by Dr. Gary Farr on 24 June 2002
Theories of Pain
Theories of pain
There have always been two theories of the sensation of pain, a quantitative or intensity theory and a stimulus-specific theory. According to the former, pain results from excessive stimulation of every kind: e.g., excessive heat or cold, excessive damage to the tissues. This theory in its simplest form entails the belief that the same afferent nerve fibers are activated by all of these various stimuli; pain is felt merely when they are conducting far more impulses than usual. But knowledge acquired in the 20th century has shown that the quantitative theory—at least in its classic form—is wrong. Peripheral nerve fibers have been found to be stimulus-specific, each one excited by certain forms of energy. The stimulus-specific theory proposes that pain results from interactions between various impulses arriving at the spinal cord and brain, that these impulses are brought to the spinal cord in certain non-myelinated and small myelinated fibers, and that the specific stimuli that excite these nerve fibers are noxious, or harmful.
In the somatic tissues there are certain kinds of nerve fiber that do not give rise to pain, no matter how many there are or how frequently they are stimulated. Included in this category are mechanoreceptors that report only deformation of the skin and the larger afferent nerve fibers from muscles and tendons that form part of the organization of posture and movement. No matter how they are excited, these receptors never give rise to pain. But the smaller fibers from these tissues do cause pain when they are excited mechanically or chemically.
Warmth and cold fibers are specific. Warmth fibers are excited by rising temperature and quieted by falling temperature, and cold fibers respond similarly with cold stimuli. Although pain arises from very hot and very cold stimulation and with intense forms of mechanical stimulation, this occurs only with the activation of afferent nerve fibers that specifically report noxious events. When no noxious events are occurring, these nerve fibers are silent.
In contrast, the quantitative theory seems to apply to the viscera, where afferent nerve fibers used in reflex organization also report events giving rise to pain. In the heart, for example, the same nerve fibers are excited by mechanical stimulation as are excited by chemical substances formed in the body that cause pain. Also, in the bladder, rectum, and colon, nerve fibers activated by substances that cause pain are the same as those activated by distension and contraction of the viscera. This means that the same nerve fibers are reporting the state that underlies the desire to urinate or defecate and the sensation underlying the pain felt when these organs are strongly contracting in an attempt to evacuate their contents. In the heart, rectum, and bladder, therefore, pain appears to be due to a summation of impulses in sensory nerve fibers and is not mediated by a special group of fibers reserved for reporting noxious events. It must be pointed out, however, that not all researchers accept the argument.
Tissues
Not all the tissues making up the body give rise to pain; furthermore, each tissue must be stimulated in an appropriate way to invoke its particular sensation of pain. Skin, being the outer covering of the body, easily raises the warning of pain, but other tissues that do not come in direct contact with the outer environment are just the opposite. The brain, for example, can be pierced, cut, and burned in neurosurgery, while the patient would require only local anesthesia of the pain-sensitive scalp. The lung, liver, and spleen also do not give rise to pain, no matter how they are stimulated. Pain arises from hollow viscera when the passage of their contents is obstructed and the musculature must undergo strong contraction and stretching. Pain cannot be induced by cutting or burning the wall of the intestine, but pulling on the mesenteric tissue that fixes the intestines to the posterior wall of the abdomen causes pain. The reason for these differences is clear. Tissues are sensitive to the kinds of damage they are likely to meet during life and not to those that they probably will never meet.
Although the warning function of pain is obvious, it is not equivalent to nociception, the perception of forces likely to damage the tissues of the body. First, nociception can occur without pain and pain without nociception; also, the sensation of pain is only a part of the total act of nociception. There are reflex effects as well, such as a local reflex withdrawal from a sudden noxious stimulation of the skin. There are autonomic effects, such as a rise in blood pressure, quickening of the heart rate and respiration, and other excitatory sympathetic nervous effects. There may even be shrieking or howling, warning other animals that something dangerous and painful is occurring.
Acute and chronic pain differ in many ways. Acute pain occurs with sudden damage, such as stepping on a nail or biting the tongue. Chronic pain is the pain of pathological conditions—the pain that accompanies gout, arthritis, inflammation, or cancer. Each type of pain has effects on the nervous system.
The effect of acute inflammation of the joints on nerves reporting the state of the joint and on the central nervous system has been studied by inducing arthritis in animals. In this condition, locally formed chemical substances excite the small myelinated and nonmyelinated afferent fibers that report noxious events. Most of these nerves, sensitized by the inflammatory exudate, begin to fire impulses continuously. This flow of impulses to the dorsal-horn neurons of the spinal cord increases their excitability so that many of them also begin to fire continuously. Neurons that are normally excited only by noxious stimulation now respond to light touch as well. Meanwhile, motor neurons in related areas also fire spontaneously, and stimuli that would not normally cause withdrawal reflexes now cause a prolonged reflex response. There is no change in the motor neurons themselves; the change is in the firing threshold of peripheral neurons coming from the inflamed area and in the interneurons between the afferent nerve fibers and the motor neurons. These interneurons are ultimately connected to the brain, so that the state of increased sensitivity is passed on to related cerebral neurons. Eventually, neurons in the cerebral hemispheres continuously and spontaneously generate impulses. Other neurons of the brain start responding to movements of the affected joints that normally would not do so.
In some people with chronic painful conditions, the constant pain impulses change the character of neurons of the thalamus and cortex. For example, one patient who had had a toothache 10 days before he had an operation on the thalamus for parkinsonism suddenly got the pain of toothache again when the thalamus was stimulated electrically. Normally, no pain can be induced by stimulating that part of the thalamus.
Most of the afferent nerves making up the dorsal roots are nonmyelinated fibers. These fibers are activated by warmth within a physiological range (and by higher temperatures likely to damage the body), by chemical substances (including those made in the body), and by strong mechanical stimulation such as pricking and crushing. The smaller myelinated fibers report mechanical stimulation of the skin, noxious stimulation, and cold.
As stated above, pain is not the inevitable result of the firing of nonmyelinated fibers reporting noxious events. These fibers may fire at a slow rate without causing pain; they may even continue to fire for an hour or so without pain. Furthermore, the pain threshold does not correspond with the onset of activity in the nonmyelinated fibers, for pain can increase while the discharge of nerve impulses decreases.
The stimulus-specific organization of the peripheral nerve fibers is not continued within the spinal cord, as the various afferent nerve fibers do not transmit their impulses exclusively to neurons of only one kind of sensibility. In the dorsal horns (the spinal region that receives afferent impulses) a few neurons are purely nociceptive, but most neurons reporting noxious events receive both noxious and mechanoreceptive input. These latter are called convergent neurons. The size of the peripheral field (the area of the body from which it receives stimuli) of a dorsal-horn neuron continually varies, depending on the state of excitability of the neuron. Furthermore, events in the peripheral field affect future responses. For example, repeated input along a group of afferent nerve fibers produces a gradually decreasing response in the central nervous system. This is called habituation. Also, the region of decreased response spreads from local neurons that received the input to neighbouring neurons.
The state of excitability of a dorsal-horn neuron depends on many variables. If it is very excitable, it will respond to impulses from many afferent peripheral nerve fibers; if it is relatively inexcitable, it will be affected only by those peripheral fibers that are habitually connected to it and located near it. A neuron excited by many afferent fibers receives input from a larger area than a neuron receiving only from the fibers most nearly related to it. For this reason the area of skin or deep tissue connected to neurons of the dorsal horn varies and changes. In experiments using damaged skin, it has been found that a barrage of nerve impulses from the damaged region increases the excitability of the dorsal-horn neurons. Once this hyperexcitable state has been set up, it continues for a time without further input from peripheral nerves. In this state of local excitability, some dorsal-horn neurons receive an input from the area of damaged skin that they would not receive were the skin in a normal state.
The convergent neurons mentioned above can have their activity inhibited by tactile stimulation of a region near their peripheral fields or of a homologous region on the opposite side of the body. Also, their responsiveness to stimuli can be increased by damage to the skin in their peripheral fields.
From these convergent neurons and from other neurons of the dorsal horns, there arise tracts of long fibers that cross the midline and lead to the thalamus and other nuclei of the brain. These constitute the spinothalamic tracts. The other main pathway of pain impulses ends in the reticular formation of the medulla oblongata and pons and is known as the spinoreticular tract. It is believed that spinoreticular input to the brain serves the autonomic responses and emotional components associated with pain, whereas the spinothalamic serves conscious sensation, with its exact temporal and spatial aspects. Neurons around the central spinal canal that receive input from the bladder and colon and their overlying somatic tissues may be connected to an ascending tract that stays within the gray matter in the neighbourhood of the central canal.
High-Level Pain Pathways
Many regions of the brain can influence the input arriving at the lower levels of the nervous system. This so-called descending inhibition can be selective, with different regions of the brain inhibiting certain inputs to the spinal cord. Some regions reduce mechanoreceptive input, and others reduce noxious and warmth inputs. Descending inhibition can also reduce input from the skin while increasing that related to movement.
Prominent regions of influence are those that themselves receive noxious input. For instance, the lateral reticular nuclei of the medulla oblongata cause a constant inhibition of input brought to the spinal cord by the nonmyelinated fibers. In the rat (in which the discovery was first made), descending inhibition can be so effective that a noxious input does not enter the spinal cord. In other words, normally painful stimuli cause no reaction or concern, and there is no change in blood pressure, respiration, and other reflex activities. In these circumstances it seems that pain simply is not felt.
Electrical stimulation of the nucleus ceruleus, a small nucleus with widely ranging axons, and the nucleus raphe magnus, a nucleus in the central reticular formation of the medulla, inhibits input from noxious stimulation of the skin, and it also inhibits activities of dorsal-horn neurons receiving mechanoreceptive input. Since it was discovered that pain could be obliterated in this manner, attempts have been made to stop the chronic pain of cancer and other conditions by implanting electrodes in the brain. These can be placed in relevant parts of the brain so that constant stimulation can inhibit the input coming from the region of the pain.
This built-in system for obliterating or reducing pain can normally be brought into play by stress. Furthermore, it has always been known that one pain can mask another. A volley of nerve impulses reaching the brain via the spinothalamic and spinoreticular tracts and causing a moderate degree of pain is stopped when the cells of origin of this tract are inhibited. Experiments have shown that this suppression can be brought about by a more severe pain or by a pain in a larger area of the body, which causes descending inhibition of neurons of the spinal tract. This descending inhibition is the main mechanism of {cra_acupuncture} acupuncture analgesia.
The {brain_e} reticular formation consists of a vast number of small interconnected neurons occupying the central area of the brain stem. Parts of the reticular formation, hypothalamus, and thalamus excite the cerebral hemispheres and keep the cerebral cortex active and alert—partly in response to noxious input. In fact, it may be said that pain reaches consciousness in the thalamus. The thalamus receives noxious input from the spinal cord in two regions, a lateral part called the ventrobasal complex and a medial part consisting of several nuclei. The ventrobasal complex is concerned with the accurate temporal and spatial localization of conscious sensation, while the medial nuclei are concerned with the emotional, affective, and autonomic components of pain and other sensations. The ventrobasal nuclei relay impulses to the sensory areas of the postcentral gyrus. Noxious stimuli also cause responses in many areas of the cortex and the deeper islands of gray matter. This is to be expected, for, of all sensations, pain is the least pure sensation: it startles, it excites, and it has unpleasant qualities. All these aspects of pain are added by different parts of the brain.
Pain arising within the central nervous system when there is no damage to the body is known as central pain. The most common central pain is due to lesions in or near the thalamus and is called the thalamic syndrome. This condition is characterized by diminution in sensibility as well as severe pain when any stimulus exceeds a certain threshold.
With central pain there is both spontaneous pain and excessive pain on stimulation of all kinds. The pain may occur in the entire half of the body, affecting even visual and auditory inputs, or it may occur in a restricted region, such as the upper limb and side of the face or the lower limb.
The term referred pain is used to describe pain felt in a region where it does not originate but to which it is “referred.” It is usually used to mean pain arising in hollow viscera and felt in somatic tissues, such as the body wall. Referred pain is always referred in one direction—from deep to superficial tissues. It is pain referred from an unknown or unfamiliar part of the body to a known or familiar part.
Certain regions of the dorsal horns of the spinal cord receive both nerve fibers from the viscera and nerve fibers reporting noxious events in the skin and musculature. For example, afferent nerve fibers from the heart come to the same regions as those from the muscles and skin of the chest wall and upper limbs. From these two body tissues, visceral and somatic, there is an intermingling of inputs, and there is similar convergence in the thalamus. This anatomical arrangement is likely to form the basis of referred pain, although the mere convergence of impulses from viscera and soma onto the same neurons does not alone account for the false localization of visceral pain. It is probable that in sensory areas of the brain, the skin is served by a large number of neurons, the muscles with fewer, and the viscera with least, the visceral representation in the cortex being very small compared to that of the somatic tissues. It is supposed that, as the input to these sensory regions of the cortex usually comes from the skin and body wall, localization of the visceral input will be to these tissues and not to the viscera, the cortical region of which is small and relatively unused.
Changes in the cerebral cortex
Normally, electrical stimulation of the sensory region of the postcentral gyrus does not cause pain. But in many patients who have a painful state on the opposite side of the body, such as a painful amputation stump or damage to the median nerve of the hand, stimulation of this region reproduces the pain. Pain also arises from stimulation of the white matter deep in this area.
In these cases the character of the sensory region of the cortex changes in such a manner that neurons that normally never cause pain when stimulated now invariably produce the pain from which the patient is suffering. Also, the cortical area subserving the limb enlarges. For instance, the sensory area receiving impulses from the opposite lower limb is normally at the upper end of the postcentral gyrus. If there is a painful amputation of the limb, then the area of cortex in which electrical stimulation induces the pain spreads downward from the normal area to include the trunk area and sometimes the upper limb area.
To the biologist, the life of animals (including that of humans) consists of seeking stimulation and responding appropriately. A reflex occurs before an individual knows what struck him, what made him lift a foot or drop an object. It is biologically correct to be alarmed before one knows the reason. It is only after the immediate and automatic response that the cerebral cortex is involved and conscious perception begins.
Perception comes between simple sensation and complex cognitional behaviour. By the time people are able to talk about it, perception has become so automatic that they hardly realize that seeing what they see, hearing what they hear, is an interpretation. Each act of perception is a hypothesis based on prior experience: the world is made up of things people expect to see, hear, or smell, and any new sensory event is perceived in relation to what they already know. People perceive trees, not brown, upright masses and blotches of green against a background of blue, gray, and white. Once one has learned to understand speech, it is all but impossible to hear words as sibilants and diphthongs, sounds of lower and higher frequencies. In other words, recognizing a thing entails knowing its total shape or pattern. This is usually called by its German name, gestalt.
As well as perception of the external environment, there is perception of oneself. Information about one's position in space, for example, comes from vision, from vestibular receptors, and from somatic receptors in the skin and deep tissues. This information is collected in the vestibular nuclei and passed on to the thalamus. From there it is relayed to the central gyri and the parietal region of the cortex, where it becomes conscious perception. (For detailed discussion of the perception of movement, see the vestibular system.)
General organization of perception
Perception relies on what are called the special senses—the visual, auditory, gustatory, and olfactory. Each begins with receptors grouped together in sensory end organs, where the sensory input is organized before it is sent on to the brain. At every synapse on a sensory pathway there is an important reorganization of impulses, so that by the time an input arrives at the thalamus, it is far from being the original input that stimulated the receptors.
The afferent parts of the thalamus fall into two divisions: a medial part, which is afferent but not sensory, and a ventral and lateral part, which is sensory. Nerve impulses reaching the medial part are derived from the reticular formation. This pathway is for emotional and other rapid reactions such as surprise, alarm, vigilance, and the readiness to react. The lateral part of the thalamus is a station on the way to areas of the {brain_b} cortex that are specific for each kind of sensation.
There are three somatosensory areas of the cortex. The primary sensory area occupies the postcentral gyrus immediately behind the motor strip. The secondary area is above the Sylvian fissure, behind the secondary motor area. The supplementary area is in the upper part of the parietal lobe on the medial surface of the hemisphere, just behind the primary area.
The primary area receives its input from the ventrolateral thalamus. The secondary area receives somatosensory input from the lateral part of the thalamus and also auditory and visual input from the medial and lateral geniculate nuclei. The primary and secondary areas are reciprocally connected.
The cerebral cortex (and the thalamus as well) is divided between nonspecific and specific sensory areas. Most neurons of the specific regions have small receptive fields in the periphery, respond to only one kind of stimulus, and follow the features of stimulation exactly. Most neurons of the nonspecific regions have large receptive fields and respond to many kinds of stimuli; many do not exactly reproduce the features of the stimulus.
Although different regions of the body are normally represented by specific parts of the somatosensory regions of the cortex, the parts where afferent impulses arrive are not fixed. For example, the leg area is at the top of the postcentral gyrus, but when there is a painful state in the periphery—sciatica, for example—the leg area of the cortex can enlarge and occupy some of the arm area. Furthermore, injury to the peripheral nerves or brain may alter the sensory “map” of the cortex. These changes in the cortex and similar changes in anatomical function are referred to as plasticity.
From the somatosensory area, nerve fibers run to other regions of the cortex, traditionally called association areas. It is thought that these areas integrate sensory and motor information and that this integration allows objects to be recognized and located in space. With these regions acting upon all their inputs, the brain is carrying out those aspects of neural activity that are commonly labeled mental. It must be remembered, though, that researchers have not precisely answered the question of how and where the brain collects messages from all the sensory receptors and then sifts and arranges them so as to give a complete representation of the world and of the individual's place in the world.
Organization of the special senses
Of the special senses, the cerebral organization of the visual and auditory senses are better understood than that behind the olfactory and gustatory. For this reason, only the former two are discussed below.
Most investigations of the visual pathways in the brain have been carried out in the cat.
The area of the human brain concerned with vision comprises the entire {brain_b} occipital lobe and the posterior parts of the {brain_b} temporal and {brain_b} parietal lobes. The primary visual area, also called the striate cortex, is on the medial side of the occipital lobe and is surrounded by the secondary visual area. The visual cortex is sensitive to the position and orientation of edges, the direction and speed of movement of objects in the visual field, stereoscopic depth, brightness, and colour. These parallel functions combine to produce visual perception.
The ganglion neurons of the retina belong to three functional types, called Y-, X-, and W-cells. X-cells are neurons needed for high-resolution vision. Y-cells respond to fast movement, whereas X- and W-cells respond poorly to fast movement. Y-cells are larger than the others and have large peripheral fields; X-cells have small fields. In the retina, 50 to 55 percent of ganglion cells are W-type, 40 percent are X-type, and 5 to 10 percent are Y-type.
As constituent fibers of the optic nerves and optic tracts, X- and Y-cells connect to the lateral geniculate nucleus of the thalamus, while W-cells connect mainly to the superior colliculus of the midbrain. From these regions input from the X-cells goes mainly to the primary visual area, that from the Y-cells goes to the secondary visual area, and that from the W-cells goes to the area surrounding the secondary area. The collicular pathway serves movement detection and direction of gaze. The tract from the lateral geniculate nucleus is the pathway for visual acuity.
The primary area sends fibers back to the lateral geniculate nucleus, the superior colliculus, and the pupillary reflex centre for feedback control of input to the visual areas. It also sends fibers to the secondary area and to the visual area of the temporal lobe. The secondary area sends fibers to the temporal and parietal lobes. Also, fibers cross from visual areas of one cerebral hemisphere to the other in the corpus callosum. This link allows neurons of the two hemispheres with similar visual fields to make direct contact with each other.
Neurons of the striate cortex may form the first step in appreciation of orientation of objects in the visual field. It is thought, however, that excitation of cortical neurons is insufficient to account for orientation and that inhibition of other neurons in the visual cortex is also necessary. Whatever the mechanism, it has been found in experiments on cats and monkeys that individual neurons are activated by lines at different angles—for example, at 90 degrees to the horizontal or at an angle of 45 degrees.
Most neurons of the deeper layers are movement analyzers. Some are direction analyzers, activated by a line or an edge moving in one direction and silenced when it changes direction (the changed direction then activating other neurons). One neuron may be excited by a dark line on a bright background and another by a light line on a dark background. In other regions of the striate cortex there are form analyzers; for example, some are activated by rectangles and others by stars. There are also position neurons, which show a strong response to a spot located in a certain position and a weak response to stimulation of a larger area; others respond only to simultaneous binocular stimulation. The striate cortex provides a fused, binocular picture of the world. There are also colour-specific neurons sensitive to red, green, or blue. Each of these neurons is excited by one colour and inhibited by another.
In the secondary visual area many neurons respond particularly to the direction of moving objects. Neurons activated by colour are not activated by white light. In the part of this area where there are many neurons responding to colour, the periphery of the visual field is not mapped; this is because there are no cones in the periphery of the retina (cones being the colour receptors). The peripheral field is mapped in an area with neurons responding to movement—notably in the region of the superior temporal gyrus.
It seems that one function of the pathway from the superior colliculus to the temporal and parietal cortices is as a tracking system, enabling the eyes and head to follow moving objects and keep them in the visual field. The pathway from the geniculate nucleus to the primary visual area may be said to perceive what the object is and also how and in what direction it moves.
Some neurons in the {brain_b} parietal cortex become active when a visual stimulus comes in from the edge of the visual field toward the centre, while others are excited by particular movements of the eyes. Other neurons react with remarkable specificity—for example, only when the visual stimulus approaches from the same direction as a stimulus moving on the skin of the animal, or during the act of reaching for an object and tracking it with the hand. These parietal neurons greatly depend on the state of vigilance. In monkeys that are apparently merely waiting for something to happen or that have nothing to which to turn their attention, the neurons are inactive or minimally active. But when the animal is looking at a visual target whose change it has to detect in order to obtain a reward, the parietal neurons become active.
A great number of neurons of the middle temporal area are sensitive to the direction of movement of a visual stimulus and to the size of an object. In the inferior temporal area are neurons concerned with shape and colour. The neurons of the superior temporal polysensory area respond best to moving stimuli—in particular to movements away from the centre of the visual field. Both these areas are concerned with the conjunction of visual stimuli and movement.
Much of the knowledge of the neurological organization of hearing has been acquired from studies on the bat, an animal that relies on acoustic information for its livelihood.
In the {ears} cochlea (the specialized auditory end organ of the inner ear) the frequency of a pure tone is reported by the location of the reacting neurons in the basilar membrane, and the loudness of the sound is reported by the rate of discharge of nerve impulses. From the cochlea the auditory input is sent to many auditory nuclei. From there, it is sent on to the medial geniculate nucleus and the inferior colliculus, as with the relay stations of the retina. The auditory input finally goes to the primary and secondary auditory areas of the temporal lobes.
The auditory cortex provides the temporal and spatial frames of reference for the auditory data that it receives. In other words, it is sensitive to aspects of sound more complex than frequency. For instance, there are neurons that react only when a sound starts or stops. Other neurons are sensitive only to particular durations of sound. When a sound is repeated many times, some neurons respond, while others stop responding. There are neurons that are sensitive to differences of the intensity and timing of sounds reaching the two ears. Certain neurons that never respond to a note of constant frequency respond when the frequency falls or rises. There are others that respond to the rate of change of frequency, providing information on whether distance from the source of a sound is increasing or decreasing. Some neurons respond to the ipsilateral ear, others to the contralateral, and yet others to both ears.
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