NOCICEPTIVE-ANTINOCICEPTIVE SYSTEM. SOMATIC SENSORY SYSTEM.

 

The sense organs for mechanical stimulation (touch and pressure), warmth, cold, and pain primary afferent neurons have their cell bodies in the dorsal root ganglia or equivalent ganglia in cranial nerves. They enter the spinal cord or brain stem and make polysynaptic reflex connections to motor neurons at many levels as well as connections that relay impulses to the cerebral cortex. Each of the sensations they mediate is considered in this chapter.

PATHWAYS

The dorsal horns are divided on the basis of histologic characteristics into laminas I-VII, with I being the most superficial and VI the deepest. Lamina II and part of lamina III make up the substantia gelatinosa, a lightly stained area near the top of each dorsal horn. There are three types of primary afferent fibers that mediate cutaneous sensation: (1) large myelinated Aα and Aβ fibers that transmit impulses generated by mechanical stimuli; (2) small myelinated Aδ fibers, some of which transmit impulses from cold receptors and nociceptors that mediate fast pain (see below) and some of which transmit impulses from mechanoreceptors; and (3) small unmyelinated C fibers that are concerned primarily with pain and temperature. However, there are also a few C fibers that transmit impulses from mechanoreceptors.

Fibers mediating fine touch and proprioception ascend in the dorsal columns to the medulla, where they synapse in the gracile and cuneate nuclei. The second-order neurons from the gracile and cuneate nuclei cross the midline and ascend in the medial lemniscus to end in the ventral posterior nucleus and related specific sensory relay nuclei of the thalamus. This ascending system is frequently called the dorsal column or lemniscal system.

Other touch fibers, along with those mediating temperature and pain, synapse on neurons in the dorsal horn. The axons from these neurons cross the midline and ascend in the anterolateral quadrant of the spinal cord, where they form the anterolateral system of ascending fibers. Others ascend more dorsally. In general, touch is associated with the ventral spinothalamic tract whereas pain and temperature are associated with the lateral spinothalamic tract, but there is no rigid localization of function. Some of the fibers of the anterolateral system end in the specific relay nuclei of the thalamus; others project to the midline and intralaminar nonspecific projection nuclei. There is a major input from the anterolateral systems into the mesencephalic reticular formation. Thus, sensory input activates the reticular activating system, which in turn maintains the cortex in the alert state

Collaterals from the fibers that enter the dorsal columns pass to the dorsal horn. These collaterals may modify the input into other cutaneous sensory systems, including the pain system. The dorsal horn represents a "gate" in which impulses in the sensory nerve fibers are translated into impulses in ascending tracts, and it appears that passage through this gate is dependent on the nature and pattern of impulses reaching the substantia gelatinosa and its environs. This gate is also affected by impulses in descending tracts from the brain. The relation of the gate to pain is discussed below.

Axons of the spinothalamic tracts from sacral and lumbar segments of the body are pushed laterally by axons crossing the midline at successively higher levels. On the other hand, sacral and lumbar dorsal column fibers are pushed medially by fibers from higher segments. Consequently, both of these ascending systems are laminated, with cervical, thoracic, lumbar, and sacral segments represented from medial to lateral in the anterolateral pathways and sacral to cervical segments from medial to lateral in the dorsal columns. Because of this lamination, tumors arising outside the spinal cord first compress the spinothalamic fibers from sacral and lumbar areas, causing the early symptom of loss of pain and temperature sensation in the sacral region. Intraspinal tumors cause loss of sensation first in higher segments.

The fibers within the lemniscal and anterolateral systems are joined in the brain stem by fibers mediating sensation from the head. Pain and temperature impulses are relayed via the spinal nucleus of the trigeminal nerve, and touch and proprioception mostly via the main sensory and mesencephalic nuclei of this nerve.

Cortical Representation

Mapping of cortical areas involved in sensation has been carried out in experimental animals and during neurosurgical procedures in humans, but it has also been carried out more recently in intact humans by techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). These techniques have led to major advances not only in sensory physiology but also in all aspects of cortical function in normal humans.

From the specific sensory nuclei of the thalamus, neurons carrying sensory information project in a highly specific way to the two somatic sensory areas of the cortex: somatic sensory area I (SI) in the postcentral gyrus and somatic sensory area II (SII) in the wall of the sylvian fissure. In addition, SI projects to SII. SI corresponds to Brodmann's areas 1, 2, and 3. Brodmann was a histologist who painstakingly divided the cerebral cortex into numbered areas based on their histologic characteristics.

The arrangement of the thalamic fibers in SI is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus. Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportionate to the number of receptors in the part. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech.

Studies of the sensory receiving area emphasize the very discrete nature of the point-for-point localization of peripheral areas in the cortex and provide further evidence for the general validity of the doctrine of specific nerve energies. Stimulation of the various parts of the postcentral gyrus gives rise to sensations projected to appropriate parts of the body. The sensations produced are usually numbness, tingling, or a sense of movement, but with fine enough electrodes it has been possible to produce relatively pure sensations of touch, warmth, and cold. The cells in the postcentral gyrus are organized in vertical columns, like cells in the visual cortex. The cells in a given column are all activated by afferents from a given part of the body, and all respond to the same sensory modality.

SII is located in the superior wall of the sylvian fissure, the fissure that separates the temporal from the frontal and parietal lobes. The head is represented at the inferior end of the postcentral gyrus, and the feet at the bottom of the sylvian fissure. The representation of the body parts is not as complete or detailed as it is in the postcentral gyrus.

Cortical Plasticity

It is now clear that the extensive neuronal connections described in the previous paragraphs are not innate and immutable but can be changed relatively rapidly by experience to reflect the use of the represented area. For example, if a digit is amputated in a monkey, the cortical representation of the neighboring digits spreads into the cortical area that was formerly occupied by the representation of the amputated digit. Conversely, if the cortical area representing a digit is removed, the somatosensory map of the digit moves to the surrounding cortex. Extensive, long-term deafferentation of limbs leads to even more dramatic shifts in somatosensory representation in the cortex, with, for example, the limb cortical area responding to touching the face. The explanation of these shifts appears to be that cortical connections of sensory units to the cortex have extensive convergence and divergence, with connections that can become weak with disuse and strong with use. In rats, the basal forebrain appears to be involved; when discharge of neurons from this area to the cortex is increased at the same time an auditory stimulus is applied, the auditory sensory area ends up bigger than when the stimuli are paired at a slow basal forebrain discharge rate.

Plasticity of this type occurs not only with input from cutaneous receptors but also with input in other sensory systems. For example, in cats with small lesions of the retina, the cortical area for the blinded spot begins to respond to light striking other areas of the retina. Development of the adult pattern of retinal projections to the visual cortex is another example of this plasticity. At a more extreme level, experimentally routing visual input to the auditory cortex during development creates visual receptive fields in the auditory system.

Plastic changes of the type described above in experimental animals also occur in humans. For example, in some individuals who have had an arm amputated, touching the face causes sensations projected to the missing arm. PET scanning also documents plastic changes, sometimes from one sensory modality to another. Thus, for example, tactile and auditory stimuli increase metabolic activity in the visual cortex in blind individuals. Conversely, deaf individuals respond faster and more accurately than normal individuals to moving stimuli in the visual periphery. Plasticity also occurs in the motor cortex. These findings illustrate the malleability of the brain and its ability to adapt.

Effects of Cortical Lesions

Ablation of SI in animals causes deficits in position sense and in the ability to discriminate size and shape. Ablation of SII causes deficits in learning based on tactile discrimination. Ablation of SI causes deficits in sensory processing in SII, whereas ablation of SII has no gross effect on processing in SI. Thus, it seems clear that SI and SII process sensory information in series rather than in parallel and that SII is concerned with further elaboration of sensory data. SI also projects to the posterior parietal cortex, and lesions of this association area produce complex abnormalities of spatial orientation on the contralateral side of the body.

It is worth emphasizing that in experimental animals and humans, cortical lesions do not abolish somatic sensation. Proprioception and fine touch are most affected by cortical lesions. Temperature sensibility is less affected, and pain sensibility is only slightly affected. Thus, perception is possible in the absence of the cortex.

Principles of Sensory Physiology

Another principle that applies to cutaneous sensation is that of punctate representation. If the skin is carefully mapped, millimeter by millimeter, with a fine hair, a sensation of touch is evoked from spots overlying touch receptors. None is evoked from the intervening areas. Similarly, temperature sensations are produced by stimulation of the skin only over the spots where the sense organs for these modalities are located.

TOUCH

Pressure is maintained touch. Touch is present in areas that have no visible specialized receptors. However, pacinian corpuscles and possibly other putative receptors may subsume special functions related to touch. Touch receptors are most numerous in the skin of the fingers and lips and relatively scarce in the skin of the trunk. There are many receptors around hair follicles in addition to those in the subcutaneous tissues of hairless areas. When a hair is moved, it acts as a lever with its fulcrum at the edge of the follicle, so that slight movements of the hairs are magnified into relatively potent stimuli to the nerve endings around the follicles. The stiff vibrissae on the snouts of some animals are highly developed examples of hairs that act as levers to magnify tactile stimuli.

The Na+ channel BNC1 is closely associated with touch receptors. This channel is one of the degenerins, so called because when they are hyperexpressed they cause the neurons they are in to degenerate. However, it is not known if BNC1 is part of the receptor complex or the neural fiber at the point of initiation of the spike potential. The receptor may be opened mechanically by pressure on the skin.

The Aβ sensory fibers that transmit impulses from touch receptors to the central nervous system are 5-12 um in diameter and have conduction velocities of 30-70 m/s. Some touch impulses are also conducted via C fibers.

Touch information is transmitted in both the lemniscal and anterolateral pathways, so that only very extensive lesions completely interrupt touch sensation. However, there are differences in the type of touch information transmitted in the two systems. When the dorsal columns are destroyed, vibratory sensation and proprioception are reduced, the touch threshold is elevated, and the number of touch-sensitive areas in the skin is decreased. In addition, localization of touch sensation is impaired. An increase in touch threshold and a decrease in the number of touch spots in the skin are also observed after interrupting the spinothalamic tracts, but the touch deficit is slight and touch localization remains normal. The information carried in the lemniscal system is concerned with the detailed localization, spatial form, and temporal pattern of tactile stimuli. The information carried in the spinothalamic tracts, on the other hand, is concerned with poorly localized, gross tactile sensations.

PROPRIOCEPTION

Proprioceptive information is transmitted up the spinal cord in the dorsal columns. A good deal of the proprioceptive input goes to the cerebellum, but some passes via the medial lemnisci and thalamic radiations to the cortex. Diseases of the dorsal columns produce ataxia because of the interruption of proprioceptive input to the cerebellum.

There is some evidence that proprioceptive information passes to consciousness in the anterolateral columns of the spinal cord. Conscious awareness of the positions of the various parts of the body in space depends in part upon impulses from sense organs in and around the joints. The organs involved are slowly adapting "spray" endings, structures that resemble Golgi tendon organs, and probably pacinian corpuscles in the synovia and ligaments. Impulses from these organs, touch receptors in the skin and other tissues, and muscle spindles are synthesized in the cortex into a conscious picture of the position of the body in space. Microelectrode studies indicate that many of the neurons in the sensory cortex respond to particular movements, not just to touch or static position. In this regard, the sensory cortex is organized like the visual cortex

TEMPERATURE

Mapping experiments show that there are discrete cold-sensitive and heat-sensitive spots in the skin. There are four to ten times as many cold-sensitive as heat-sensitive spots. Cold receptors respond from 10 °C to 38 °C and heat receptors from 30 °C to over 45 °C. The afferents for cold are Aδ and C fibers, whereas the afferents for heat are C fibers. Temperature has generally been regarded as closely related to touch, but new evidence indicates that in addition to ending in the postcentral gyrus, thermal fibers from the thalamus end in the ipsilateral insular cortex. It has even been suggested that this is the true primary thermal receiving area.

Three receptors involved in temperature perception have been cloned. The receptor for moderate cold is the cold- and menthol-sensitive receptor 1 (CMR 1). Two receptors respond to high, potentially noxious heat: VR1, which also responds to the pain-producing chemical capsaicin and is clearly a nociceptor; and VRL-1, a closely related receptor that does not respond to capsaicin but is probably a nociceptor as well. All three are members of the TRP family of cation channels. The receptor that responds to moderate heat (warmth receptor) could be the ATP P2X receptor because injection of ATP causes a feeling of warmth, and mice in which the P2X receptor gene has been knocked out do not show the activity in the spinal cord normally produced by mild skin warming.

Because the sense organs are located subepithelially, it is the temperature of the subcutaneous tissues that determines the responses. Cool metal objects feel colder than wooden objects of the same temperature because the metal conducts heat away from the skin more rapidly, cooling the subcutaneous tissues to a greater degree.

PAIN

Pain differs from other sensations in that it sounds a warning that something is wrong, and it preempts other signals. It turns out to be immensely complex because when pain is prolonged and tissue is damaged, central nociceptor pathways are facilitated and reorganized. There is much still to be learned, but in a general way it is convenient to talk about physiologic or acute pain and two pathologic states, inflammatory pain and neuropathic pain.

Receptors & Pathways

The sense organs for pain are the naked nerve endings found in almost every tissue of the body. Pain impulses are transmitted to the CNS by two fiber systems. One nociceptor system is made up of small myelinated Aδ fibers 2-5 um in diameter, which conduct at rates of 12-30 m/s. The other consists of unmyelinated C fibers 0.4-1.2 um in diameter. These latter fibers are found in the lateral division of the dorsal roots and are often called dorsal root C fibers. They conduct at the low rate of 0.5-2 m/s. Both fiber groups end in the dorsal horn; Aδ fibers terminate primarily on neurons in laminas I and V, whereas the dorsal root C fibers terminate on neurons in laminas I and II. The synaptic transmitter secreted by primary afferent fibers subserving fast mild pain (see below) is glutamate, and the transmitter subserving slow severe pain is substance P.

The synaptic junctions between the peripheral nociceptor fibers and the dorsal horn cells in the spinal cord are the sites of considerable plasticity. For this reason, the dorsal horn has been called a gate, where pain impulses can be "gated," ie, modified.

Some of the axons of the dorsal horn neurons end in the spinal cord and brain stem. Others enter the anterolateral system, including the lateral spinothalamic tract. A few ascend in the posterolateral portion of the cord. Some of the ascending fibers project to the ventral posterior nuclei, which are the specific sensory relay nuclei of the thalamus, and from there to the cerebral cortex. PET and fMRI studies in normal humans indicate that pain activates cortical areas SI, SII, and the cingulate gyrus on the side opposite the stimulus. In addition, the mediofrontal cortex, the insular cortex, and the cerebellum are activated.

Pain was called by Sherrington "the physical adjunct of an imperative protective reflex." Painful stimuli generally initiate potent withdrawal and avoidance responses. Furthermore, pain is unique among the sensations in that it has a "built-in" unpleasant affect.

Fast & Slow Pain

The presence of two pain pathways, one slow and one fast, explains the physiologic observation that there are two kinds of pain. A painful stimulus causes a "bright," sharp, localized sensation followed by a dull, intense, diffuse, and unpleasant feeling. These two sensations are variously called fast and slow pain or first and second pain. The farther from the brain the stimulus is applied, the greater the temporal separation of the two components. This and other evidence make it clear that fast pain is due to activity in the Aδ pain fibers whereas slow pain is due to activity in the C pain fibers.

Receptors & Stimuli

An important recent event was the isolation of vanilloid receptor-1 (VR1). Vanillins are a group of compounds, including capsaicin, that cause pain. This necessitated revision of the concept that a single pathway carries pain and only pain to the cerebral cortex. The VR1 receptors respond not only to the pain-causing agents such as capsaicin but also to protons and to potentially harmful temperatures above 43 °C. Another receptor, VRL-1, which responds to temperatures above 50 °C but not to capsaicin, has been isolated from C fibers. There may be many types of receptors on single peripheral C fiber endings, so single fibers can respond to many different noxious stimuli. However, the different properties of the VR1 and the VRL-1 receptors make it likely that there are many different nociceptor C fibers systems as well.

Subcortical Perception & Affect

There is considerable evidence that sensory stimuli are perceived in the absence of the cerebral cortex, and this is especially true of pain. The cortical receiving areas are apparently concerned with the discriminative, exact, and meaningful interpretation of pain and some of its emotional components, but perception alone does not require the cortex.

Deep Pain

The main difference between superficial and deep sensibility is the different nature of the pain evoked by noxious stimuli. This is probably due to a relative deficiency of Aδ nerve fibers in deep structures, so there is little rapid, bright pain. In addition, deep pain and visceral pain are poorly localized, nauseating, and frequently associated with sweating and changes in blood pressure. Pain can be elicited experimentally from the periosteum and ligaments by injecting hypertonic saline into them. The pain produced in this fashion initiates reflex contraction of nearby skeletal muscles. This reflex contraction is similar to the muscle spasm associated with injuries to bones, tendons, and joints. The steadily contracting muscles become ischemic, and ischemia stimulates the pain receptors in the muscles (see below). The pain in turn initiates more spasm, setting up a vicious circle.

Muscle Pain

If a muscle contracts rhythmically in the presence of an adequate blood supply, pain does not usually result. However, if the blood supply to a muscle is occluded, contraction soon causes pain. The pain persists after the contraction until blood flow is reestablished.

These observations are difficult to interpret except in terms of the release during contraction of a chemical agent (Lewis's "P factor") that causes pain when its local concentration is high enough. When the blood supply is restored, the material is washed out or metabolized. The identity of the P factor is not settled, but it could be K+.

Clinically, the substernal pain that develops when the myocardium becomes ischemic during exertion (angina pectoris) is a classic example of the accumulation of P factor in a muscle. Angina is relieved by rest because this decreases the myocardial O2 requirement and permits the blood supply to remove the factor. Intermittent claudication, the pain produced in the leg muscles of persons with occlusive vascular disease, is another example. It characteristically comes on while the patient is walking and disappears upon resting.

Visceral Pain

In addition to being poorly localized, unpleasant, and associated with nausea and autonomic symptoms, visceral pain often radiates or is referred to other areas. The autonomic nervous system, like the somatic, has afferent components, central integrating stations, and effector pathways. The receptors for pain and the other sensory modalities present in the viscera are similar to those in skin, but there are marked differences in their distribution. There are no proprioceptors in the viscera, and few temperature and touch sense organs. Pain receptors are present, although they are more sparsely distributed than in somatic structures. Afferent fibers from visceral structures reach the CNS via sympathetic and parasympathetic pathways. Their cell bodies are located in the dorsal roots and the homologous cranial nerve ganglia. Specifically, there are visceral afferents in the facial, glossopharyngeal, and vagus nerves; in the thoracic and upper lumbar dorsal roots; and in the sacral roots. There may also be visceral afferent fibers from the eye in the trigeminal nerve. At least some substance P-containing afferents make connections via collaterals to postganglionic sympathetic neurons in collateral sympathetic ganglia such as the inferior mesenteric ganglion. These connections may play a part in reflex control of the viscera independent of the CNS.

In the CNS, visceral sensation travels along the same pathways as somatic sensation in the spinothalamic tracts and thalamic radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas.

Stimulation of Pain Fibers

As almost everyone knows from personal experience, visceral pain can be very severe. The receptors in the walls of the hollow viscera are especially sensitive to distention of these organs. Such distention can be produced experimentally in the gastrointestinal tract by inflation of a swallowed balloon attached to a tube. This produces pain that waxes and wanes (intestinal colic) as the intestine contracts and relaxes on the balloon. Similar colic is produced in intestinal obstruction by the contractions of the dilated intestine above the obstruction. When a viscus is inflamed or hyperemic, relatively minor stimuli cause severe pain. This is probably a form of primary hyperalgesia (see below). Traction on the mesentery is also claimed to be painful, but the significance of this observation in the production of visceral pain is not clear.

Muscle Spasm & Rigidity

Visceral pain, like deep somatic pain, initiates reflex contraction of nearby skeletal muscle. This reflex spasm is usually in the abdominal wall and makes the abdominal wall rigid. It is most marked when visceral inflammatory processes involve the peritoneum. However, it can occur without such involvement. The spasm protects the underlying inflamed structures from inadvertent trauma. Indeed, this reflex spasm is sometimes called "guarding."

Referred Pain

Irritation of a viscus frequently produces pain which is felt not in the viscus but in some somatic structure that may be a considerable distance away. Such pain is said to be referred to the somatic structure. Deep somatic pain may also be referred, but superficial pain is not. When visceral pain is both local and referred, it sometimes seems to spread (radiate) from the local to the distant site.

Obviously, a knowledge of referred pain and the common sites of pain referral from each of the viscera is of great importance to the physician. Perhaps the best known example is referral of cardiac pain to the inner aspect of the left arm. Other dramatic examples include pain in the tip of the shoulder caused by irritation of the central portion of the diaphragm and pain in the testicle due to distention of the ureter. Additional instances abound in the practice of medicine, surgery, and dentistry. However, sites of reference are not stereotyped, and unusual reference sites occur with considerable frequency. Heart pain, for instance, may be purely abdominal, may be referred to the right arm, and may even be referred to the neck. Referred pain can be produced experimentally by stimulation of the cut end of a splanchnic nerve.

Dermatomal Rule

When pain is referred, it is usually to a structure that developed from the same embryonic segment or dermatome as the structure in which the pain originates. This principle is called the dermatomal rule. For example, during embryonic development, the diaphragm migrates from the neck region to its adult location between the chest and the abdomen and takes its nerve supply, the phrenic nerve, with it. One-third of the fibers in the phrenic nerve are afferent, and they enter the spinal cord at the level of the second to fourth cervical segments, the same location at which afferents from the tip of the shoulder enter. Similarly, the heart and the arm have the same segmental origin, and the testicle has migrated with its nerve supply from the primitive urogenital ridge from which the kidney and ureter has developed.

The main cause of referred pain appears to be plasticity in the CNS coupled with convergence of peripheral and visceral pain fibers on the same second-order neuron that projects to the brain. Peripheral and visceral neurons do not converge in laminas I-VI of the dorsal horn but do converge in lamina VII. In addition, lamina VII neurons receive afferents from both sides of the body—a requirement if convergence is to explain referral to the side opposite that of the source of pain. The peripheral pain fibers normally do not fire the second-order neurons, but when the visceral stimulus is prolonged there is facilitation of the peripheral fibers. They now stimulate the second-order neurons, and of course the brain cannot determine whether the stimulus came from the viscera or from the area of referral.

Central Inhibition & Counterirritants

It is well known that soldiers wounded in the heat of battle may feel no pain until the battle is over (stress analgesia). Many people have learned from practical experience that touching or shaking an injured area decreases the pain of the injury. Stimulation with an electric vibrator at the site of pain also gives some relief. The relief is due primarily to inhibition of pain pathways in the dorsal horn gate by stimulation of large-diameter touch-pressure afferents. The same mechanism is probably responsible for the efficacy of counterirritants. Stimulation of the skin over an area of visceral inflammation produces some relief of the pain due to the visceral disease. The old-fashioned mustard plaster works on this principle.

Inflammatory Pain

After anything more than a minor injury, inflammatory pain sets in and persists until the injury heals. Characteristically, stimuli in the injured area that would normally cause only minor pain produce an exaggerated response (hyperalgesia) and normally innocuous stimuli such as touch cause pain (allodynia). Inflammation of any type causes the release of many different cytokines and growth factors (the "inflammatory soup") in the inflamed area. Many of these facilitate perception and transmission in cutaneous areas as well as in the dorsal horn. This is what causes the hyperalgesia and allodynia.

Neuropathic Pain

Neuropathic pain may occur when nerve fibers are injured. Commonly, it is excruciating and a difficult condition to treat. It occurs in various forms in humans. One is pain in addition to other sensations in a limb that has been amputated (phantom limb). In causalgia, there is spontaneous burning pain long after seemingly trivial injuries. The pain is often accompanied by hyperalgesia and allodynia. Reflex sympathetic dystrophy is often present as well. In this condition, the skin in the affected area is thin and shiny, and there is increased hair growth. Research in animals indicates that nerve injury leads to sprouting and eventual overgrowth of noradrenergic sympathetic nerve fibers into the dorsal root ganglia of the sensory nerves from the injured area. Sympathetic discharge then brings on pain. Thus, it appears that the periphery has been short-circuited and that the relevant altered fibers are being stimulated by norepinephrine at the dorsal root ganglion level. Alpha-adrenergic blockade produces relief of causalgia-type pain in humans, though for unknown reasons α1-adrenergic blockers are more effective than α2-adrenergic blocking agents.

Surgical procedures undertaken to relieve severe pain include cutting the nerve from the site of injury or anterolateral cordotomy, in which the spinothalamic tracts are carefully cut. However, the effects of these procedures are transient at best if the periphery has been short-circuited by sympathetic or other reorganization of the central pathways.

Pain can often be handled by administration of analgesic drugs in adequate doses, though this is not always the case. The most effective of these agents is morphine.

Action of Morphine & Enkephalins

Morphine is particularly effective when given intrathecally. The receptors that bind morphine and the "body's own morphines," the opioid peptides. There are at least three nonmutually exclusive sites at which opioids could act to produce analgesia: peripherally, at the site of an injury; in the dorsal horn "gate," where nociceptive fibers synapse on dorsal root ganglion cells; and at more rostral sites in the brain stem. Opioid receptors are produced in dorsal root ganglion cells and migrate both peripherally and centrally along their nerve fibers. In the periphery, inflammation causes the production of opioid peptides by immune cells, and these presumably act on the receptors in the afferent nerve fibers to reduce the pain that would otherwise be felt. The opioid receptors in the dorsal horn region could act presynaptically to decrease release of substance P, although presynaptic nerve endings have not been identified. Finally, injections of morphine into the periaqueductal gray of the midbrain relieve pain by activating descending pathways that produce inhibition of primary afferent transmission in the dorsal horn. There is evidence that this activation occurs via projections from the periaqueductal gray to the nearby raphe magnus nucleus and that descending serotonergic fibers from this nucleus mediate the inhibition. However, the mechanism by which serotonin inhibits transmission in the dorsal horn is unsettled.

Morphine is, of course, an addicting drug in that it causes tolerance, defined as the need for an increasing dose to cause a given analgesic or other effect; and dependence, defined as a compulsive need to keep taking the drug at almost any cost. Despite intensive study, relatively little is known about the brain mechanisms that cause tolerance and dependence. However, the two can be separated. Absence of β-arrestin-2 blocks tolerance but has no effect on dependence. β-Arrestin-2 is a member of a family of proteins that phosphorylate and thus alter heterotrimeric G proteins.

Placebos appear to be capable of producing the release of endogenous opioids, and this helps to relieve pain. Their effects are inhibited in part by morphine antagonists such as naloxone. Acupuncture at a location distant from the site of a pain also acts by releasing endorphins. Acupuncture at the site of the pain appears to act primarily in the same way as touching or shaking (see above). There appears to be a component of stress analgesia that is mediated by endogenous opioids, because in experimental animals, some forms of stress analgesia are prevented by naloxone. However, other forms are unaffected, and so other components are also involved.

Acetylcholine

Epibatidine, a cholinergic agonist first isolated from the skin of a frog, is a potent nonopioid analgesic agent, and even more potent synthetic congeners of this compound have been developed. Their effects are blocked by cholinergic blocking drugs, and as yet there is no evidence that they are addictive. Conversely, the analgesic effect of nicotine is reduced in mice lacking the α4 and β2 nicotine cholinergic receptor subunits. These observations make it clear that a nicotinic cholinergic mechanism is involved in the regulation of pain, though its exact role remains to be determined.

Cannabinoids

The cannabinoids anandamide and PEA are produced endogenously and bind to CB1 and CB2 receptors, respectively. Anandamide has now been shown to have definite analgesic effects, and there are anandamide-containing neurons in the periaqueductal gray and other areas concerned with pain. When PEA is administered, it acts peripherally to augment the analgesic effects of anandamide.

OTHER SENSATIONS

Itching (pruritus) is not much of a problem for normal individuals, but severe itching that is difficult to treat occurs in diseases such as chronic renal failure, some forms of liver disease, atopic dermatitis, and HIV infection. For many years, convincing evidence for an itch-specific neural system was not obtained, so hypotheses were advanced that itch was due to a specific pattern of discharge in other systems. There are indeed many interactions, particularly with pain, but itch-specific fibers have been demonstrated in the spinothalamic tract. This and other evidence has caused the pendulum to swing back toward the idea of an itch-specific path.

Itch & Tickle

Relatively mild stimulation, especially if produced by something that moves across the skin, produces itch and tickle. Itch spots can be identified on the skin by careful mapping; they are especially common in regions where there are many naked endings of unmyelinated fibers. Scratching relieves itching because it activates large, fast-conducting afferents that gate transmission in the dorsal horn in a manner analogous to the inhibition of pain by stimulation of similar afferents (see above). It is interesting that a tickling sensation is usually regarded as pleasurable, whereas itching is annoying and pain is unpleasant.

Itching can be produced not only by repeated local mechanical stimulation of the skin but also by a variety of chemical agents. Histamine produces intense itching, and injuries cause its liberation in the skin. However, in most instances of itching, endogenous histamine does not appear to be the responsible agent; doses of histamine that are too small to produce itching still produce redness and swelling on injection into the skin, and severe itching frequently occurs without any visible change in the skin. The kinins cause severe itching.

"Synthetic Senses"

The cutaneous senses for which separate neural pathways exist are touch, warmth, cold, pain, and probably itching. Combinations of these sensations, patterns of stimulation, and, in some cases, cortical components are synthesized into the sensations of vibratory sensation, two-point discrimination, and stereognosis.

Vibratory Sensibility

When a vibrating tuning fork is applied to the skin, a buzzing or thrill is felt. The sensation is most marked over bones, but it can be felt when the tuning fork is placed in other locations. The receptors involved are the receptors for touch, especially pacinian corpuscles, but a time factor is also necessary. A pattern of rhythmic pressure stimuli is interpreted as vibration. The impulses responsible for the vibrating sensation are carried in the dorsal columns. Degeneration of this part of the spinal cord occurs in poorly controlled diabetes, pernicious anemia, some vitamin deficiencies, and occasionally other conditions; elevation of the threshold for vibratory stimuli is an early symptom of this degeneration. Vibratory sensation and proprioception are closely related; when one is depressed, so is the other.

Two-Point Discrimination

The minimal distance by which two touch stimuli must be separated to be perceived as separate is called the two-point threshold. It depends upon touch plus the cortical component of identifying one or two stimuli. Its magnitude varies from place to place on the body and is smallest where the touch receptors are most abundant. Points on the back, for instance, must be separated by 65 mm or more before they can be distinguished as separate points, whereas on the fingers two stimuli can be resolved if they are separated by as little as 3 mm. On the hands, the magnitude of the two-point threshold is also small. However, the peripheral neural basis of discriminating two points is not completely understood, and in view of the extensive interdigitation and overlapping of the sensory units, it is probably complex.

Stereognosis

The ability to identify objects by handling them without looking at them is called stereognosis. Normal persons can readily identify objects such as keys and coins of various denominations. This ability obviously depends upon relatively intact touch and pressure sensation and is compromised when the dorsal columns are damaged. It also has a large cortical component; impaired stereognosis is an early sign of damage to the cerebral cortex and sometimes occurs in the absence of any detectable defect in touch and pressure sensation when there is a lesion in the parietal lobe posterior to the postcentral gyrus.