peptide (CGRP)] from their sensory endings. Thereby they induce vasodilatation, plasma extravasation, attraction

of macrophages or degranulation of mast cells, etc. This inflammation is called neurogenic inflammation (Lynn 1996; Schaible et al. 2005).

Nociceptors project to the spinal cord and form synapses with second order neurons in the grey matter of the dorsal horn. A proportion of second-order

neurons  have ascending axons and project to the brain stem or to the thala- mocortical system that produces the conscious pain response upon noxious

stimulation. Other spinal cord neurons are involved in nociceptive motor re- flexes, more complex motor behaviour such as avoidance of movements, and the generation of autonomic reflexes that are elicited by noxious stimuli.

Descending tracts reduce or facilitate the spinal nociceptive processing. The descending tracts are formed by pathways that originate from brainstem nuclei (in particular the periaqueductal  grey, the rostral ventromedial medulla) and descend in the dorsolateral funiculus of the spinal cord. Descending inhibition is part of an intrinsic antinociceptive system (Fields and Basbaum 1999).


The Peripheral Pain System: Primary Afferent Nociceptors


Responses to Noxious Stimulation of Normal Tissue

Nociceptors of different tissues are assumed to share most of their general properties. However, qualitative and quantitative  differences of neurons sup- plying different  tissues cannot  be ruled out, e.g. the mechanical  threshold of nociceptors may be quite different in different tissues because the poten- tially damaging stimuli may be of low (as in the cornea) or higher intensity (in the skin, muscle or joint). Furthermore,  evidence was provided that dor- sal root ganglion (DRG) neurons supplying fibres to different tissues differ in their passive and active electrophysiological properties (Gold and Traub 2004). Thus, subtle differences in nociceptor properties  may be important for pain mechanisms in different tissues.

In skin, muscle and joint, many Aδ andC fibres have elevated thresholds for mechanical stimuli, thus acting as specific nociceptors that detect potentially

or actually damaging mechanical stimuli. At least in the skin many nociceptors respond  to noxious heat. The heat threshold  may be below the frankly nox- ious range but the neurons encode different heat intensities by their response frequency. In some visceral organs such as the bladder, most slow-conducting

fibres have thresholds  in the innocuous  range and stronger responses in the noxious range, raising the possibility that visceral noxious stimuli are also en- coded by “wide dynamic range neurons” and not only by specific nociceptors.

In addition, many nociceptors are sensitive to chemical stimuli (chemosensi- tivity). Most of the nociceptors are thus polymodal (cf. Belmonte and Cervero).

Nociceptors are different from afferents subserving other modalities. Most fast-conducting Aβ afferents with corpuscular endings are mechano-receptors that respond vigorously to innocuous mechanical stimuli. Although they may show their strongest response to a noxious stimulus, their discharge pattern does not discriminate  innocuous  from noxious stimuli. A proportion of Aδ and C fibres are warmth or cold receptors encoding innocuous warm and cold stimuli but not noxious heat and cold.

In addition to polymodal nociceptors, joint, skin and visceral nerves contain Aδ and C fibres that were named silent or initially mechano-insensitive  noci- ceptors. These neurons are not activated by noxious mechanical and thermal stimuli in normal  tissue. However, they are sensitized during inflammation

and then start to respond  to mechanical and thermal  stimuli (Schaible and Schmidt 1988; Weidner et al. 1999). In humans this class of nociceptors exhibits a particular  long-lasting response to algogenic chemicals, and such nocicep- tors are crucial in mediating neurogenic inflammation (Ringkamp et al. 2001). Moreover, they play a major role in initiating  central sensitization  (Kleede et al. 2003). These neurons  have distinct  axonal biophysical characteristics separating them from polymodal nociceptors (Orstavik et al. 2003; Weidner et al. 1999).

Changes of Neuronal Responses During Inflammation

(Peripheral Sensitization)

During inflammation the excitation threshold of polymodal nociceptors drops such that even normally innocuous, light stimuli activate them. Noxious stimuli evoke stronger responses than in the non-sensitized  state. After sensitization of “pain fibres”, normally non-painful stimuli can cause pain. Cutaneous no- ciceptors are in particular  sensitized to thermal stimuli; nociceptors in deep somatic tissue such as joint and muscle show pronounced sensitization to me- chanical stimuli (Campbell and Meyer 2005; Mense 1993; Schaible and Grubb

1993). In addition, during inflammation  initially mechano-insensitive  nerve fibres become mechano-sensitive. This recruitment  of silent nociceptors adds

significantly to the inflammatory nociceptive input to the spinal cord. Resting discharges may be induced or increased in nociceptors because of inflamma- tion, providing a continuous afferent barrage into the spinal cord.


Peripheral Neuronal Mechanisms of Neuropathic Pain

In healthy sensory nerve fibres action potentials are generated in the sensory endings upon stimulation  of the receptive field. Impaired  nerve fibres often show pathological ectopic discharges. These action potentials are generated at the site of nerve injury or in the cell body in DRG. The discharge patterns vary from rhythmic firing to intermittent bursts (Han et al. 2000; Liu et al. 2000).

Ectopic discharges occur in Aδ and C fibres and in thick myelinated Aβ fibres. Thus, after nerve injury both low threshold Aβ as well as high threshold Aδ and C fibres may be involved in the generation of pain. Aβ fibres may evoke exaggerated responses in spinal cord neurons that have undergone the process

of central sensitization (see Sect. 3.3.2). Recently, however, it was proposed that pain is not generated by the injured nerve fibres themselves but rather by intact

nerve fibres in the vicinity of injured nerve fibres. After an experimental lesion in the L5 dorsal root, spontaneous  action potential discharges were observed in C fibres in the uninjured L4 dorsal root. These fibres may be affected by the process of a Wallerian degeneration (Wu et al. 2001).


Molecular Mechanisms of Activation and Sensitization of Nociceptors

Recent years have witnessed considerable  progress in the understanding of molecular events that lead to activation and sensitization of nociceptors. No- ciceptors express ion channels for stimulus transduction and action potential generation, and a large number of receptors for inflammatory and other medi- ators (Fig. 1). These receptors are either coupled to ion channels or, more often, activate second messenger systems that influence ion channels. Sensitization of nociceptors  by inflammatory  mediators  is induced within a few minutes. If noxious stimuli or inflammatory  conditions  persist, the expression of ion channels, receptors and mediator substances may change. An up-regulation of excitatory receptors may contribute to the maintenance of pain. Furthermore, some receptors exert trophic influences on the neurons regulating synthesis of mediators and expression of ion channels and receptors in these cells.

Molecular Mechanisms

Fig. 1 Model of the sensory ending of a nociceptor showing ion channels for transduction of thermal and mechanical stimuli and action potential generation and metabotropic receptors subserving chemosensitivity


TRP Channels

The first cloned nociceptive ion channel was the TRPV1 receptor,  which is expressed in about 40% of DRG cells. This ion channel is opened by binding of capsaicin, the compound  in hot pepper that causes burning pain. In par- ticular, Ca2+ flows through this channel and depolarizes the cell. The TRPV1

receptor  is considered  one of the transducers  of noxious heat because it is opened by heat (>43°C). In TRPV1 knock-out mice, the heat response is not abolished but the mice do not exhibit thermal  hyperalgesia during  inflam- mation,  showing the importance  of TRPV1 for inflammatory  hyperalgesia (Caterina et al. 2000; Davis et al. 2000). Up-regulation of TRPV1 transcription during  inflammation  explains longer-lasting  heat hypersensitivity  (Ji et al.

2002; Wilson-Gering et al. 2005). Following experimental  nerve injury and in animal models of diabetic neuropathy,  TRPV1 receptor is present on neu- rons that do not normally express TRPV1 (Rashid et al. 2003; Hong and Wi- ley 2005).

The TRPV1 receptor is a member of the TRP (transient  receptor protein) family. Other TRP members may be transducers of temperature stimuli in other ranges (Papapoutian et al. 2003). The TRPV2 receptor in nociceptors is thought to be a transducer  for extreme heat (threshold  >50°C). TRPA1 could be the transducer molecule in nociceptors responding to cold (Peier et al. 2002). It is activated by pungent compounds, e.g. those present in cinnamon oil, mustard oil and ginger (Bandell et al. 2004). By contrast, TRPV3 and/or  TRPV4 may be transduction molecules for innocuous  warmth  in warm receptors,  and TRPM8 may transduce cold stimuli in innocuous cold receptors. Although the putative warmth transducer TRPV4 shows some mechano-sensitivity, it is still unclear whether TRPV4 is involved in the transduction of mechanical stimuli (Marchand et al. 2005).

Voltage-Gated Sodium Channels and ASICs

While most voltage-gated Na+  channels are blocked by tetrodotoxin (TTX), many small DRG cells express TTX-resistant (R) Na+  channels (NaV1.8 and NaV1.9) in addition to TTX-sensitive (S) Na+ channels. Both TTX-S and TTX-R Na+ channels contribute  to the Na+ influx during the action potential. Inter- estingly, TTX-R Na+ currents are influenced by inflammatory mediators. They

are enhanced e.g. by prostaglandin E2 (PGE2) that sensitizes nociceptors (Mc- Cleskey and Gold 1999). This raises the possibility that TTX-R Na+ channels also play a role in the transduction process of noxious stimuli (Brock et al.

1998). SNS−/−  knock-out  mice (SNS is a TTX-R Na+  channel)  exhibit pro-

nounced  mechanical hypoalgesia but only small deficits in the response  to thermal stimuli (Akopian et al. 1999).

Acid sensing ion channels (ASICs) are Na+ channels that are opened by low pH. This is of interest because many inflammatory exudates exhibit a low pH. Protons directly activate ASICs with subsequent generation of action potentials (Sutherland et al. 2001).


Receptors of Inflammatory Mediators (Chemosensitivity of Nociceptors)

The chemosensitivity of nociceptors allows inflammatory  and trophic medi- ators to act on these neurons. Sources of inflammatory  mediators are inflam- matory cells and non-neuronal tissue cells. The field of chemosensitivity  is extremely complicated due to the large numbers of receptors that have been identified in primary afferent neurons (Gold 2005; Marchand et al. 2005). Re- ceptors that are involved in the activation and sensitization  of neurons  are either ionotropic  (the mediator  opens an ion channel) or metabotropic  (the mediator activates a second messenger cascade that influences ion channels and other cell functions). Many receptors are coupled to G proteins, which signal via the production of the second messengers cyclic AMP (cAMP), cyclic guano- sine monophosphate (cGMP), diacylglycerol and phospholipase  C. Other re- ceptor subgroups include receptors bearing intrinsic protein tyrosine kinase domains, receptors that associate with cytosolic tyrosine kinases and protein serine/threonine kinases (Gold 2005). Table 1 shows the mediators to which re- ceptors are expressed in sensory neurons (Gold 2005; Marchand et al. 2005). It is beyond the scope of this chapter to describe all the important mediators. Many of the mediators and their receptors will be addressed in the following chapters.

Functions  of mediators  are several-fold. Some of them activate neurons directly (e.g. the application of bradykinin evokes action potentials by itself ) and/or  they sensitize neurons  for mechanical, thermal and chemical stimuli (e.g. bradykinin and prostaglandins increase the excitability of neurons so that mechanical stimuli evoke action potentials  at a lower threshold  than under control conditions). PGE2, for example, activates G protein-coupled EP recep- tors that cause an increase of cellular cAMP. This second messenger activates protein kinase A, and this pathway influences ion channels in the membrane, leading to an enhanced excitability of the neuron with lowered threshold and increased action potential frequency elicited during suprathreshold stimula- tion. Bradykinin receptors are of great interest because bradykinin  activates

numerous  Aδ and C fibres and sensitizes them for mechanical and thermal stimuli (Liang et al. 2001). Bradykinin receptor  antagonists  reverse thermal

hyperalgesia, and Freund’s complete adjuvant induced mechanical hyperalge- sia of the rat knee joints. Some reports suggest that in particular  bradykinin B1 receptors are up-regulated in sensory neurons following tissue or nerve in- jury, and that B1 antagonists reduce hyperalgesia. Other authors also found an

up-regulation  of B2 receptors during inflammation  (Banik et al. 2001; Segond von Banchet et al. 2000).

Peripheral and Central Mechanisms of Pain Generation

Table 1 Receptors in subgroups of sensory neurons

Ionotropic receptors for

ATP, H+  (acid-sensitive ion channels, ASICs), glutamate (AMPA, kainate, NMDA

receptors), acetylcholine (nicotinic receptors), serotonin (5-HT3)

Metabotropic receptors for

Acetylcholine, adrenaline, serotonin, dopamine, glutamate, GABA, ATP

Prostanoids (prostaglandin E2 and I2 ), bradykinin, histamine, adenosine, endothelin Neuropeptides (e.g. substance P, calcitonin gene-related peptide, somatostatin,  opioids) Proteases (protease-activated receptors, PAR1 and PAR2)

Neurotrophins [tyrosine kinase (Trk) receptors] Glial cell line-derived neurotrophic factor (GDNF)

Inflammatory cytokines (non-tyrosine  kinase receptors)

While prostaglandins  and bradykinin  are “classical” inflammatory  medi- ators, the list of important  mediators  will be extended  by cytokines. Some cytokines such as interleukin (IL)-1β are pro-nociceptive upon application to the tissue (Obreja et al. 2003). It is likely that cytokines play an important role

in both inflammatory  and neuropathic  pain (Marchand  et al. 2005; Sommer and Schröder 1995).

Neurotrophins are survival factors during the development of the nervous system, but during inflammation of the tissue, the level of nerve growth factor

(NGF) is substantially enhanced. By acting on the tyrosine kinase A (trk A) receptors, NGF increases the synthesis of SP and CGRP in the primary afferents. NGF may also act on mast cells and thereby activate and sensitize sensory

endings by mast cell degranulation (cf. Schaible and Richter 2004).

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