INTRODUCTION

Ask any group of people to define what is meant by the word ‘pain’ and they will invariably each come up with a different set of words and terms to describe it. This reflects the general difficulty shared by scientists in trying to come up with a meaningful and accurate definition of what pain is and, perhaps more importantly, what it means in the context of the normal functioning of the human body. In addition, the relationship between the physiological events occurring in the body and the psychological state of the subject during the experience of pain is an important one.

As a starting point, therefore, it might be useful to provide a loose definition of pain as being the subjective sensations that accompany the activation of nociceptors (pain receptors) and which signal the location and strength of actual or potential tissue-damaging stimuli. As will be discussed later, this definition does not always apply in situations where pain might be experienced without apparent nociceptor activation.

Despite the difficulty in arriving at an acceptable definition of pain, most people would agree that it can be of a variable quality, ranging from mild irritation, through itching, burning and pricking sensations to more intense stabbing and throbbing sensations and finally to agonizing, intractable pain, which for some subjects can be beyond endurance. In most cases these sensations are associated with the activation of nociceptors and the sensation of pain, but the differences in the subjective responses reflect both the strength and severity of the nociceptor activation and subjects’ individual psychological and emotional responses to this information. As will be discussed later, these differences can be important in the modulation of pain in certain circumstances.

There are also circumstances, however, where subjective pain can be felt in the absence of any tissue damage or nociceptor activation. In these cases, the pain arises as a result of changes in the sensitivity of cells within the central nervous system (CNS; see later).

PERIPHERAL ASPECTS

Nociceptors are generally free nerve endings embedded throughout the tissues; there are variations in the density of these receptors in different tissues. The free nerve endings are no more than simple nerve endings without any of the associated accessory structures that can be found with other sensory nerve endings (Fig. 6.1). The free nerve endings have a relatively high threshold to activation and are sensitive to potentially tissue-damaging stimuli such as mechanical, thermal, electrical and chemical stimuli.

Figure 6.1 Types of sensory endings found in the skin. The endings giving rise to large-diameter afferents are those serving the sensations of touch, vibration, pressure and temperature. The non-myelinated afferents from the free nerve endings convey nociceptive information to the central nervous system.

These free nerve endings give rise to small-diameter afferent nerve fibres, which convey action potentials to the spinal cord and higher centres in the CNS. These afferent fibres are classed as either myelinated Aδ fibres, with conduction velocities of between 5 and 30m/s, or non-myelinated C fibres, which conduct action potentials at velocities between 0.5 and 2m/s. (Note: Aδ fibres are sometimes referred to as group III fibres and C fibres as group IV fibres.) These two types of afferent fibre are responsible for what is termed ‘fast’ and ‘slow’ pain, the properties of which are outlined in Table 6.1.

Table 6.1 Properties of ‘fast’ and ‘slow’ pain fibres

These two pain modalities underlie the concepts of transient and prolonged pain sensations. Transient pain is the first sensation to accompany a noxious stimulus and usually involves only minimal tissue damage. It is of short duration and has no real long-term consequences for the subject. The Aδ afferent nerve fibres that are responsible for these sensations are also involved in the withdrawal reflex (see below). Prolonged pain is associated with activation of the group C afferent nerve fibres and usually accompanies a greater degree of tissue damage. This damage to the tissue cells results in the release of chemical mediators — such as bradykinin, substance P, histamine, 5-hydroxytryptamine (5-HT) and prostaglandins — from the damaged cells themselves and from activated nociceptor nerve endings. These chemical mediators can activate nociceptive nerve terminals directly and can also sensitize the response of the nociceptors to normal stimuli by altering the transduction properties of the free nerve endings. As well as activating group C nociceptive endings, these chemical mediators are also responsible for initiating the inflammatory responses in the damaged tissue. Figure 6.2 summarizes how tissue damage and the release of chemical mediators can activate nociceptors and transmit this information to the CNS.

Figure 6.2 The role of chemical mediators in the activation of nociceptors and in the generation of inflammatory processes. Action potentials generated in the nociceptive afferents can travel along axonal branches to cause the release of the neurotransmitter substance P from other terminals. This, in turn, can influence mast cells, causing them to release histamine, which further activates the free nerve endings and also causing vasodilation and increased permeability of nearby blood vessels. 5-HT, 5-hydroxytryptamine.

The subjective involvement of both transient and prolonged pain can be best illustrated by referring to the pain sensations that accompany an injury such as stubbing a toe. Initially, there is a sharp pain associated with the physical contact of the toe with a hard object. This transient pain is followed by a duller, throbbing pain, which lasts for much longer. This is the prolonged pain caused by the ongoing release of chemical mediators from the damaged tissue in the toe. As part of this process, the injured area can become much more sensitive to what were previously innocuous stimuli but which now produce painful sensations. This sensitization can take place either at the free nerve endings themselves (peripheral sensitization; see above) or in the neurons of the dorsal horn of the spinal cord (central sensitization; see later). This increase in sensitivity is termed hyperalgesia and is also associated with allodynia (tenderness) attributed to the affected tissue.

CENTRAL ASPECTS

Information from the nociceptive afferent nerves is transmitted to the spinal cord, where it influences reflex activity, or is further transmitted via specific pathways to higher brain centres. Nociceptive afferents enter the spinal cord via the dorsal root and make synaptic connections with other neurons located in the dorsal horn of the spinal cord grey matter. The dorsal horn is the site of convergence of several inputs relating to nociception, including the peripheral afferents described above, spinal interneurons and also descending neurons from higher centres in the brain.

The main reflexes involving nociceptive afferents are the flexor withdrawal and crossed extensor reflexes. These are polysynaptic reflexes and involve several muscle groups as well as operating over several spinal segmental levels. Nociceptive inputs make excitatory polysynaptic connections with motoneurons supplying flexor muscle groups and inhibitory polysynaptic connections with extensor motoneurons on the ipsilateral side. When these pathways are activated, they produce flexion in the limb where the original noxious stimulus arose while simultaneously switching off activity in the extensor muscles of this limb. These actions serve to move the limb away from the initial stimulus and, therefore, act in a protective fashion by removing the area from potential damage. At the same time, different polysynaptic connections from the same nociceptive afferents excite extensor motoneurons and inhibit flexor motoneurons in the contralateral limb. This action serves to stabilize the body during flexion of the ipsilateral limb. Figure 6.3 summarizes these connections.

Figure 6.3 Spinal reflex pathways for the flexor withdrawal and crossed extensor reflexes. Excitatory interneurons are shown in white, and inhibitory interneurons in black.

The nociceptive afferents entering the spinal cord grey matter terminate in the dorsal horn, where they make synaptic connections either with interneurons serving the reflexes described above or with second-order neurons (so-called transmission cells, or T cells). These cross the midline of the spinal cord to transmit information to the higher centres via the lateral spinothalamic pathways on the contralateral side of the spinal cord (Fig. 6.4). The axons travelling in these pathways are therefore always second-order neurons, which have their cell bodies in the marginal zone or substantia gelatinosa (SG) of the spinal cord grey matter. Some of these second-order axons will ascend ipsilaterally for a few spinal segments before crossing the midline, whereas others will cross immediately. When these ascending neurons reach the ventrobasal nucleus of the thalamus, they terminate on third-order neurons, which then convey the information on the noxious stimulus to the cerebral cortex.

Figure 6.4 Ascending pathways conveying nociceptive information to higher centres. Primary nociceptive afferents (I) enter the dorsal horn where they synapse with second-order neurons, which cross the midline to ascend in the anterolateral pathways (II). Some axons terminate in the reticular formation of the pons and medulla (dashed lines) whereas other axons ascend to the thalamus where they synapse with third-order neurons (III), which ascend to the somatosensory cortex.

In addition, information is also passed to higher centres via the multisynaptic spinoreticular tract. This pathway sends projections from several brainstem terminations via the intralaminar nucleus of the thalamus to areas such as the hypothalamus, the frontal lobe and the limbic system of the brain. These areas coordinate the autonomic, psychological and emotional responses to pain.

MODULATION OF PAIN TRANSMISSION

It is in the spinal cord that the possibility for the modulation of transmission of nociceptive information to higher centres exists. To understand how this operates, it is useful to look in more detail at what happens in the dorsal horn of the spinal cord grey matter.

As we have already noted, primary nociceptive afferents terminate on second-order neurons, which then transmit the nociceptive information to higher centres. The excitability of this pathway can be altered by other interneurons present in the dorsal horn. Cells of the substantia gelatinosa (SG cells) have an inhibitory influence on the transmission cells. This is achieved by presynaptic inhibition of the nociceptive afferent terminals at the point where they synapse with the transmission cells (Fig. 6.5A). However, the SG cells are inhibited when the nociceptive afferents are activated (Fig. 6.5B), reducing the presynaptic inhibition of the nociceptor afferent terminal and thereby allowing nociceptive information to be passed to higher centres.

Figure 6.5 Neural circuits in the dorsal horn that influence pain transmission to higher centres. See text for detailed explanation. SG, substantia gelatinosa; T, transmission cell.

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