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.
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.