• small-diameter thinly myelinated fibres (Aδ) with a conduction velocity of 5–30 m/s – activation of these fibres is associated with well-localized sensations of sharp, pricking pain.

• small-diameter, unmyelinated C fibres that conduct slowly (0.5–2 m/s) – these fibres carry diffuse pain sensations that can be dull, poorly localized and persistent (Torebjörk & Ochoa 1980). A class of C fibres, called C-tactile afferents, are present only in hairy skin, and mediate pleasant touch (Löken et al 2009).

Nociceptors

Nociceptors are complex structures that have heterogeneous properties, responding to multiple stimulus modalities (polymodal). Investigation of responses of specific nociceptors is fraught with difficulty, as a lack of response may indicate a failure to apply a sufficient intensity of stimulation. Moreover, application of the stimulus may induce long-term changes in the response properties of the nociceptor (Meyer et al 2006).

Aδ nociceptors, although polymodal, can be divided into two main classes on the basis of response to mechanical stimuli, leading to a distinction between mechanically sensitive afferents (MSA) and mechanically insensitive afferents (MIA).

Type I Aδ nociceptors were initially called high-threshold mechanoreceptors (HTM; Burgess & Perl 1967) because they respond with a slowly adapting discharge to strong punctate pressure and were thought to be unresponsive to heat. However, they have been shown to have very high heat thresholds, usually 53°C or higher (Treede et al 1991). With maintained heat stimuli, HTM receptors will respond and become sensitized with tissue injury (Basbaum et al 2009). Meyer et al (1994) have suggested that the Aδ Type I receptors be termed A-fibre mechano-heat sensitive receptors (AMHs), as they are responsive to both mechanical and heat stimuli. Heat sensitivity in AMHs is mediated by the vanilloid receptor-like protein 1 (TRPV2) receptors (Caterina et al 1999). These units are densely distributed in hairy and glabrous skin (Campbell et al 1979). Their receptive fields are distinctive, consisting of a series of sensitive points that may be spread evenly over an area of several square centimetres in proximal areas. In distal areas, such as the glabrous skin of the hands and feet, or on the face, receptive fields are smaller and may comprise only a single point. These units have myelinated axons (Aδ) with a conducting speed of 5–25 m/s, with a few conducting more quickly in the A–β range (55 m/s). They mediate the ‘first’ response to pinprick and other intense mechanical stimuli (Basbaum et al 2009).

Type II Aδ nociceptors have a lower heat threshold than Type 1 units, but have very high mechanical thresholds, so they are termed heat-responsive MIAs. Mean conduction velocity is 15 m/s. These mediate the ‘first’ acute pain response to noxious heat. They have been reported in the knee joint (Schaible & Schmidt 1985), viscera (Häbler et al 1990) and cornea (Tanelian 1991). Some of the cutaneous MIAs may be chemospecific receptors, while others may respond to intense cold or heat stimuli (Meyer et al 1991). MIAs are not found in glabrous skin. These receptors may become sensitized to mechanical stimuli after injury.

The unmyelinated C fibres are heterogeneous. Most C fibres are polymodal, responding to both mechanical and heat stimuli, hence the term C-fibre mechano-heat sensitive receptor (CMH). Bessou and Perl (1969) have shown that these are the predominant type of C-fibre nociceptor in mammalian skin, comprising about 90% of all afferent C fibres.

The heat responsive terminals of CMHs lie at varying depths beneath the skin (between 20 and 570 μm) and so their heat threshold is dependent on the temperature at the heat responsive terminal and not on the rate of temperature increase (Tillman et al 1995). Mechanical nociceptors with C-axons have a slowly adapting response to mechanical stimuli. They lack the distinctive multipoint receptive fields of the A-fibre units; instead their fields usually consist of a small zone of uniform sensitivity (Iggo 1960; Lynn 1984).

C-tactile fibres are low-threshold mechanoreceptors found in hairy skin. They have small receptive fields (Wessberg et al 2003) and respond vigorously to slow and light stroking (Bessou et al 1971; Vallbo et al 1999). These fibres mediate pleasant touch sensation, i.e. the affective dimension of sensation.

The chemosensitivity of C-polymodal nociceptors has not been studied as much as their sensitivity to heat and pressure. They can be excited by potassium, histamine, serotonin, bradykinin, capsaicin, mustard oil, acetylcholine and dilute acids, by various means (topical application, intradermal injection, arterial injection) and all in doses that would be painful in humans (see Willis & Coggeshall 1991 for review). Chemicals act on nociceptors by altering the conductance of ion channels in the cell membrane and causing depolarization (Rang et al 1991). This may result in sensitization of the nociceptors, such that they have an increased responsiveness to stimulation. Further information on peripheral sensitization will be presented in Chapter 6.

Cold nociceptors, transmitting along C fibres, have been reported in monkeys (LaMotte & Thalhammer 1982) and in humans (Campero et al 1996). These respond strongly to prolonged cooling of the skin by ice and weakly to strong pressure, but are not responsive to heat. The threshold for cold pain is about 14°C. Because of the delay in response between the onset of the stimulus and report of pain, it has been suggested that cold pain is subserved by deeper receptors than heat pain. The sense of cooling is subserved by primary afferents called cold fibres, which are predominantly Aδ in type. However, cold fibres do not faithfully encode stimuli that induce cold pain (Meyer et al 2005). Cutaneous Aδ nociceptors have ongoing activity at room temperature. They also respond to temperatures below 0°C and encode stimulus intensity (Simone & Kajander 1997). Cold pain is thought to be mediated by nociceptors located in cutaneous veins (Klement & Arndt 1992).

Another way of classifying nociceptors is through identification of neuroanatomical and molecular characteristics (Snider & McMahon 1998). A peptidergic population releases neuropeptides such as substance P and calcitonin gene-related peptide (CGRP), as well as the TrkA neurotrophin receptor. A non-peptidergic population expresses the Ret tyrosine kinase receptor and is sensitive to glial-derived neurotrophic factor (GDNF). These two populations of nociceptors have different central projection patterns. The peptidergic population terminates in lamina I and the outer part of lamina II of the dorsal horn, while the non-peptidergic group terminates in the inner part of lamina II. The functional difference between the two populations is not yet clear (Snider & McMahon 1998).

Skeletal muscle nociceptors

The terminology of Lloyd (1943) is usually used in relation to muscle and joint nerves (Table 5.1). Group III afferent fibres are small-diameter myelinated fibres; group IV fibres are unmyelinated and constitute the majority of muscle nociceptors. Numerous unencapsulated endings can be located in the connective tissue and in the wall of arterioles in skeletal muscle, and can be subdivided into mechanical and polymodal types (Stacey 1969). Effective stimuli are high-intensity mechanical forces, as well as endogenous pain-producing substances such as bradykinin, serotonin and potassium ions. Hypoxia and impaired metabolism following trauma or unaccustomed exercise and increased levels of adrenaline may also activate nociceptors (Kieschke et al 1988; Mense 1993). Group III afferent fibres are responsive to mechanical stimulation of muscle, including stretch (Mense & Stahnke 1983), and many would be activated by exercise and therefore probably function as ergoreceptors. However, a significant proportion of these are nociceptive. Some group III afferents are responsive to the injection of chemicals such as hypertonic sodium chloride (Abrahams et al 1984). Approximately 40% of group IV afferents are classified as low-threshold mechanosensitive (LTM) units and respond to gentle muscle stretch or contraction (Hoheisel et al 2005). These non-nociceptive units control the adjustment of circulation and respiration to the demands of physical exercise (McCloskey & Mitchell 1972). The remaining proportion of group IV afferents are activated with tissue-threatening mechanical stimulation, e.g. when muscle contractions occur during ischaemia (Mense & Meyer 1985), and are called HTM units (Mense 2009). Many are readily activated by pain producing chemicals (Mense & Meyer 1988) or thermal stimuli (Hertel et al 1976).

One of the most relevant chemical causes of muscle pain is a drop in tissue pH (an increase in proton concentration), possibly related to tonic contractions leading to ischaemia or accumulation of lactic acid (Mense 2009). The mechanism is related to the large number of acid-sensing ion channels (ASICs) in the membrane of muscle nociceptors (Hoheisel et al 2004; Sluka et al 2003). Another cause is a release of adenosine triphosphate (ATP) resulting from damage to muscle cells or an increase in permeability of the muscle cell membrane (Burnstock 2007). Other chemical factors are bradykinin, formed in damaged tissue, and serotonin, prostaglandins and nerve growth factor, which have a sensitizing action of group IV afferents (see Mense 2009 for review).

Joint nociceptors

Nociceptors in joints are located in the joint capsule and ligaments, bone, periosteum, articular fat pads and around blood vessels, but not in the joint cartilage. They have been studied predominantly in the knee joint. The terminals of group III and group IV sensory nerve endings comprise multiple axonal beads ensheathed by Schwann cell processes except for some areas of exposed axon membrane containing structural specializations characteristic of receptive sites. The beads thus represent multiple receptive sites (Heppelmann et al 1990). Some of these receptors may be nociceptive.

Joint nociceptors can be classified as:

In the normal joint, only the first type are activated, but all joint afferents become sensitized if the joint becomes inflamed (see Chapter 6).

Visceral nociceptors

In somatic tissue such as skin and muscle there is a clear distinction between mechanorecptive and nociceptive afferents. However, this is not the case in visceral tissue, for which pain may not be reported even in response to tissue-damaging stimuli. Nociceptors are located in visceral organs, including the heart, gastrointestinal tract and reproductive organs, and in the walls of blood vessels. Pain-producing stimuli in the viscera include inflammation, distension of hollow muscular-walled organs such as the gastrointestinal tract, the urinary tract and the gall bladder, ischaemia in organs such as the heart, and traction in the mesentery. Inflammation of visceral organs can induce central sensitization (see Chapter 6) of dorsal horn neurons and may lead to referred hyperalgesia.

Visceral nociceptors are also sensitive to irritating chemicals. Afferent nociceptive fibres in viscera are found in association with both sympathetic and parasympathetic efferents (Meyer et al 1994).

Terminations of afferent fibres in the dorsal horn

The incoming afferent fibres of all types establish a web of connections with dorsal horn neurons, exerting a changing pattern of excitatory and inhibitory inputs that determines the firing of dorsal horn projection neurons and of interneurons that mediate spinal reflex responses (Table 5.2). Normally there is a certain degree of segregation in the termination pattern for different afferent fibre classifications in the dorsal horn, but this may not be the case in pathological situations. Woolf et al (1992) showed that peripheral nerve injury triggers sprouting of myelinated afferents into lamina II, resulting in the possibility of functional contacts of low-threshold mechanoreceptive afferents with cells that normally have only C-fibre input.

Somatotopic organization of dorsal horn

The dorsal horn in the cervical and lumbar enlargements appears to be somatotopically organized with distal regions being represented medially and proximal areas laterally. There is a rostrocaudal representation of the digits, with the first digit being represented most rostrally and the fifth digit most caudally (Brown et al 1989; Florence et al 1988; Wilson et al 1986).

Response properties of dorsal horn neurons

Three major classes of dorsal horn neurons have been recognized (McMahon 1984):

This classification does not imply that each class of neurons is homogeneous. The properties of neurons in the dorsal horn depend to some extent on their location. A proportion of lamina I neurons is NS (Christensen & Perl 1970), but WDR cells form the largest population of neurons in this lamina. The dendrites of lamina I cells remain within the lamina and these cells give rise to an ascending projection to the thalamus (Trevino & Carstens 1975). Lamina II cells are predominantly of the WDR type, while lamina III cells are predominantly LTM.

Wall (1967) demonstrated that lamina IV cells were predominantly of the LTM type and often received input from large-diameter afferents only. Their receptive fields, located in distal regions of the body, tend to be smaller and have distinct edges. In lamina V, all three classes of cells are represented but the WDR type more frequently. Many of these cells have long ascending axons that reach supraspinal levels, some of them directly reaching the thalamus. WDR cells are excited by C fibres as well as by A fibres, and this input reaches them either via lamina II cells or by synapses on their distant dendrites. Many lamina V cells have dendrites which reach lamina II.

Ascending tracts

Somatosensory signals are conveyed along two major ascending systems in the spinal cord: the anterolateral system and the dorsal column-medial lemniscal system. The latter carries information about tactile sensation and limb proprioception. The anterolateral system relays information predominantly about pain and temperature, but also some tactile information. It comprises three pathways: the spinothalamic tract, the spinoreticular tract and the spinomesencephalic tract (Fig. 5.4).

The spinothalamic tract (STT) originates from neurons along the length of the spinal cord, with a particularly large concentration of STT cells in the uppermost cervical segments, including a large ipsilateral group of neurons in the ventral horn. Below this level, the majority of STT neurons are contralateral to their target. In the primate, STT neurons are located in three main regions: laminae I, IV–V and VII–VIII and comprise both nociceptive-specific and wide dynamic range neurons. Some STT neurons are also in laminae II, III and X (Apkarian & Hodge 1989a). The axons cross the midline in the dorsal and ventral white commissures at a level near the cell body and ascend to the thalamus in the lateral funiculus on the contralateral side. While most of the axons occupy the ventral lateral quadrant of the spinal white matter, some axons, particularly those originating from lamina I cells, ascend in the dorsal lateral quadrant (Apkarian & Hodge 1989b). The STT in the lateral funiculus has a somatotopic organization. Axons from the most caudal regions of the spinal cord occupy the most dorsolateral position, with axons from progressively more rostral levels joining the tract in more ventromedial positions (Applebaum et al 1975). In the brain stem the STT passes dorsolateral to the inferior olivary nucleus in the medulla, then ascends dorsolateral to the medial lemniscus through higher levels of the brain stem to the thalamus. The spinothalamic tract transmits nociceptive and thermal information, as well as touch sensations.

The spinoreticular tract (SRT) in the primate originates from neurons in laminae VII and VIII, as well as the lateral part of lamina V. Some neurons are in lamina X. The majority of neurons giving rise to the SRT are in the uppermost cervical segments, although cells from all levels of the spinal cord are involved (Kevetter et al 1982). There are two components: a projection to the lateral reticular nucleus (a pre-cerebellar nucleus) and a projection to the pontine and medullary reticular formation, which gives rise to descending pathways to the spinal cord. Most of the projections from the cervical and lumbar enlargements cross the midline near the level of the cell bodies, but some axons originating from cervical segments remain uncrossed. They ascend in the ventral lateral column of the spinal cord with the STT and form a prominent bundle lateral to it in the brain stem. The SRT has no obvious somatotopic organization and terminates in the following nuclei of the reticular formation: nucleus medullae oblongatae centralis, lateral reticular nucleus, nucleus reticularis gigantocellularis, nucleus reticularis pontis caudalis and oralis, nucleus paragigantocellularis dorsalis and lateralis, and nucleus subcoeruleus (Mehler et al 1960).

The spinomesencephalic tract (SMT) is a collection of pathways from the spinal cord to several different midbrain nuclei. It originates primarily from neurons in laminae I, V, VII and X (Zhang et al 1990). The majority of axons cross the midline and ascend with the STT and SRT in the ventral lateral column. The SMT projects to the nucleus cuneiformis, the parabrachial nucleus, the intercollicular nucleus, the deep layers of the superior colliculus, the nucleus of Darkschewitsch, the anterior and posterior pretectal nuclei, the red nucleus, the Edinger–Westphal nucleus, the interstitial nucleus of Cajal and the periaqueductal grey (Yezierski 1988). The SMT is roughly somatotopically organized, with the projection from the cervical enlargement terminating more rostrally than that from the lumbosacral region. The periaqueductal grey contains neurons that are part of a descending pathway that regulates pain transmission.

Other tracts in the dorsolateral funiculus and the dorsal columns also convey nociceptive information (Fig. 5.5). The spinocervical tract (SCT) originates from laminae III and IV at all levels of the cord where neurons respond predominantly to tactile stimuli, but some are activated by noxious stimuli. The axons project ipsilaterally in the dorsolateral funiculus to the lateral cervical nucleus, located just ventrolateral to the dorsal horn in segments C1–C3. The lateral cervical nucleus is quite small in the primate (Mizuno et al 1967), and may be present in some humans, although it is possible that the nucleus may not be distinctly separate from the dorsal horn in some cases (Ha & Morin 1964; Kircher & Ha 1968; Truex et al 1965). Most of the neurons in the lateral cervical nucleus cross the midline in the ventral white commissure and ascend in the medial lemniscus to midbrain nuclei and to the thalamus.

The dorsal column-medial lemniscal system consists of branches of primary afferent fibres conveying tactile and proprioceptive information, as well as the axons of neurons in laminae IV–VI. There are also unmyelinated primary afferent fibres that synapse in the dorsal column nuclei, presumably arising from nociceptors (Patterson et al 1990). In addition, there is a visceral pain pathway ascending in the dorsal column (Al-Chaer et al 1998; Hirschberg et al 1996; Willis et al 1999). The medially located fasciculus gracilis contains a representation of the lower part of the trunk and lower extremity, whereas the fasciculus cuneatus lateral to it contains a representation of the upper part of the trunk and the upper extremity. This tract projects to the dorsal column nuclei in the medulla, from which axons ascend in the medial lemniscus to the thalamus. The sensory representation in the dorsal column nuclei is somatotopic with caudal parts of the body represented medially in the nucleus gracilis and the rostral regions laterally in the nucleus cuneatus. The trunk representation is in a region between the two nuclei. The distal extremities are represented dorsally and the proximal body ventrally (Johnson et al 1968).