NOCICEPTORS AND PAIN TRANSMISSION
There was a faith-healer from Deal,
Who said, 'Although pain isn’t real,'
If I sit on a pin
And it punctures my skin,
I dislike what I fancy I feel.
This poem reflects what we hear from persons such as Lawrence of Arabia, that pain is all in the mind. Now we shall discuss the mechanisms by which we feel pain, starting with pain-sensitive endings.
The prevailing theory of pain perception in the 17 th century is shown in Figure 1. Descartes had a fairly good notion of
"lines" connecting the periphery to the brain as part of this process; he just used a mechanical action instead of nerve conduction to carry the signal.

What is a nociceptor? This term is sometimes used for specialized pain endings, but a more complete definition is a primary afferent nerve with peripheral terminals that can respond differentially to noxious stimuli. Most nociceptor afferents conduct in either the A  or C velocity range (see below). These two types of pain receptors are differentiated by their conduction velocities and the types of stimuli to which they are sensitive.
A  (myelinated) nociceptors
These conduct at about 20 m/s and respond to noxious mechanical stimulation, especially pinching or pinpricks. A noxious stimulus is defined as one which produces pain; in humans

a noxious mechanical stimulus is a pinch of more than about 7 grams, applied to a small area of skin. The receptive field of A  nociceptors in humans is a small cluster of sensitive spots a few mm 2 in area; it is slightly smaller in primate hairy skin
(Georgopoulos, 1974). Some A  nociceptors also respond to heat stimuli.
Kruger et al. (1981) have published a description of a myelinated nociceptor ending in the skin of the cat. By recording from peripheral nerve fibers, they identified receptive areas which only responded to noxious squeezes or pinches delivered to the skin. They then performed biopsies on the sensitive areas and obtained electronmicrographs of the underlying structures, as shown in Figure 2. The endings were innervated by thinly myelinated axons, which could be traced up to the layer of the dermal papillae. At this point the axons (a) lost their sheaths and axons or small branches penetrated into the epidermis (K = keratinocytes). It was considered that peripheral nociceptors of this type were mainly mechanosensitive.

C-polymodal nociceptors
By far the greatest number of nociceptors in peripheral nerves are unmyelinated C-fibers, which conduct at velocities less than 2 m/s. C-fibers are the most common element in peripheral nerves, and almost all C-fibers are nociceptors (Torebjork, 1974).
The major class of nociceptors of this type is C-polymodal nociceptors, or C-PMNs. These respond to mechanical, thermal or chemical stimuli applied to the skin. They have smaller receptive fields than A  nociceptors, and are usually single spots rather than clusters. The discovery of so many C-nociceptors in

peripheral nerves made the overall gate theory of pain unnecessary. The properties of A  and C nociceptors are compared in the Table:
Nociceptor Cond.
Type
Receptive Myelin Thresh. Modality
Velocity Field
A  20 m/s Cluster- few mm 2
+ Low Mech.& heat
C <2 Spots - High Mech., heat,
Chem.
Considerable evidence has been collected about the roles of
A  and C nociceptors in pain perception. Myelinated A  axons have lower thresholds for electrical stimulation and are stimulated at lower stimulus levels than are C-fibers. When peripheral nerves are stimulated in this way in humans (Collins et al., 1960), excitation of A  fibers alone produces a tingling sensation. When the stimulus is increased to also excite C-fibers, a persistent burning sensation is produced. Local anesthetics likewise have a selective action, and block unmyelinated C-fibers before myelinated fibers. The clinical result is that pain is the first sensation to disappear with application of a local anesthetic.
Pressure block produced by inflating a cuff around a limb affects myelinated fibers before unmyelinated ones (Price et al., 1977).
Pain Sensory Pathways
Peripheral nerves
As mentioned in Chapter 3, it was not until 1967 that large groups of specific pain-carrying fibers were identified in limb nerves. This was because previous methods could not record from the most numerous population, the C-fibers. We now know that the

composition of a typical peripheral nerve is that shown in Figure
3. The principal fiber types are A  axons of motoneurons and A  sensory axons from muscle spindles, A  and C nociceptors, and sympathetic postganglionic C-fibers.
The roles of A  and C fibers in pain perception are seen in the phenomenon of first and second pain, shown in Figure 4. (An example is banging your thumb with a hammer and feeling a rapid, sharp pain followed after about a second by a prolonged dull, burning sensation.) Application of pressure, which selectively blocks myelinated fibers, eliminates the first, sharp pain (middle part of Fig. 4). Injection of small quantities of local anesthetic blocks the C fibers and eliminates the second, burning pain

(bottom part). The delays to the onset of the first and second pains also agree with the known conduction times of the two fiber groups.
Central pain pathways
Nociceptors synapse on interneurons in lamina of the dorsal horn, whose axons make up the lateral spinothalamic pathway
(Figure 5). Dorsal horn cells are often classified, based on their responses to peripheral stimuli, as (1) low-threshold mechanoreceptive, (2) wide dynamic range or multireceptive
(responding to both low-level and painful stimuli), and (3)

nociceptive specific neurons. Nociceptive axons synapse mainly in laminae I and II, and non-nociceptive axons in laminae IV and V.
The axons from dorsal horn cells cross near the level of entry of the dorsal roots and send branches to the reticular formation as well as the thalamus.

At the level of the medulla oblongata, the principal paincarrying pathways are in the trigeminal system (see Chapter 6,
Fig. 6). Nociceptive fibers in the face and head pass via the Vth nerve to the principal and spinal sensory nuclei of V, where they synapse and relay to the thalamus and reticular formation.
Experiments with PET scans by Jones et al. (1991) have shown an increase in blood flow in different parts of the human brain when painful heat stimuli are applied to the back of the hand. The blood flow is increased in the contralateral cingulate cortex
(over the hippocampus), thalamus and lenticular (or lentiform) nucleus, and not in the sensory cortex.

The cingulate cortex is known to be important in the attribution of emotional stimuli. The lenticular nucleus is part of the extrapyramidal system; activity in this area is thought to be an alerting or priming of the motor system, as for fight-or-flight responses.
The complex pain responses discussed in Chapter 3 are thus likely to be mediated through these areas of the central nervous system. Both somatic and autonomic motor systems participate in the pain response, which is organized at a more ancient, subcortical level than are other sensory discriminations.
Referred Pain
Referred, or heterotopic, pain is defined as pain felt at a normal site as a result of an injury or disease process in another region. A familiar example is coronary ischemia, which may produce

an intense pain in the pectoral muscles or sternum; this is known as angina pectoris. The mechanism involves a convergence of sensory inputs, as shown in Figure 8.
The example shown is one where irritation of the stomach or bowel produces pain in the overlying skin, but the mechanism is the same with angina pectoris. The afferents from the gut pass through sympathetic ganglia and then into the dorsal horn of the spinal cord, where they relay on some of the same interneurons as the afferents from the skin. Gut distension produces an unusual barrage of afferent impulses through the sympathetic ganglia, which sets up an irritable focus in the spinal interneurons; the activity of these interneurons becomes greater than normal. Then

afferent inputs from normal areas of skin evoke greater-than normal discharges in the spinal pathways which are interpreted as pain felt in the skin.
Referred pain is in this way a misinterpretation of strong afferent signals in spinal pathways. It may arise because of the relative unfamiliarity of the signals from the deeper organs - in the case of the heart, the ischemic pain may never have been felt before by the individual. The pain can be intense, even though the areas in which it is perceived are perfectly normal. Referred pains of this type can be an important diagnostic tool (Mumford,
1976; Bell, 1989). We shall consider referred pain in connection with the teeth in Chapter 6.
Sensitization, Allodynia and Hyperalgesia
We have been discussing relatively brief pain sensations which can be produced in the laboratory under controlled conditions. However, some types of injury produce lasting pain and altered perception of non-painful stimuli. Recent studies have shown important roles in this process for chemical intermediates such as those studied by Keele and Armstrong (1969).
From the list of pain terms in the book by Bell (1989), we find the following definitions:
Allodynia = painful sensation with usually non-painful stimuli
Hyperalgesia = heightened perception of painful stimuli
It is known that the area of skin around an injury exhibits allodynia and hyperalgesia, developing within minutes and sometimes lasting for days. Experiments since the 1970s have suggested that these phenomena are due to two types of sensitization: The first is an increased sensitivity, or increased firing with a given stimulus, of primary afferent nociceptors (Perl, 1976; Fitzgerald,

1979). This is called peripheral sensitization. The second mechanism involves an increased excitability of neurons in the
CNS, in response to an afferent pain signal; this is known as central sensitization (Woolf, 1983; Coderre and Melzack, 1985).
Peripheral sensitization
A variety of mechanisms is now known to contribute to this process. The triple response which occurs with injury to the skin includes some of the same mechanisms that occur with sensitization: (1) The red line which appears in the area of injury is due to capillary dilatation. (2) The wheal, or swelling which occurs around the area of injury is caused by loss of proteins and other blood components from the circulation, including potassium, bradykinin and prostaglandins. (3) The flare consists of secondary vasodilatation in areas slightly removed from the injury. This results from antidromic activation of branches of nociceptor fibers, causing release of the dilator polypeptide, substance P, from the nerve terminals. These events are diagrammed in Figure 9.
The release of substance P from the active nerve fibers itself activates the release of two neuroactive chemicals - histamine from mast cells and 5-hydroxytryptamine (serotonin, 5-HT) from platelets. It also causes local vasodilatation and sensitization of neighboring C-PMNs. This process is called neurogenic inflammation .

Substance P is an undecapeptide, or 11-amino-acid protein.
Its structure is similar to other identified neurokinins (Leeman,
1987):
Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH
2
Neurokinin A His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH
2
Neurokinin B Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH
2
(Neurokinins are the mammalian version of tachykinins, compounds that have a direct stimulating effect on smooth muscles.) The above neurokinins act on nerve, muscle and glandular receptors by binding to neurokinin receptors called NK
1
, NK
2
and NK
3
on the cell membranes. Substance P is much more potent than NKA or NKB at the
NK
1
receptor (Cooper et al., 1996). It has been localized in

various parts of the nervous system, but is especially rich in nociceptors projecting into the substantia gelatinosa region of the dorsal horn. Glutamate is also an excitatory transmitter released at these synapses, and is probably the fast transmitter for these pain signals. Substance P may as a slower neuromodulator, by activating G-proteins associated with the NK
1 receptor.
The connection of the above responses to tissue injury and hyperalgesia is that all of the substances released in the process excite or cause sensitization of C-polymodal nociceptors. This sensitization is likely to be one cause of the observed pain or hyperalgesia. Another likely result of the release of various chemicals is vasodilatation. Histamine is a potent vasodilator and contributes to edema. Kinins such as bradykinin have an indirect mechanism of activating cells by releasing neuropeptides from sensory nerves (Geppetti et al, 1998). Thus, the process of nociception is a complex activation of nerve endings, with release of chemical intermediates and involving other cell types in the affected region. The spread of vasodilatation and hyperalgesia around an injury is caused by activation of nociceptors with release of substance P, histamine, 5-HT and other compounds.
Nociception may not be merely a passive signal; it may play an active role in body defenses by participating in the inflammatory response.
Central Sensitization
This may be studied either by recording from second-order neurons in the dorsal horn of the spinal cord (or the trigeminal subnucleus caudalis, for facial pain inputs), or by looking at changes in the flexion reflex. Neurons in the spinal cord show an increase in the number of evoked action potentials with repeated stimulation of afferent C-fibers. This is called " wind-up " of the

evoked discharges (Mendell, 1966; Hamba et al., 1992), and is illustrated in Figure 10. Part A shows responses of a wide dynamic range neuron in the trigeminal nucleus to tooth pulp stimulation applied to an incisor on the same side. Part B shows the increased response to the 7th such stimulus, repeated once per second, and
Part C the response to the 17th stimulus. This kind of increased neural response with repeated noxious stimulation has been associated with the development of pain and hyperalgesia in the receptive field.
It has been shown that a type of glutamate receptor contributes to this phenomenon of central sensitization:
Application of NMDA (N-methyl-D-aspartic acid) receptor

antagonists abolished the windup and the hyperalgesia (Davies and
Lodge, 1987; Coderre and Melzack, 1992). The next figure shows wind-up in an interneuron of the trigeminal nucleus caudalis with repeated stimulation of the receptive field at an intensity that excites C-fibers. A repetition rate greater than 0.1 Hz caused wind-up. The phenomenon was blocked by administration of ketamine, an NMDA antagonist.
Woolf (1983) studied the changes in CNS excitability produced by an injury to the foot of a rat, by means of the flexion reflex:
He recorded from efferent axons of  -motoneurons and excited them by noxious mechanical and thermal noxious stimuli on the same

(ipsilateral) and opposite (contralateral) side. The response of the motoneurons constituted the flexion reflex. After a burning injury was made to one foot, which set up a strong afferent barrage to the spinal cord, the ipsilateral and contralateral reflexes to mechanical and thermal stimuli were augmented. The augmentation on the same side could have been due to sensitization of peripheral nociceptors, but not on the opposite side, where no injury had been made. Further, when the reflex was tested by electrical stimulation of the sensory nerve to the skin (bypassing the nociceptors), the injury also produced augmentation. Evidently some long-lasting increase in excitability of the pain response
(flexion) was produced by the injury. This was substantial evidence for central sensitization.

Here again, the subclass of glutamate receptors stimulated by NMDA has been implicated in the facilitation of flexion reflexes produced by noxious stimulation (Woolf and Thompson, 1991). As above, flexion reflexes were measured by motoneuron discharges.
The sensitizing procedure consisted of stimulating pain fibers or treatment of nociceptors with the irritant, mustard oil.
Intravascular injection of NMDA receptor antagonists after the sensitization eliminated the facilitation, returning the reflex to pre-sensitization levels.
Some later studies (Woolf et al., 1993) showed that one week after injury of peripheral nerves, large-diameter myelinated fibers of low-threshold mechanoreceptors extended their projections to terminate within the superficial dorsal horn. This is shown in the slide.

The top part shows normal dorsal horn, with non-nociceptive afferents projecting mainly into Lamina IV. (The dotted line is the division between lamina II and lamina III.) The bottom part shows that, following axotomy, normally non-nociceptive afferents have sprouted into Lamina II. This sprouting provides an opportunity for low-threshold mechanoreceptors to make direct connection with a population of nociceptive-specific interneurons. This may contribute to the phenomenon of allodynia.
Thus, sensitization resulting in hyperalgesia can take place both at the peripheral (nociceptor) level, by a complex interaction of several chemical intermediates, and in the central nervous system, by activation of NMDA receptors (see also Coderre and

Melzack, 1992). We shall see in the next chapter how descending impulses in a pain-inhibitory pathway can also modulate pain per ception at the spinal level.