Information is conducted along nerves in the form of ‘all or nothing’ electrical signals known as action potentials (Fig. 117A). Intracellular recordings from axons show that the inside is normally negative with respect to the outside, i.e., there is a resting membrane potential (about −70 mV). If a stimulus decreases this potential (i.e., makes it less negative), so that the membrane reaches the threshold potential, then there is further, automatic and rapid depolarization which reverses the potential across the cell membrane. This is an active event and is followed by repolarization to resting conditions. The properties of this action potential, and the membrane mechanisms which generate it, have been considered in detail in Section 1.4. Little more need be said here other than to remind ourselves that depolarization reflects a voltage-dependent increase in the membrane permeability, or conductance, to Na⁺, while repolarization is caused by the slower onset of a similar rise in K⁺ conductance.

Fig. 117 Action potentials in nerves. (A) Intracellular recording from a single axon showing the ‘all or nothing’ response to a suprathreshold stimulus. (B) Extracellular recording of the compound action potential from a nerve containing many axons. The increasing response with increasing stimulus strength reflects recruitment of axons with higher thresholds.

Compound action potentials

An anatomically identifiable peripheral nerve, such as the sciatic nerve in the pelvis and thigh, is made up of a large number of individual axons. The extracellularly recorded electrical activity in such a nerve reflects the total effect of all the individual action potentials in different axons and is called a compound action potential. When such a nerve is stimulated electrically, it can be shown that the amplitude of the compound action potential increases as the stimulus strength is increased (Fig. 117B). This observation appears to contravene the ‘all or nothing’ law for excitable cells but, in fact, it simply reflects the presence of axons with differing thresholds within the nerve. As the stimulus is increased, more and more axons reach threshold so that a greater proportion of the available fibres fire an action potential. Eventually all the axons will have been recruited in this way and further increases in the stimulus produce no further change in the compound action potential. These are referred to as supramaximal stimuli.

Action potential conduction velocity

Once initiated, action potentials are propagated, or conducted along an axon by means of local currents (Section 1.4). Positive current spreads along the axon away from the site of an action potential and this depolarizes the adjacent membrane. Once threshold potential is reached, an action potential will be actively generated, and the whole process is repeated. Although the local currents are conducted equally in both directions along the axon, the fact that the nerve membrane remains refractory to further stimulation for a few milliseconds after firing an action potential ensures that the signal is conducted along the axon in one direction only.

The speed with which a signal can be conducted along an axon, i.e., the nerve conduction velocity, is determined by two aspects of nerve structure.

Axon diameter

Conduction velocity increases as axon diameter increases, so that rapid conduction is a feature of large nerve fibres. This reflects the reduction in the electrical resistance to the spread of current along the axoplasm which accompanies any increase in the cross-sectional area available for conduction. As a result, the voltage change resulting from an action potential generates a larger local current along the axon, causing a greater length of membrane to be depolarized to threshold, and so the action potential is propagated more rapidly along the nerve.

Myelination

Conduction velocity is greatly increased in myelinated, as opposed to unmyelinated, nerves. Myelin sheaths are produced by Schwann cells in peripheral nerves and oligodendrocytes in the CNS. These glial cells wrap their plasma membranes round and round the axon to produce a sheath of tightly stacked bilipid layers (Fig. 118). This myelin is not continuous, however, and there are gaps in the sheath, known as nodes of Ranvier, spaced at regular intervals along the axon. Action potentials are only generated at these sites, where the excitable membrane of the neurone is exposed. The spread of depolarizing current along the myelinated region to the next node is very rapid and the electrical insulation provided by the lipid myelin sheath helps to promote this rapid conduction by reducing the leakage of local current across the nerve membrane, leaving more available to depolarize the axon at the nodes. This type of conduction, in which the action potential effectively jumps from one node to the next along the axon, is referred to as saltatory conduction and is considerably more rapid than continuous conduction in unmyelinated nerves. Myelinated nerves conduct with velocities in the range 10–120 m s⁻¹, depending on their size, with the large somatic nerves to skeletal muscles conducting the fastest. Small, unmyelinated nerves, by comparison, may conduct at less than 1 m s⁻¹, e.g., slow pain fibres and autonomic motor nerves.

Fig. 118 Action potential conduction (saltatory conduction) in a myelinated axon.

Synaptic transmission

When an action potential reaches an axon ending, it must then influence the adjacent nerve if the signal is to be passed on. This occurs at the synapses between the axon of one neurone and the dendrites or cell body of the next (Fig. 116), and the process is referred to as synaptic transmission. Transmission usually depends on the release of a messenger molecule called a neurotransmitter from the nerve terminal, and this chemical affects the adjacent cell, tending either to excite or to inhibit action potential generation in that neurone. This is an example of chemical transmission.

Structure and function of the synapse

The nerve along which incoming signals arrive at the synapse is called the presynaptic nerve and this characteristically terminates in an expanded structure called a terminal bouton (Fig. 119A). Electron micrographs demonstrate that these boutons enclose a large number of membrane-bound vesicles containing neurotransmitter. A narrow gap (about 20 nm) known as the synaptic cleft separates the presynaptic membrane from that of the postsynaptic neurone. The existence of this separation between adjacent nerves suggests a chemical transmission mechanism, since electrical transmission (the possible alternative mode of transmission) requires electrical continuity between the cytoplasm of adjacent cells (e.g., the gap junctions between cardiac cells; Section 3.1).

Fig. 119 Synaptic transmission. (A) Major structural features of a chemically transmitting synapse. (B) Main events in neurotransmission. See main text for full explanation of the numbered processes.

The general sequence of events in synaptic transmission may be summarized as indicated by the numbered steps in Figure 119B.

1. Arrival of an action potential at a nerve terminal depolarizes the presynaptic membrane, increasing its permeability to Ca²⁺ by opening voltage-operated Ca²⁺ channels.

2. Calcium ions diffuse down their electrochemical gradient into the nerve terminal, since the [Ca²⁺] is higher in the extracellular fluid than in the cytoplasm.

3. The resulting increase in intracellular [Ca²⁺] triggers fusion of the synaptic vesicles with the presynaptic membrane and neurotransmitter is released into the synaptic cleft by exocytosis.

4. Transmitter diffuses across to the postsynaptic membrane where it binds with postsynaptic receptors.

5. Receptor-operated ion channels are opened as a result, generating a postsynaptic ion current.

6. Depending on the transmitter and receptor involved, this may either excite or inhibit the postsynaptic neurone.

7. The signal is terminated when the transmitter is released from the receptor. The transmitter is then broken down or taken up again by the nerves.

Excitatory transmission

Excitatory neurotransmitters act on the postsynaptic membrane to produce depolarization, thus favouring the firing of an action potential. The electrical response recorded from the postsynaptic neurone consists of a brief depolarization followed by a slower decline to the resting potential (Fig. 121), and is known as an excitatory postsynaptic potential (EPSP). This differs from the action potential in two main ways.

Fig. 121 Recording of an excitatory postsynaptic potential (EPSP) from the cell body of a neurone following stimulation by an excitatory nerve.

Passive conduction over the cell

The EPSP is not conducted over the cell in an active fashion. It does depolarize the adjacent membrane but this occurs passively because of the local currents which are set up. The further one gets from a synapse, however, the smaller the effect of the EPSP becomes. This is quite different from a propagated action potential, whose size remains constant as it is actively propagated along the membrane.

Graded response

The EPSP is a graded response, not an ‘all or nothing’ response like the action potential (Fig. 122A). The larger the number of excitatory nerves which are stimulated simultaneously, the larger is the resulting EPSP. This is called spatial summation, since the effects of excitatory neurotrans-mitter release at many different synapses on the postsynaptic neurone add together to give a larger total response. Similarly, repeated stimulation in a single excitatory nerve may increase the peak of the EPSP, since further depolarization occurs before the membrane returns to resting potential. This is temporal summation (Fig. 122B). If summation leads to a large enough depolarization (i.e., reaches threshold), the postsynaptic cell will generate an action potential which then travels down its axon.

Fig. 122 EPSP summation may lead to an action potential if threshold is reached. (A) Spatial summation. (B) Temporal summation.

Inhibitory transmission

The simplest form of inhibition (postsynaptic inhibition) is analogous to excitation in that synaptic transmission produces a change in postsynaptic membrane potential. In this case, however, hyperpolarization results (Fig. 123A), and this is termed the inhibitory postsynaptic potential (IPSP). By moving the membrane further away from the threshold potential, this makes it less likely that an action potential will be generated in response to other excitatory stimuli. In other words, IPSPs and EPSPs from different synapses acting on a given neurone will summate algebraically (Fig. 123B). The signals from the many different inputs to a cell are integrated in this way and an action potential will only be generated if the postsynaptic membrane in the region of the axon reaches threshold. Overall, the action potential frequency will reflect the balance between excitatory and inhibitory influences at any time.

Fig. 123 Postsynaptic inhibitory effects. (A) Recording of an inhibitory postsynaptic potential (IPSP) following stimulation of an inhibitory nerve. (B) Recording of membrane potential showing how summation of an IPSP and an EPSP may prevent the firing of an action potential.

Presynaptic inhibition

It is possible to reduce the size of the EPSP generated by excitatory stimulation through inhibitory nerves which do not produce any IPSP in the postsynaptic neurone. This presynaptic inhibition depends on inhibitory nerves which synapse with the incoming excitatory axon, rather than the postsynaptic cell itself (Fig. 124A). Activity in this inhibitory pathway reduces the amount of excitatory neurotransmitter released when the axon is stimulated. This depends on depolarization of the axon by the presynaptic neurotransmitter, which decreases the amplitude of any action potentials within that nerve terminal since the potential rises from an elevated baseline potential. The quantity of transmitter released is dependent on the size of the action potential and so the resulting EPSP is smaller than normal (Fig. 124B). Certain inhibitory interneurones in the spinal cord are believed to exert their influence on spinal motoneurones through presynaptic inhibition of this kind.

Fig. 124 Presynaptic inhibition. (A) Structure of a presynaptic inhibitory synapse. (B) Potential recordings show that stimulating the presynaptic inhibitory nerve has no direct effect on postsynaptic membrane potential but greatly reduces the size of a subsequently induced EPSP.

Ionic mechanisms of postsynaptic potentials

Neurotransmitters produce the changes in postsynaptic potential described in the preceding sections by opening receptor-operated ion channels. In the case of spinal motoneurones it seems likely that:

EPSPs are produced in response to the excitatory transmitter glutamate which opens channels allowing both Na⁺ and K⁺ to flow through them (nonselective cation channels). Overall, this increases the permeability of the membrane to Na⁺ relative to that to K⁺ and, since E_Na (the equilibrium potential for sodium) is positive, this tends to depolarize the cell (Section 1.4).

IPSPs are generated in response to the inhibitory transmitter glycine as the result of opening of receptor-operated channels which allow Cl⁻ to flow through them. This shifts the membrane potential towards E_Cl which is slightly negative with respect to the resting potential.

7.3 General sensory mechanisms

Sensory physiology deals with the mechanisms involved in the detection and interpretation of a wide variety of different stimuli. This relies on sensory receptors to convert these stimuli into electrical signals within the sensory nerves, which relay the information to the CNS. Within the CNS the sensory inputs are used both to control the movements of the body and to regulate the internal environment (homeostasis). This requires storage of reference information about normal conditions, e.g., the set points for different controlled variables (Section 1.1), and appropriate connections between the sensory (afferent) and motor (efferent) pathways so that compensatory adjustments can be made. Conscious awareness and interpretation of sensation is also a central nervous function, with particular areas of the cerebral cortex being devoted to processing activity from specific types of receptor.

Receptor types

Sensory receptors convert the energy in a sensory stimulus into action potentials within sensory nerves. Energy converting devices are known as transducers and so they are also called sensory transducers. These provide the first link in the communication chain which keeps the central nervous system informed about conditions within the body (the internal environment) and in the outside world (the external environment). Some receptors are structurally complex while others consist of nothing more than an exposed nerve ending.

Receptors may be classified in terms of the general class of stimulus to which they respond.

• Mechanoreceptors detect mechanical distortion or movement, e.g., pressure receptors in the skin and stretch receptors in muscles.

• Photoreceptors, like the rods and cones in the eye, detect electromagnetic radiation.

• Chemoreceptors are sensitive to chemical stimuli, e.g., taste receptors in the tongue or respiratory chemoreceptors responsive to blood gases and pH.

• Thermoreceptors detect hot and cold.

Receptors may also be classified in terms of the purpose they serve. This is subtly different from a classification based on stimulus type. For example, nociceptors consist of all receptors responsible for painful sensations but this grouping contains a mixture of mechano-, thermo- and chemoreceptors (Section 7.4). Similarly, proprioceptors represent a specific subgroup of mechanoreceptors, all of which provide information about joint position.

Sensory modalities and the law of specific nerve energies

We may divide our conscious sensory experiences into a number of different sensory modalities, e.g., touch, taste, sight, hearing, etc. How the brain converts the indistinguishable action potentials conducted along different sensory nerves into these separate perceived sensations is not well understood. Receptors show a high sensitivity to only one type of stimulus, however, and activity in the sensory nerves connecting a receptor with the CNS will always be interpreted as being caused by that stimulus. For example, photoreceptors are sensitive to light and signals in the optic nerve from the retina are always interpreted in visual terms. This remains true, even if the receptors have been stimulated by a very strong stimulus of some other type, such as direct pressure over the eyeball. Equally, direct electrical stimulation of the optic nerve in the absence of any stimulus to the photoreceptors will evoke visual sensations. This demonstrates the general principle that a fixed interpretation is given to activity in a sensory nerve based on the nature of the receptor of origin, a rule referred to as the law of specific nerve energy.

Receptive fields

A receptive field may be defined as the region within which a stimulus will produce activity in a given sensory receptor. For a touch receptor, this will be determined by the area of skin overlying the branching sensory terminals; for a photoreceptor, it will depend on the target area presented by that receptor in the retina. Receptive fields can also be defined for more central neurones along the sensory pathway, and in this case the extent of each field will depend not just on effective receptor area but also on the degree of convergence of information between the periphery and the central sensory neurones. Thus, if a single neurone in the cerebral cortex receives inputs from many adjacent peripheral receptors (a highly convergent sensory pathway), its receptive field will be considerably larger than that of the individual receptors themselves. The receptive fields of the central neurones form a sensory map of the body, in which areas demonstrating a high degree of spatial resolution are represented by a large number of neurones, each with a small receptive field.

Differences of this kind can be demonstrated for touch using the two-point discrimination test. A subject is tested with two sharp points placed close to each other and asked whether they feel them as a single or separate stimuli. For example, the skin over the fingertips, which has a high receptor density and is represented centrally by a relatively extensive area of sensory cortex, can discriminate much more closely spaced stimuli than the skin of the arm or leg.

Receptor potentials

Sensory receptors convert a stimulus into an electrical response known as a receptor potential. This is often a graded depolarization that increases in amplitude as the stimulus strength increases (Fig. 125). Receptor potentials are localized to the receptor region itself and are not actively propagated along the sensory nerve. However, if the receptor potential depolarizes the nerve to threshold level, it stimulates action potentials that are then conducted along the sensory axon to the spinal cord. This relies on passive depolarization of the axon in receptors formed by adaptation of a sensory nerve ending, e.g., mechanoreceptors in the skin. In other cases, e.g., the hair cells in the inner ear, the receptor cells may be distinct from the relevant sensory axons. Here, the receptor potential controls transmitter release from the receptor itself, and this depolarizes the sensory axon, producing a graded generator potential. If this reaches threshold, propagating sensory action potentials result.

Fig. 125 Changes in receptor potentials of a slowly adapting receptor, in response to an increasing stimulus (recorded from a sensory axon adjacent to the receptor). Changes in membrane potential show a depolarizing receptor potential. If the receptor potential depolarizes the nerve to threshold level, this generates action potentials in the sensory nerve.

The mechanism underlying the receptor potential depends on the type of receptor. In the case of cutaneous sensation, the appropriate stimulus often leads to an increase in the Na⁺ permeability of the receptor membrane. The resulting inward movement of Na⁺ ions depolarizes the receptor and thus the sensory axon associated with it. When the relevant stimulus is applied at other points along the length of the sensory axon, however, it has no such effect.

Sensory adaptation

If a constant stimulus is applied continuously to a receptor, the resulting receptor potential (and, therefore, the action potential frequency in the relevant sensory nerve) tends to decline as time passes (Fig. 126). This is referred to as adaptation, since the receptor has adapted itself to the new stimulus level. Receptors like the Pacinian corpuscle, a pressure receptor in the skin, adapt very rapidly and so are more sensitive to changes in stimulus strength than to a constant stimulus. Such rapidly adapting receptors are said to be phasic. Tonic receptors, by comparison, adapt very slowly and so continue to generate sensory action potentials during sustained stimuli. Some of the proprioceptors in the musculoskeletal system behave in this way, providing continuous information about joint position.

Fig. 126 Adaptation of sensory receptors. (A) Receptor potential response to a constant stimulus in a fast-adapting (phasic) receptor. Such receptors are sensitive to changes in stimulus strength. (B) Receptor potential during a constant stimulus in a slowly adapting (tonic) receptor.

7.4 Specific sensory systems

Learning objectives

At the end of this section you should be able to:

• describe the receptors, nerve pathways and cortical areas involved in somatosensory perception, taste, smell, hearing, balance and vision

• classify pain, explain how nociceptors work and outline how pain is modified in the CNS

• identify the main structures of the ear

• explain what is meant by auditory threshold and how it varies with frequency

• describe how sound is transmitted to the cochlea and transduced by hair cells

• explain how sound frequency and loudness are coded

• describe how the vestibular apparatus detects movement and body position

• draw a labelled diagram of the eye

• outline the optical properties of the eye and how these can be reflexly adjusted

• explain the principles of phototransduction, adaptation and colour vision

• describe some simple refractive and visual field defects.

Having considered the general properties of sensory systems, we can look at some specific details of individual modalities of sensation. In each case, we shall consider the receptors involved, a simple outline of the sensory pathways by which the information is relayed to the CNS and what is known about the processing of that information within the brain itself. Some of the more common sensory abnormalities will also be considered.

The somatosensory system

This is responsible for the sensations of touch, temperature, proprioception (joint position) and pain.

Somatosensory pathways

Information is relayed from the relevant peripheral receptors via unipolar sensory neurones which have their cell bodies in the dorsal root ganglia. The information enters the spinal cord through the dorsal nerve roots and is then transferred up to the brain (Fig. 127). Some sensory pathways (touch, pressure, temperature, pain) cross to the opposite (contralateral) side of the cord before ascending in the spinothalamic tracts. Others (proprioception, touch) travel up the dorsal columns on the same (ipsilateral) side of the cord before crossing the midline in the region of the medulla oblongata. Ultimately, therefore, all the sensory information from the right side of the body is routed through the left thalamus up to the left cerebral cortex. This explains why damage to the sensory pathways in the right cerebral hemisphere leads to sensory loss on the left side of the body. All sensory pathways also send inputs to the reticular-activating system in the brainstem area. This region is involved in controlling the level of consciousness, especially patterns of wakefulness and sleep. Increased sensory input increases awareness, making sleep less likely.

Fig. 127 The somatosensory pathways. Sensory information ascends the spinal cord in the ipsilateral dorsal columns and the contralateral spinothalamic tracts. These paths converge on the contralateral thalamus and thalamic neurones then connect to the somatosensory cortex in the postcentral gyrus of the parietal lobe.

Somatosensory cortex

Although we may become aware of some cutaneous sensations (particularly pain) at the level of the thalamus, conscious awareness and localization of sensory stimuli is mainly a function of the somatosensory cortex in the postcentral gyrus of the parietal lobe (Fig. 128). Different parts of the body are represented by distinct regions within the sensory cortex. The site of origin of any stimulus is thus coded for in the brain by the anatomical position of the activated cortical neurones, an example of somatotopic representation. As a result, one can plot out a cortical map of the body, called the somatosensory homunculus. In this, the area of cortex devoted to a given region reflects touch sensitivity rather than anatomical bulk, e.g., the cortex representing the skin over the fingertips is more extensive than that representing the skin of the leg or back. This can be illustrated by drawing the body with each part scaled in proportion to the area of sensory cortex devoted to it—the so-called sensory homunculus (Fig. 129).

Fig. 128 Lateral view of the left cerebral hemisphere showing the four cerebral lobes and the areas of cortex involved in conscious awareness of sensation. Note the central sulcus which marks the boundary between the frontal and parietal lobes.

Fig. 129 Sensory homunculus for the left sensory cortex, which is responsible for sensation from the right side of the body.

Somatosensory defects

Defects may arise because of a problem in a peripheral nerve, producing fairly localized symptoms, or because of defects in the spinal cord or brain, giving more widespread deficits.

Defective conduction in the primary sensory axons may result from trauma to a peripheral nerve, impaired conduction as part of a neuropathy, or damage to the spinal nerve roots as they enter the cord. The patient will typically complain of numbness (anaesthesia) or pins and needles (paraesthesia), and testing usually reveals a defect in all modalities, i.e., temperature, pain and joint position as well as touch. When the area of sensory loss is mapped out clinically, the nerve or nerve roots involved are often clear.

Damage to the ascending tracts in the spinal cord is normally bilateral, producing sensory loss below that level in all modalities and on both sides. If only one side of the spinal cord is involved, however, then the two sides of the body may be affected differently. A right-sided lesion, for example, would cause right-sided loss of joint position sense below that level (travels up the ipsilateral side of the cord) and left-sided loss of temperature and pain sensation (travel in contralateral tracts). Such defects are rare, however.

Somatosensory damage within the brain is frequently caused by a stroke involving the internal capsule, a region carrying ascending tracts from the thalamus to the sensory cortex. This always produces sensory loss involving the opposite side of the body. There are usually associated motor defects, since sensory and motor axons lie in close proximity within the inner capsule (Section 7.5).

Pain

The clinical significance of pain and its relief justifies further consideration of this somatosensory modality. Pain is an unpleasant sensation with a protective function and is normally generated by stimuli which are capable of causing tissue damage. The subjective perception of pain has a strong emotional, or affective, component and the fear and anxiety which are often experienced along with the pain itself contribute a lot to the unpleasantness of painful events. Pain is, therefore, a complex sensation which is influenced both by the peripheral transduction and conduction of information about damaging stimuli through nociceptors and sensory nerves, and by the central pathways which process this information. These central mechanisms include control loops which modify pain perception by regulating the ease with which signals are transmitted along the pain pathways.

Types of pain

Pain may be classified in several ways, but one general division is between pain coming from the skin, muscles, bones and joints (somatic pain), and pain originating in the viscera (visceral pain). Itch may be added to the list as a related, unpleasant sensation.

Somatic pain can be subdivided into:

• superficial pain, from the skin itself

• deep pain, from the underlying muscles, joints and bones.

Visceral pain has many causes including ischaemia and inflammation, as well as excess stretch or contraction of smooth muscle in hollow organs. It is often very hard to localize the source of visceral pain within the body, since we do not appear to have a neural map of our internal organs equivalent to the somatic map in the somatosensory cortex. In fact, visceral pain may appear to be coming from a part of the body anatomically distant from the true source, a phenomenon called referred pain. Ischaemic pain from the heart (angina), for example, may be experienced both as chest pain and as pain in the left arm. This seems to occur because sensory nerves from the heart enter the spinal cord at the same level as those from the arm. Similarly, irritation of the diaphragm produces pain referred to the shoulder tip since the sensory nerves from both diaphragm and shoulder enter the spinal cord in the cervical region. These are examples of the dermatome rule, i.e., pain from visceral afferents is often referred to the somatic dermatome whose sensory nerves enter the cord at the same nerve root level. Such considerations are important when seeking to interpret a patient’s description of their pain in terms of a possible cause.

Responses to pain

Pain in general, and visceral pain in particular, is often associated with a variety of reflex autonomic responses. The nature of these is unpredictable, although sweating, nausea and vomiting are common, as is bradycardia caused by vagal slowing of the heart. This may reduce the blood pressure producing dizziness or fainting.

Fast and slow pain

Pain is also classified in terms of its speed of onset, with fast pain starting and stopping rapidly after the beginning and end of the painful stimulus itself. This type of pain is well localized and of a distinctive nature, so that the damaging stimulus can often be identified, e.g., fast pain from contact with a hot object is quite different from that caused by an incision. Fast pain is conducted by rapidly conducting, myelinated sensory axons and is only important in skin. Slow pain is much more diffuse, with an aching, burning or throbbing nature, and can persist for hours or days after the initial insult. This type of pain may originate in superficial or deep somatic structures, or from internal viscera, and is usually carried by slow conducting, unmyelinated nerves.

Itch

Itch is not strictly a form of pain but is a distinct, potentially very unpleasant sensation. Indeed, persistent and widespread itching may be just as distressing as chronic pain, e.g., in patients with severe atopic eczema. One important cause of itch is the release of histamine from mast cells, as occurs in skin allergies.

Pain receptors or nociceptors

Pain seems to be detected by specific receptors, called nociceptors, and is not simply the result of overstimulation of other types of receptor. Structurally, nociceptors are bare nerve endings and are distributed more densely within the skin than are other sensory receptors. Some are sensitive to specific damaging stimuli, e.g., mechanical or thermal nociceptors, but others respond to a range of different noxious stimuli (multimodal pain receptors). Many are chemoreceptors sensitive to substances released within damaged tissues, regardless of the cause of that damage. These chemicals include normal cell constituents, such as K⁺ and ATP, which may be released following cell destruction, as well as inflammatory mediators like 5-hydroxytryptamine and bradykinin (Section 2.5).

Nociceptors do not adapt during prolonged stimulation, as anyone who has suffered from toothache for several days can testify. Their level of sensitivity can be modified, however, by other chemicals within the tissues. Prostaglandins are particularly important in this respect since they sensitize nociceptors, reducing the level of stimulation necessary to produce action potentials in the relevant sensory axons. This explains why drugs which inhibit prostaglandin synthesis (e.g., aspirin) have pain-relieving (analgesic) effects. It must be underlined that prostaglandins themselves do not directly stimulate nociceptor activity, they simply reduce the pain threshold in the presence of other damaging stimuli.

Central pathways in pain perception

Incoming afferents from nociceptors synapse within the dorsal horn of the spinal cord. There are a number of spinal cord reflexes which may be triggered directly at this level, e.g., withdrawal from the painful stimulus (Section 7.5), but there is no conscious awareness of pain at the spinal cord level. Axons cross the midline and ascend the cord in the anterolateral spinothalamic tract (Fig. 127). This makes important collateral connections with the reticular formation in the brainstem, which activates the autonomic nervous system and increases general cortical awareness (painful stimuli increase arousal). The thalamus relays the pain signals on to the cortex. The parietal cortex is important in localizing pain while associated frontal lobe activity contributes to the accompanying distress.

Regulation of pain by endogenous opiates: pain gate

The transmission of signals from neurone to neurone in the pain pathways can be inhibited by the activity of other, pain-regulating pathways. A group of peptides known as endogenous opioids or opiates, which include the endorphins, enkephalins and dynorphins, play an important role in this activity. They are naturally produced within the body (endogenous) and bind to the same cell receptors as opiate analgesic drugs like morphine. Conditions associated with increased endogenous opiate production, including exercise and certain forms of emotional stress, are also known to have analgesic influences. One proposed mechanism for this is release of enkephalin from a descending, inhibitory pathway, which blocks the transmission of the pain signal within the spinal cord. This may rely on presynaptic inhibition in which the enkephalin reduces the release of excitatory transmitter (possibly substance P) from the incoming pain fibre. It is sometimes said that there is a pain gate in the spinal cord, controlling the onward transmission of pain signals. In this model, the descending enkephalin pathways act to close the gate, reducing pain perception. Inputs from other peripheral sensory nerves may also inhibit the transmission of pain within the CNS, although not necessarily at the spinal cord level. This may explain why rubbing the site of an injury brings some relief; the increased sensory input inhibits the central transmission of pain signals from that region.

Box 26 Clinical note: Analgesia

Analgesics are treatments which are used to reduce pain. They may act at the level of the nociceptor (e.g., salicylates and other nonsteroidal anti-inflammatory drugs which inhibit prostaglandin synthesis, preventing receptor sensitization), the pain afferent axon (e.g., the use of local anaesthetics, like lidocaine (lignocaine), or local cooling to block nerve conduction) or within the CNS (e.g., the narcotic analgesics, such as codeine and morphine, which inhibit pain transmission centrally). Narcotic analgesics may also depress CNS activity in a nonspecific fashion, producing drowsiness and respiratory depression. Dissociative analgesics have little effect on the pain pathways themselves but greatly reduce the level of associated anxiety and distress, while general anaesthetics globally inhibit higher central nervous function, producing reversible loss of consciousness, e.g., during surgery.

Taste

Taste is dependent on chemoreceptors in taste buds within the mouth. These are particularly densely distributed along the sides of the papillae which cover the upper, or dorsal, surface of the tongue. The receptor consists of 40–50 chemosensitive cells which are exposed to the chemicals in their vicinity through an opening, or pore, in the upper surface of the taste bud (Fig. 130A). Microvilli, or gustatory hairs, project into this pore. Binding of a chemical to receptors on the microvilli causes release of neurotransmitter from the cell. This activates sensory nerves which connect the taste buds to the ipsilateral cortex (postcentral gyrus) via the thalamus, as well as sending relays to the brainstem and hypothalamus, regions involved in the control of feeding.

Fig. 130 Taste receptors. (A) A taste bud. (B) Areas of elemental taste sensitivity over the dorsal (upper) surface of the tongue.

Taste is usually described in terms of one of four basic tastes, sweet, salt, sour (or acid) and bitter, and different regions of the tongue show varying sensitivities to each (Fig. 130B). These elementary tastes seem to reflect different overall patterns of taste bud stimulation rather than being caused by taste buds sensitive to only one type of chemical. Mammals are particularly sensitive to bitter tastes, which are often generated by chemicals in poisonous plants, presumably providing protection against their accidental ingestion.

Smell or olfaction

This depends on chemoreceptors in a small area of olfactory mucosa in the upper and posterior part of the nasal lining. The receptors are specialized neurones with microvilli projecting from their mucosal surface. Mucus-secreting cells support the receptor cells and molecules can only be detected once dissolved in the mucus layer. Axons emerging from the basal surface of the receptor neurones from the olfactory nerve, which passes through the bony cribriform plate and enters the olfactory bulb. This then connects directly with the olfactory cortex, which is part of the limbic system. The autonomic and behavioural controls exerted through hypothalamic and limbic mechanisms help explain the important emotional associations, and nervous and endocrine responses, which the sense of smell may evoke (Section 7.7).

Odour molecules can be detected at extremely low concentrations and produce a wide range of different perceived smells. These contribute greatly to the appreciation of food, for example, since much of what we term flavour is smell dependent; hence the loss of ‘taste’ when the nasal mucosa is inflamed during a common cold.

The auditory system

Hearing and balance both depend on specialized mechanoreceptors in the inner ear, with distinct but connected structures detecting sound (the auditory system) and the position and movement of the head (the vestibular system).

Auditory thresholds and audiometry

Sound is the perceived sensation generated in response to pressure waves travelling through the air to our ears. These sound waves may be charac-terized physically in terms of their frequency and amplitude, features which are perceived as pitch (high frequency, high pitch) and loudness, respectively. Although normal sounds are a complex mixture of frequencies and pressure amplitudes, hearing sensitivity is usually measured in terms of the threshold amplitude at which notes of a single frequency can just be detected by the subject (audio-metry). The threshold pressure is measured for the different frequencies tested and plotted as an audiogram. Absolute sound pressure (P) is usually converted to a relative logarithmic scale measured in decibels (dB).

The sensitivity of hearing varies with the frequency of sound, being maximal around 2000–3000 Hz (the upper frequency range in speech) and falling off above and below this value (Fig. 131A). Clinical audiograms do not always make this point clear, however, since the threshold pressure is often plotted in terms of hearing loss relative to the expected threshold at any given frequency, giving a normal value of zero for all frequencies (Fig. 131B).

Fig. 131 Audiometry. (A) The pressure at which a sound can just be detected (i.e., the auditory threshold) is plotted against sound frequency. (B) Clinical audiograms compare the threshold pressure with the expected value and plot this in terms of hearing loss. This audiogram indicates a bilateral decline in sensitivity in the higher frequency range and is typical of noise-induced hearing loss and hearing loss with ageing (presbycousis).

Structure of the ear

The ear is divided into the outer, middle and inner ears (Fig. 132). The first two structures conduct sound to the cochlear portion of the inner ear where it is detected by specialized receptors. The vestibular apparatus, which is important for balance control, is also located within the inner ear and will be considered in more detail below.

Fig. 132 The main auditory structures of the ear (the vestibular elements of the inner ear are not represented). The cochlea has been ‘uncoiled’ for clarity. The arrows represent sound vibrations transmitted from the oval window through the basilar membrane to the round window.

The outer ear consists of the visible ear, or pinna, and the auditory canal. Sound waves are channelled through this canal to the tympanic membrane at its inner end. This is set vibrating and these vibrations are conducted across the middle ear by movements of three bony ossicles, the malleus, incus and stapes. This rather elaborate construction allows vibration in the air to be converted into vibration in the fluid of the inner ear through the footplate of the stapes, which fits into the oval window of the cochlea. The direct transmission of sound waves between air and liquid would, in fact, be very inefficient, and the structures of the middle ear effectively act to amplify the pressure waves generated in the cochlear fluid by:

• transmitting the total force caused by vibration of the tympanic membrane to the much smaller area of the oval window, increasing the pressure generated

• providing a lever system which increases the force delivered to the foot of the stapes.

The structures of the middle ear are protected from damage caused by loud noises through reflex contraction of the tensor tympani and stapedius muscles in the middle ear. This restricts the movement of the tympanic membrane and ossicular chain. The middle ear is also connected to the nasopharynx by the eustachian tube, which is opened during swallowing and yawning. This allows the pressures inside and outside the tympanic membrane to be equalized if the external pressure changes, e.g., during ascent and descent in an aeroplane.

Cochlear structure and function

The cochlea consists of a coiled tube which forms part of the bony labyrinth. In cross-section, the cochlea is seen to be divided into three chambers by two membranes. Reissner’s membrane (or the vestibular membrane) separates the scala vestibuli from the scala media (or cochlear duct), which is, in turn, divided from the scala tympani by the basilar membrane (Fig. 133). The scala vestibuli and scala tympani are filled with perilymph (similar in composition to cerebrospinal fluid) and are in continuity with each other via an opening at the very end of the basilar membrane known as the helicotrema. The scala media contains a K⁺-rich fluid known as endolymph and forms part of the membranous labyrinth in continuity with the vestibular apparatus (see Fig. 134).

Fig. 133 The cochlea cut in cross-section to show the three main chambers and the membranes which divide them.

Fig. 134 The resonant frequency of the basilar membrane (shown in the diagram of the ‘uncoiled’ cochlea in the upper part of the figure) decreases with distance away from the oval window (at the base) towards the helicotrema (at the apex).

Vibrations in the stapes are communicated to the fluid of the scala vestibuli via the oval window. Very-low-frequency movements simply displace fluid from the scala vestibuli to the scala tympani through the helicotrema and are not detected as sound. Higher frequencies, however, set the basilar membrane in motion and this movement is detected by hair cells in the organ of Corti, which generate an auditory signal. Basilar membrane vibration is possible because movement of the membranous round window, which opens back onto the middle ear, accommodates the displacement of fluid in the scala tympani.

Organ of Corti

The auditory receptor is the organ of Corti which lies within the scala media (Fig. 133). It sits on the basilar membrane and contains a number of hair cells, each projecting a series of stereocilia (the ‘hairs’ in question) from its upper pole. The ends of these cilia are embedded in the overlying tectorial membrane so that sound-induced vibration of the basilar membrane produces shearing movements between the cilia and the body of the hair cells. It is this distortion which sets up the receptor potentials in these specialized mechanoreceptors. Hair cells synapse with the neurones of the cochlear nerve, releasing excitatory transmitter when activated. The sensory nerve fibres carry auditory information centrally to the brain.